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Alharbi A, Albasyouni S, Al-Shaebi E, Al Quraishy S, Abdel-Gaber R. Neuroprotective and antimalarial effects of Juglans regia leaf extracts in a murine model of cerebral malaria. Front Vet Sci 2025; 12:1537686. [PMID: 40260212 PMCID: PMC12009927 DOI: 10.3389/fvets.2025.1537686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 03/24/2025] [Indexed: 04/23/2025] Open
Abstract
Background Malaria is a major public health problem caused by the apicomplexan Plasmodium parasite. Cerebral malaria (CM) is the most critical outcome of Plasmodium infection. It is becoming more difficult to manage, particularly in areas of multi-drug resistance. Scientists are focused on identifying alternative strategies to combat malaria infection. Therefore, this study was designed to evaluate the activity of Juglans regia leaf extract (JRLE) in Plasmodium berghei-infected C57BL/6 mice. Methods The J. regia leaf extract (JRLE) was prepared using methanol and characterized by Fourier-transform infrared spectroscopy (FT-IR). Female C57BL/6 mice were divided into six groups (5 mice/group): control, non-infected but JRLE-treated (500 mg/kg), P. berghei-infected non-treated, and P. berghei-infected treated with JRLE (250 or 500 mg/kg) or chloroquine (10 mg/kg). Groups (3-6) were infected intraperitoneally with P. berghei (1 × 10⁵). Treatment (oral JRLE or chloroquine) was administered for 5 days starting on day 4. Parasitemia, survival, and body weight were assessed, and brains were collected on day 9 p.i. for histopathological analysis (H&E staining) and GFAP immunohistochemistry. GABA, glutamate, neurotransmitters (epinephrine, norepinephrine, dopamine, serotonin), and mRNA expression of signaling genes (Chrnb2, Gabbr1, Gnai1, Gria2) were evaluated using ELISA and real-time PCR. Results Phytochemical screening by FT-IR demonstrated the presence of 10 functional groups in the JRLE. By day 9 after infection with the P. berghei parasite, the parasitemia was significantly reduced after JRLE treatment with a dose of 500 mg/kg (6.33% ± 1.18%) compared to the infected group (23.84% ± 2.06%) with a positive correlation with body weight. Our data showed that JRLE prolonged the survival curve of the infected mice. JRLE ameliorates the reduction of the brain index caused by P. berghei infection. Furthermore, histological analysis showed that infection with P. berghei exacerbates brain damage as evidenced by degeneration of Purkinje cells, cerebral hemorrhage, intravascular sequestrations of parasitized red blood corpuscles (pRBCs), and infiltration of lymphocytes. At the same time, treatment with JRLE mitigates the brain injury induced by the infection. JRLE reduced the level of GFAP expression in the brain tissue of the infected mice. Additionally, treatment with JRLE ameliorates the brain neurotransmitter disbalance (i.e., epinephrine, norepinephrine, dopamine, and serotonin) after Plasmodium infection. Upon JRLE treatment, Chrnb2, Gnai1, and Gabbr1 mRNA expression were down-regulated in the brain tissues derived from infected female C57BL/6 mice. Meanwhile, mRNA expression of Gria2 was up-regulated after JRLE inoculation. Our study proved that JRLE significantly ameliorated the neurotransmitter markers by increasing GABA levels and decreasing the glutamate level in the brain of P. berghei-infected mice. Conclusion Taken together, the data reported here illustrate that J. regia leaf extracts possess potent antimalarial effects and may offer a potential drug lead for developing a safe, effective, and affordable antimalarial therapy. Further studies are recommended to include the broader organ-specific effects of plant extract.
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Affiliation(s)
| | | | | | | | - Rewaida Abdel-Gaber
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
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Cummings MJ, Lutwama JJ, Owor N, Tomoiaga AS, Ross JE, Muwanga M, Nsereko C, Nayiga I, Kyebambe S, Shinyale J, Ochar T, Nie K, Xie H, Miake-Lye S, Villagomez B, Qi J, Reynolds SJ, Nakibuuka MC, Lu X, Kayiwa J, Haumba M, Nakaseegu J, Che X, Byakika-Kibwika P, Wayengera M, Achan J, Kim-Schulze S, Lipkin WI, O'Donnell MR, Bakamutumaho B. Host Response Stratification in Malarial and Non-malarial Sepsis: A Prospective, Multicenter Analysis From Uganda. Crit Care Med 2025:00003246-990000000-00459. [PMID: 39937058 DOI: 10.1097/ccm.0000000000006591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025]
Abstract
OBJECTIVES Globally, the burden of sepsis is highest in malaria endemic areas of sub-Saharan Africa. The influence of malaria on biological heterogeneity inherent to sepsis in this setting is poorly understood. We sought to determine shared and distinct features of the host response in malarial and non-malarial sepsis in sub-Saharan Africa. DESIGN AND SETTING Analysis of Olink proteomic data from prospective observational cohort studies of sepsis conducted at public hospitals in Uganda (discovery cohort [Entebbe, urban], n = 238; validation cohort [Tororo, rural], n = 253). PATIENTS Adults (age ≥ 18 yr) hospitalized with sepsis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The frequency of malaria-associated (malarial) sepsis was 20% in the discovery cohort and 28% in the validation cohort. In both cohorts, a shared host response was predominant, with less than or equal to 8% of proteins differentially expressed (Benjamini-Hochberg-adjusted p ≤ 0.05) between malarial and non-malarial sepsis, after adjustment for demographic variables and HIV and tuberculosis coinfection. In both cohorts, malarial sepsis was associated with increased expression of immunosuppressive proteins (interleukin-10, leukocyte immunoglobulin-like receptor B1, killer cell immunoglobulin-like receptor 3DL1), including those associated with Tcell exhaustion and apoptosis (lymphocyte activation gene 3, T cell immunoglobulin and mucin domain containing 4). A classifier model including these immunosuppressive proteins showed reasonable discrimination (area under the receiver operating characteristic curves, 0.73 [95% CI, 0.65-0.81] and 0.72 [0.65-0.79]) and calibration (Brier scores 0.14 and 0.18) for stratification of malarial sepsis in the discovery and validation cohorts, respectively. CONCLUSIONS Host responses are largely conserved in malarial and non-malarial sepsis but may be distinguished by a signature of relative immunosuppression in the former. Further investigations are needed to differentiate mechanisms of malarial and non-malarial sepsis, with the goal of informing pathogen-stratified and pathogen-agnostic treatment strategies.
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Affiliation(s)
- Matthew J Cummings
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY
| | - Julius J Lutwama
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Nicholas Owor
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Alin S Tomoiaga
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Accounting, Business Analytics, Computer Information Systems, and Law, Manhattan College, Bronx, NY
| | - Jesse E Ross
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Moses Muwanga
- Entebbe Regional Referral Hospital, Ministry of Health, Entebbe, Uganda
| | | | - Irene Nayiga
- Entebbe Regional Referral Hospital, Ministry of Health, Entebbe, Uganda
| | - Stephen Kyebambe
- Entebbe Regional Referral Hospital, Ministry of Health, Entebbe, Uganda
| | - Joseph Shinyale
- Entebbe Regional Referral Hospital, Ministry of Health, Entebbe, Uganda
| | - Thomas Ochar
- Tororo General Hospital, Ministry of Health, Tororo, Uganda
| | - Kai Nie
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Hui Xie
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Sam Miake-Lye
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Bryan Villagomez
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jingjing Qi
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Steven J Reynolds
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD
- Rakai Health Sciences Program, Kalisizo, Uganda
| | | | - Xuan Lu
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - John Kayiwa
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Mercy Haumba
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Joweria Nakaseegu
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
| | - Xiaoyu Che
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY
| | | | - Misaki Wayengera
- Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Jane Achan
- Global Technical Team, Malaria Consortium, London, United Kingdom
| | - Seunghee Kim-Schulze
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - W Ian Lipkin
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
| | - Max R O'Donnell
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
| | - Barnabas Bakamutumaho
- Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda
- Immunizable Diseases Unit, Uganda Virus Research Institute, Entebbe, Uganda
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Chen J, Bai Y, He X, Xiao W, Chen L, Wong YK, Wang C, Gao P, Cheng G, Xu L, Yang C, Liao F, Han G, Sun J, Xu C, Wang J. The spatiotemporal transcriptional profiling of murine brain during cerebral malaria progression and after artemisinin treatment. Nat Commun 2025; 16:1540. [PMID: 39934099 PMCID: PMC11814382 DOI: 10.1038/s41467-024-52223-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 08/28/2024] [Indexed: 02/13/2025] Open
Abstract
Cerebral malaria (CM) is a severe encephalopathy caused by Plasmodium parasite infection, resulting in thousands of annual deaths and neuro-cognitive sequelae even after anti-malarial drugs treatment. Despite efforts to dissect the mechanism, the cellular transcriptomic reprogramming within the spatial context remains elusive. Here, we constructed single-cell and spatial transcriptome atlases of experimental CM (ECM) male murine brain tissues with or without artesunate (ART) treatment. We identified activated inflammatory endothelial cells during ECM, characterized by a disrupted blood-brain barrier, increased antigen presentation, and leukocyte adhesion. We also observed that inflammatory microglia enhance antigen presentation pathway such as MHC-I to CD8+ cytotoxic T cells. The latter underwent an inflammatory state transition with up-regulated cytokine expression and cytotoxic activity. Multi-omics analysis revealed that the activated interferon-gamma response of injured neurons during ECM and persisted after ART treatment. Overall, our research provides valuable resources for understanding malaria parasite-host interaction mechanisms and adjuvant therapy development.
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Affiliation(s)
- Jiayun Chen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Yunmeng Bai
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Xueling He
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Wei Xiao
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
- Department of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Lina Chen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Yin Kwan Wong
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Chen Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Peng Gao
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, 475004, Henan, China
| | - Guangqing Cheng
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Liting Xu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Chuanbin Yang
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China
| | - Fulong Liao
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Guang Han
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, 475004, Henan, China
| | - Jichao Sun
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
| | - Chengchao Xu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
| | - Jigang Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
- Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatric, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
- Department of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, 475004, Henan, China.
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Mehta Y, Kaur D, Kaur U, Shree R, Singh P, Modi M, Lal V, Sehgal R. Efficiency of Cysticidal Therapy Impacted by the Host's Immune Response in Neurocysticercosis Patients. Mol Neurobiol 2025; 62:2203-2211. [PMID: 39090352 DOI: 10.1007/s12035-024-04377-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/17/2024] [Indexed: 08/04/2024]
Abstract
Neurocysticercosis (NCC) is a neurological condition caused by the presence of cysts of Taenia solium in the brain, which manifests with a range of clinical symptoms. The severity of NCC and its prognosis following anti-helminth drug (AHD) treatment are closely linked to peripheral and local inflammation. The study aimed to analyse the efficiency of cysticidal therapy impacted by the host's immune response in NCC patients. A total of 104 patients were screened in this study, and blood samples were collected from 30 patients. The follow-up samples within 3 to 6 months of treatment were collected. Patients were categorised as Responder (R) and Non-Responder (NR). Cytokines IL-6, IL-10, IFN-γ and TNF-α were estimated using ELISA kits in PBMC cells. T0 is the time point before the AHD treatment begins, and T1 is between 3 to 6 months after the treatment starts. The responder patients showed significantly lower IL-10 and IL-6 levels in the supernatants at T0 as compared to T1, while in non-responder patients, IL-10 and IL-6 levels were higher at T0 as compared to T1. The IFN-γ and TNF-α levels were found to be higher in the supernatants at T0 as compared to T1 in both the responder and non-responder patients. These observations imply that these cytokines might have an impact on the efficacy of AHD treatment in NCC patients.
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Affiliation(s)
- Yashvi Mehta
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Davinder Kaur
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Upninder Kaur
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Ritu Shree
- Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Paramjeet Singh
- Department of Radiodiagnosis, Neuroimaging & Interventional Neuroradiology Division, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Manish Modi
- Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Vivek Lal
- Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Rakesh Sehgal
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
- Department of Microbiology, Aarupadai Veedu Medical College & Hospital, Puducherry, 607402, India.
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Hirako IC, Ramalho T, Gazzinelli RT. Immune regulation of host energy metabolism and periodicity of malaria parasites. Philos Trans R Soc Lond B Biol Sci 2025; 380:20230511. [PMID: 39842477 PMCID: PMC11753876 DOI: 10.1098/rstb.2023.0511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 08/29/2024] [Accepted: 11/06/2024] [Indexed: 01/24/2025] Open
Abstract
The synchronization of Plasmodium parasites as they replicate within red blood cells of their vertebrate host remains largely unexplored. Understanding this synchronization could reveal how parasites optimize their lifecycle to maximize transmission, evade the immune response and maximize energy acquisition. Rhythmic replication fulfils some criteria of an endogenous oscillator with time of day cues potentially provided by temperature, oxygen levels, hormones and/or nutrient availability. Recent research on a rodent malaria model has highlighted that rhythms associated with the host's feeding/fasting cycle are a crucial factor influencing the synchronization of the erythrocytic stages of Plasmodium to the host's circadian cycle. Innate immune responses are also rhythmic and can regulate host metabolism, suggesting that the innate immune response triggered by Plasmodium contributes to its rhythmic replication. Here, we outline how the interplay between immune responses and metabolism could influence the timing and synchronization of Plasmodium's replication rhythm, focusing on the roles of the cytokine tumour necrosis factor, mitochondrial function and metabolites generated by the tricarboxylic acid cycle in highly activated monocytes. These processes are pivotal in controlling parasitemia and determining disease outcome, suggesting that a better understanding of energy metabolism on rhythmic host-parasite interactions may provide new insights for therapeutic interventions against malaria.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.
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Affiliation(s)
- Isabella Cristina Hirako
- Laboratory of Immunopathology - Instituto René Rachou, Fundação Oswaldo Cruz - Minas, Belo Horizonte30190-002, Brazil
| | - Theresa Ramalho
- Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA01605, USA
| | - Ricardo Tostes Gazzinelli
- Laboratory of Immunopathology - Instituto René Rachou, Fundação Oswaldo Cruz - Minas, Belo Horizonte30190-002, Brazil
- Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA01605, USA
- Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
- Centro de Tecnologia de Vacinas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Deshmukh R, Dewangan B, Harwansh RK, Agrawal R, Garg A, Chopra H. Current Trends in Nanotechnology-Based Drug Delivery Systems for the Diagnosis and Treatment of Malaria: A Review. Curr Drug Deliv 2025; 22:310-331. [PMID: 38265385 DOI: 10.2174/0115672018291253240115012327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 12/19/2023] [Accepted: 01/08/2024] [Indexed: 01/25/2024]
Abstract
Malaria is still a major endemic disease transmitted in humans via Plasmodium-infected mosquitoes. The eradication of malarial parasites and the control measures have been rigorously and extensively deployed by local and international health organizations. Malaria's recurrence is a result of the failure to entirely eradicate it. The drawbacks related to malarial chemotherapy, non-specific targeting, multiple drug resistance, requirement of high doses, intolerable toxicity, indefinable complexity of Plasmodium's life cycle, and advent of drug-resistant strains of P. falciparum are the causes of the ineffective eradication measures. With the emergence of nanotechnology and its application in various industrial domains, the rising interest in the medical field, especially in epidemiology, has skyrocketed. The applications of nanosized carriers have sparked special attention, aiming towards minimizing the overall side effects caused due to drug therapy and avoiding bioavailability. The applications of concepts of nanobiotechnology to both vector control and patient therapy can also be one of the approaches. The current study focuses on the use of hybrid drugs as next-generation antimalarial drugs because they involve fewer drug adverse effects. The paper encompasses the numerous nanosized delivery-based systems that have been found to be effective among higher animal models, especially in treating malarial prophylaxis. This paper delivers a detailed review of diagnostic techniques, various nanotechnology approaches, the application of nanocarriers, and the underlying mechanisms for the management of malaria, thereby providing insights and the direction in which the current trends are imparted from the innovative and technological perspective.
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Affiliation(s)
- Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
| | | | - Ranjit K Harwansh
- Institute of Pharmaceutical Research, GLA University, Mathura, 281406, India
| | - Rutvi Agrawal
- Rajiv Academy for pharmacy, NH-2, Mathura-Delhi Road, Mathura- 281001, India
| | - Akash Garg
- Rajiv Academy for pharmacy, NH-2, Mathura-Delhi Road, Mathura- 281001, India
| | - Himansu Chopra
- Rajiv Academy for pharmacy, NH-2, Mathura-Delhi Road, Mathura- 281001, India
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7
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Moreira ET, Lourenço MP, Cunha-Fernandes T, Silva TI, Siqueira LD, Castro-Faria-Neto HC, Reis PA. Minocycline inhibits microglial activation in the CA1 hippocampal region and prevents long-term cognitive sequel after experimental cerebral malaria. J Neuroimmunol 2024; 397:578480. [PMID: 39504755 DOI: 10.1016/j.jneuroim.2024.578480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/24/2024] [Accepted: 10/27/2024] [Indexed: 11/08/2024]
Abstract
Cerebral malaria is the worst complication of malaria infection, has a high mortality rate, and may cause different neurodysfunctions, including cognitive decline. Neuroinflammation is an important cause of cognitive damage in neurodegenerative diseases, and microglial cells can be activated in a disease-associated profile leading to tissue damage and neuronal death. Here, we demonstrated that treatment with minocycline reduced blood-brain barrier breakdown and modulated ICAM1 mRNA expression; reduced proinflammatory cytokines, such as TNF-α, IL-1β, IFN-γ, and IL-6; and prevented long-term cognitive decline in contextual and aversive memory tasks. Taken together, our data suggest that microglial cells are activated during experimental cerebral malaria, leading to neuroinflammatory events that end up in cognitive damage. In addition, pharmacological modulation of microglial activation, by drugs such as minocycline may be an important therapeutic strategy in the prevention of long-term memory impairment.
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Affiliation(s)
- E T Moreira
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Universidade Cruzeiro do Sul, Brazil; Departamento de Bioquímica, Instituto de Biologia Roberto Alcântara Gomes, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, Brazil.
| | - M P Lourenço
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - T Cunha-Fernandes
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - T I Silva
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - L D Siqueira
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - H C Castro-Faria-Neto
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - P A Reis
- Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil; Departamento de Bioquímica, Instituto de Biologia Roberto Alcântara Gomes, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, Brazil
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Bamgbose T, Quadri A, Abdullahi IO, Inabo HI, Bello M, Kori LD, Anvikar AR, de la Fuente J, Piloto-Sardiñas E, Cabezas-Cruz A. Antiplasmodial Activity of Probiotic Limosilactobacillus fermentum YZ01 in Plasmodium berghei ANKA Infected BALB/c Mice. J Trop Med 2024; 2024:6697859. [PMID: 39703208 PMCID: PMC11658835 DOI: 10.1155/jotm/6697859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 11/30/2024] [Indexed: 12/21/2024] Open
Abstract
Malaria remains a significant global health challenge, with the deadliest infections caused by Plasmodium falciparum. In light of the escalating drug resistance and the limited effectiveness of available vaccines, innovative treatment approaches are urgently needed. This study explores the potential of the probiotic Limosilactobacillus fermentum YZ01, isolated from traditionally fermented kindirmo milk, to modify host responses to Plasmodium berghei ANKA infection. Twenty-five male BALB/c mice were grouped and administered various treatments, including probiotic-enriched yogurt alone or in combination with antibiotics. Parameters assessed included gut lactic acid bacteria (LAB) composition, parasitaemia progression, survival rates, and immune response dynamics over a 21-day postinfection period. The probiotic treatment significantly altered gut microbiota, evidenced by increased LAB counts and modulated immune responses, notably enhancing IgM and IL-4 production while reducing IFN-γ levels. Mice receiving prolonged probiotic treatment exhibited delayed parasitaemia onset, reduced mortality rates, and a more robust immune response compared to control groups. These outcomes suggest that probiotic intervention not only tempers the pathological effects of malaria but also enhances host resilience against infection. This study underscores the role of gut microbiota in infectious disease pathogenesis and supports probiotics as a promising adjunct therapy for malaria management.
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Affiliation(s)
- Timothy Bamgbose
- ICMR-National Institute of Malaria Research, Sector 8, Dwarka, New Delhi, India
- Department of Microbiology, Ahmadu Bello University, Samaru Zaria, Kaduna, Nigeria
| | - Afshana Quadri
- ICMR-National Institute of Malaria Research, Sector 8, Dwarka, New Delhi, India
| | - Isa O. Abdullahi
- Department of Microbiology, Ahmadu Bello University, Samaru Zaria, Kaduna, Nigeria
| | - Helen I. Inabo
- Department of Microbiology, Ahmadu Bello University, Samaru Zaria, Kaduna, Nigeria
| | - Mohammed Bello
- Department of Veterinary Public Health and Preventive Medicine, Ahmadu Bello University, Samaru Zaria, Kaduna, Nigeria
| | - Lokesh D. Kori
- ICMR-National Institute of Malaria Research, Sector 8, Dwarka, New Delhi, India
| | | | - José de la Fuente
- SaBio Instituto de Investigación en Recursos Cinegéticos IREC-CSIC-UCLM-JCCM, Ronda de Toledo s/n, Ciudad Real 13005, Spain
- Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater 74078, Oklahoma, USA
| | - Elianne Piloto-Sardiñas
- Direction of Animal Health, National Center for Animal and Plant Health, Carretera de Tapaste y Autopista Nacional, Apartado Postal 10, San José de las Lajas 32700, Mayabeque, Cuba
- ANSES, INRAE, Ecole Nationale Vétérinaire d'Alfort, UMR BIPAR, Laboratoire de Santé Animale, Maisons-Alfort F-94700, France
| | - Alejandro Cabezas-Cruz
- ANSES, INRAE, Ecole Nationale Vétérinaire d'Alfort, UMR BIPAR, Laboratoire de Santé Animale, Maisons-Alfort F-94700, France
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9
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Ziliotto M, Ellwanger JH, Kulmann-Leal B, Pontillo A, Chies JAB. Role of C-C chemokine receptor type 5 in pathogenesis of malaria and its severe forms. Int J Immunogenet 2024; 51:369-379. [PMID: 39449652 DOI: 10.1111/iji.12700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/19/2024] [Accepted: 10/09/2024] [Indexed: 10/26/2024]
Abstract
Malaria is a mosquito-borne disease caused by Plasmodium parasites, responsible for a significant impact on public health in several tropical and sub-tropical countries. The majority of infection cases are classified as uncomplicated malaria, causing mild symptoms such as fever and headache. However, the disease may progress to severe malaria and death if the infection is not properly treated. Furthermore, malaria poses a major concern for children, pregnant women and immunosuppressed individuals. Exacerbated inflammation is characteristic of severe malaria cases. The C-C chemokine receptor type 5 (CCR5) is an important molecule for leukocyte migration and regulation of inflammation. Although widely known as an HIV-1 co-receptor, CCR5 also affects the susceptibility and progression of autoimmune and inflammatory diseases. There is evidence supporting the participation of CCR5 in malaria manifestations, with the evaluation of CCR5 gene expression levels suggested as a marker to monitor malaria severity. Certain genetic variants in the CCR5 gene affect CCR5 expression, potentially altering CCR5-mediated inflammatory responses during malaria infection. However, the complex influences of CCR5 on malaria remain underexplored. Therefore, this review examines and updates the role of CCR5 in various contexts of malaria infection, including uncomplicated malaria, Plasmodium/HIV co-infection, pregnancy and severe (cerebral) malaria.
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Affiliation(s)
- Marina Ziliotto
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Joel Henrique Ellwanger
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Bruna Kulmann-Leal
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Alessandra Pontillo
- Laboratory of Immunogenetics, Department of Immunology, Universidade de São Paulo (USP), São Paulo, São Paulo, Brazil
| | - José Artur Bogo Chies
- Laboratory of Immunobiology and Immunogenetics, Department of Genetics, Postgraduate Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
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10
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Li X, Jiang N, Li Q, Zheng K, Zhang Y, Sang X, Feng Y, Chen R, Chen Q. Taurine potentiates artemisinin efficacy against malaria by modulating the immune response in Plasmodium berghei-infected mice. Parasit Vectors 2024; 17:493. [PMID: 39614280 DOI: 10.1186/s13071-024-06585-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 11/13/2024] [Indexed: 12/01/2024] Open
Abstract
BACKGROUND Artemisinin (ART) is a frontline drug for the treatment of malaria; however, the emergence of ART-resistant Plasmodium strains necessitates increasing ART sensitivity. Given that taurine (TAU) has been shown to have immunomodulatory activity, we investigated the effects of TAU as an adjunct therapy to ART in mice infected with Plasmodium berghei. METHODS Mice infected with P. berghei ANKA strain (P. berghei ANKA) were treated with TAU alone, ART alone or a combination of TAU and ART (TAU + ART), and their survival time and parasitaemia were recorded. The cytotoxic effects of TAU and ART were subsequently assessed. The expression levels of inflammasome-related genes and inflammatory factors in mice infected with P. berghei ANKA were analysed in relation to those in mice treated with TAU alone, ART alone or the TAU + ART combination. The therapeutic effects were further evaluated by histological analysis and measurement of the spleen index. RESULTS Compared with the control mice, P. berghei ANKA-infected mice treated with ART in combination with TAU presented significantly lower parasitaemia and prolonged survival. The combined treatment resulted in significant reductions in the expression levels of inflammasome-related genes in the spleen, including absent in melanoma 2 (AIM2), caspase-1, NOD-, LRR- and pyrin domain-containing protein 3 (Nlrp3), Nlrp1b, Nlrp1b, NLR family CARD domain containing 4 (Nlrc4), Nlrp6, nucleotide binding oligomerization domain containing 1 (NOD1) and NOD2, and decreases in the levels of inflammatory cytokines in the serum, including interleukin (IL)-12p70, tumour necrosis factor-alpha, monocyte chemoattractant protein-1, IL-10 and IL-6. Histopathological analysis confirmed that TAU + ART combination treatment reduced spleen pathology caused by P. berghei ANKA infection. CONCLUSIONS The findings indicate that TAU potentiates ART efficacy by modulating the immune response in P. berghei-infected mice.
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Affiliation(s)
- Xin Li
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang, 110866, China
| | - Ning Jiang
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang, 110866, China
| | - Qilong Li
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang, 110866, China
| | - Kexin Zheng
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang, 110866, China
| | - Yiwei Zhang
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang, 110866, China
| | - Xiaoyu Sang
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang, 110866, China
| | - Ying Feng
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang, 110866, China
| | - Ran Chen
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang, 110866, China
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang, 110866, China
| | - Qijun Chen
- Key Laboratory of Livestock Infectious Diseases, Ministry of Education, and Key Laboratory of Ruminant Infectious Disease Prevention and Control (East), Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, 120 Dongling Road, Shenyang, 110866, China.
- Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, 120 Dongling Road, Shenyang, 110866, China.
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11
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Aboul-Ella H, Gohar A, Ali AA, Ismail LM, Mahmoud AEER, Elkhatib WF, Aboul-Ella H. Monoclonal antibodies: From magic bullet to precision weapon. MOLECULAR BIOMEDICINE 2024; 5:47. [PMID: 39390211 PMCID: PMC11467159 DOI: 10.1186/s43556-024-00210-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Monoclonal antibodies (mAbs) are used to prevent, detect, and treat a broad spectrum of non-communicable and communicable diseases. Over the past few years, the market for mAbs has grown exponentially with an expected compound annual growth rate (CAGR) of 11.07% from 2024 (237.64 billion USD estimated at the end of 2023) to 2033 (679.03 billion USD expected by the end of 2033). Ever since the advent of hybridoma technology introduced in 1975, antibody-based therapeutics were realized using murine antibodies which further progressed into humanized and fully human antibodies, reducing the risk of immunogenicity. Some benefits of using mAbs over conventional drugs include a drastic reduction in the chances of adverse reactions, interactions between drugs, and targeting specific proteins. While antibodies are very efficient, their higher production costs impede the process of commercialization. However, their cost factor has been improved by developing biosimilar antibodies as affordable versions of therapeutic antibodies. Along with the recent advancements and innovations in antibody engineering have helped and will furtherly help to design bio-better antibodies with improved efficacy than the conventional ones. These novel mAb-based therapeutics are set to revolutionize existing drug therapies targeting a wide spectrum of diseases, thereby meeting several unmet medical needs. This review provides comprehensive insights into the current fundamental landscape of mAbs development and applications and the key factors influencing the future projections, advancement, and incorporation of such promising immunotherapeutic candidates as a confrontation approach against a wide list of diseases, with a rationalistic mentioning of any limitations facing this field.
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Affiliation(s)
- Hassan Aboul-Ella
- Department of Microbiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
| | - Asmaa Gohar
- Department of Microbiology and Immunology, Faculty of Pharmacy, Galala University, Suez, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University (ACU), Giza, Egypt
- Egyptian Drug Authority (EDA), Giza, Egypt
| | - Aya Ahmed Ali
- Department of Microbiology and Immunology, Faculty of Pharmacy, Sinai University, Sinai, Egypt
| | - Lina M Ismail
- Department of Biotechnology and Molecular Chemistry, Faculty of Science, Cairo University, Giza, Egypt
- Creative Egyptian Biotechnologists (CEB), Giza, Egypt
| | | | - Walid F Elkhatib
- Department of Microbiology and Immunology, Faculty of Pharmacy, Galala University, Suez, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Heba Aboul-Ella
- Department of Pharmacognosy, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University (ECU), Cairo, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
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12
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Pollenus E, Possemiers H, Knoops S, Prenen F, Vandermosten L, Pham TT, Buysrogge L, Matthys P, Van den Steen PE. NK cells contribute to the resolution of experimental malaria-associated acute respiratory distress syndrome after antimalarial treatment. Front Immunol 2024; 15:1433904. [PMID: 39355242 PMCID: PMC11442241 DOI: 10.3389/fimmu.2024.1433904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 08/27/2024] [Indexed: 10/03/2024] Open
Abstract
In both humans and mice, natural killer (NK) cells are important lymphocytes of the innate immune system. They are often considered pro-inflammatory effector cells but may also have a regulatory or pro-resolving function by switching their cytokine profile towards the production of anti-inflammatory cytokines, including interleukin-10 (IL-10) and transforming growth factor-β, and by killing pro-inflammatory immune cells. Here, the role of NK cells in the resolution of malaria lung pathology was studied. Malaria complications, such as malaria-associated acute respiratory distress syndrome (MA-ARDS), are often lethal despite the rapid and efficient killing of Plasmodium parasites with antimalarial drugs. Hence, studying the resolution and healing mechanisms involved in the recovery from these complications could be useful to develop adjunctive treatments. Treatment of Plasmodium berghei NK65-infected C57BL/6 mice with a combination of artesunate and chloroquine starting at the appearance of symptoms was used as a model to study the resolution of MA-ARDS. The role of NK cells was studied using anti-NK1.1 depletion antibodies and NK cell-deficient mice. Using both methods, NK cells were found to be dispensable in the development of MA-ARDS, as shown previously. In contrast, NK cells were crucial in the initiation of resolution upon antimalarial treatment, as survival was significantly decreased in the absence of NK cells. Considerably increased IL-10 expression by NK cells suggested an anti-inflammatory and pro-resolving phenotype. Despite the increase in Il10 expression in the NK cells, inhibition of the IL-10/IL-10R axis using anti-IL10R antibodies had no effect on the resolution for MA-ARDS, suggesting that the pro-resolving effect of NK cells cannot solely be attributed to their IL-10 production. In conclusion, NK cells contribute to the resolution of experimental MA-ARDS.
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Affiliation(s)
- Emilie Pollenus
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Hendrik Possemiers
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Sofie Knoops
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Fran Prenen
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Leen Vandermosten
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Thao-Thy Pham
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
- Clinical Immunology Unit, Department of Clinical Sciences, Institute of Tropical Medicine Antwerp, Antwerp, Belgium
| | - Laura Buysrogge
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Patrick Matthys
- Laboratory of Immunobiology, Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Philippe E. Van den Steen
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology & Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
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13
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Hart TM, Sonnert ND, Tang X, Chaurasia R, Allen PE, Hunt JR, Read CB, Johnson EE, Arora G, Dai Y, Cui Y, Chuang YM, Yu Q, Rahman MS, Mendes MT, Rolandelli A, Singh P, Tripathi AK, Ben Mamoun C, Caimano MJ, Radolf JD, Lin YP, Fingerle V, Margos G, Pal U, Johnson RM, Pedra JHF, Azad AF, Salje J, Dimopoulos G, Vinetz JM, Carlyon JA, Palm NW, Fikrig E, Ring AM. An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms. Cell 2024; 187:4113-4127.e13. [PMID: 38876107 PMCID: PMC11959484 DOI: 10.1016/j.cell.2024.05.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 01/15/2024] [Accepted: 05/13/2024] [Indexed: 06/16/2024]
Abstract
Vector-borne diseases are a leading cause of death worldwide and pose a substantial unmet medical need. Pathogens binding to host extracellular proteins (the "exoproteome") represents a crucial interface in the etiology of vector-borne disease. Here, we used bacterial selection to elucidate host-microbe interactions in high throughput (BASEHIT)-a technique enabling interrogation of microbial interactions with 3,324 human exoproteins-to profile the interactomes of 82 human-pathogen samples, including 30 strains of arthropod-borne pathogens and 8 strains of related non-vector-borne pathogens. The resulting atlas revealed 1,303 putative interactions, including hundreds of pairings with potential roles in pathogenesis, including cell invasion, tissue colonization, immune evasion, and host sensing. Subsequent functional investigations uncovered that Lyme disease spirochetes recognize epidermal growth factor as an environmental cue of transcriptional regulation and that conserved interactions between intracellular pathogens and thioredoxins facilitate cell invasion. In summary, this interactome atlas provides molecular-level insights into microbial pathogenesis and reveals potential host-directed targets for next-generation therapeutics.
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Affiliation(s)
- Thomas M Hart
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Nicole D Sonnert
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA; Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06510, USA
| | - Xiaotian Tang
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Reetika Chaurasia
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Paige E Allen
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
| | - Jason R Hunt
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
| | - Curtis B Read
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
| | - Emily E Johnson
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Epidemiology and Microbial Diseases, Yale School of Public Health, New Haven, CT 06510, USA
| | - Gunjan Arora
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Yile Dai
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Yingjun Cui
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Yu-Min Chuang
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Qian Yu
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - M Sayeedur Rahman
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - M Tays Mendes
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Agustin Rolandelli
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Pallavi Singh
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Abhai K Tripathi
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Choukri Ben Mamoun
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06510, USA
| | - Melissa J Caimano
- Department of Medicine, UConn Health, Farmington, CT 06030, USA; Department of Pediatrics, UConn Health, Farmington, CT 06030, USA; Department of Molecular Biology and Biophysics, UConn Health, Farmington, CT 06030, USA
| | - Justin D Radolf
- Department of Medicine, UConn Health, Farmington, CT 06030, USA; Department of Pediatrics, UConn Health, Farmington, CT 06030, USA; Department of Molecular Biology and Biophysics, UConn Health, Farmington, CT 06030, USA; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT 06030, USA; Department of Immunology, UConn Health, Farmington, CT 06030, USA
| | - Yi-Pin Lin
- Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA
| | - Volker Fingerle
- Bavarian Health and Food Safety Authority, Oberschleißheim, Munich 85764, Bavaria, Germany
| | - Gabriele Margos
- Bavarian Health and Food Safety Authority, Oberschleißheim, Munich 85764, Bavaria, Germany
| | - Utpal Pal
- Department of Veterinary Medicine, University of Maryland, College Park, MD 20742, USA
| | - Raymond M Johnson
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06510, USA
| | - Joao H F Pedra
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Abdu F Azad
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jeanne Salje
- Department of Pathology, University of Cambridge, Cambridge CB2 1TN, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1TN, UK
| | - George Dimopoulos
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Joseph M Vinetz
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Laboratorio ICEMR-Amazonia, Laboratorios de Investigación Y Desarrollo, Facultad de Ciencias Y Filosofia, Universidad Peruana Cayetano Heredia, Lima 15102, Peru; Instituto de Medicina Tropical Alexander Von Humboldt, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
| | - Jason A Carlyon
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
| | - Noah W Palm
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.
| | - Erol Fikrig
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
| | - Aaron M Ring
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98102, USA.
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14
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Zhu Y, Zhou L, Mo L, Hong C, Pan L, Lin J, Qi Y, Tan S, Qian M, Hu T, Zhao Y, Qiu H, Lin P, Ma X, Yang Q. Plasmodium yoelii Infection Enhances the Expansion of Myeloid-Derived Suppressor Cells via JAK/STAT3 Pathway. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:170-186. [PMID: 38819229 DOI: 10.4049/jimmunol.2300541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 05/07/2024] [Indexed: 06/01/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs), the negative immune regulators, have been demonstrated to be involved in immune responses to a variety of pathological conditions, such as tumors, chronic inflammation, and infectious diseases. However, the roles and mechanisms underlying the expansion of MDSCs in malaria remain unclear. In this study, the phenotypic and functional characteristics of splenic MDSCs during Plasmodium yoelii NSM infection are described. Furthermore, we provide compelling evidence that the sera from P. yoelii-infected C57BL/6 mice containing excess IL-6 and granulocyte-macrophage colony-stimulating factor promote the accumulation of MDSCs by inducing Bcl2 expression. Serum-induced MDSCs exert more potent suppressive effects on T cell responses than control MDSCs within both in vivo P. yoelii infection and in vitro serum-treated bone marrow cells experiments. Serum treatment increases the MDSC inhibitory effect, which is dependent on Arg1 expression. Moreover, mechanistic studies reveal that the serum effects are mediated by JAK/STAT3 signaling. By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti-Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii-infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria.
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Affiliation(s)
- Yiqiang Zhu
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China
| | - Lu Zhou
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Lengshan Mo
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Cansheng Hong
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Lingxia Pan
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jie Lin
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yanwei Qi
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Simin Tan
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Manhongtian Qian
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Tengfei Hu
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yi Zhao
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Huaina Qiu
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Peibin Lin
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Xiancai Ma
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China
| | - Quan Yang
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
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15
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Ojueromi OO, Oboh G, Ademosun AO. Nigella sativa-Fortified Cookies Ameliorate Oxidative Stress, Inflammatory and Immune Dysfunction in Plasmodium berghei-Infected Murine Model. J Med Food 2024; 27:552-562. [PMID: 38935918 DOI: 10.1089/jmf.2023.0181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2024] Open
Abstract
Malaria impedes the ability of primary cells of the immune system to generate an efficacious inflammatory and immune response. Black seed (Nigella sativa) is a core dietary supplement and food additive in folklore. This study investigated the antioxidant, immunomodulatory, and anti-inflammatory effects of N. sativa cookies in Plasmodium berghei-infected mice. Aqueous extract of black seed was prepared, and the total phenol and flavonoid contents were determined. The mice were infected with standard inoculum of the strain NK65 P. berghei. The mice weight and behavioral changes were observed. The mice were fed with the N. sativa cookies (2.5%, 5%, and 10%) and 10 mg/kg chloroquine for 5 consecutive days after the infection was established. The reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase, catalase, and hematological parameters (red cell indices, leukocytes, and its differentials) in the infected mice were determined. The inflammatory mediators, C-reactive protein (CRP), and myeloperoxidase (MPO) were also assayed. The result revealed that black seed had a total phenol content of 18.73 mgGAE/g and total flavonoid content of 0.36 mgQUE/g. The infected mice treated with N. sativa cookies showed significantly decreased parasitaemia, MDA, and ROS levels. Furthermore, the results showed significant suppression in proinflammatory mediators (CRP and MPO) levels and enhanced antioxidant status of infected mice treated with N. sativa. The study suggests that N. sativa could function as nutraceuticals in the management of Plasmodium infection associated with inflammatory and immunomodulatory disorders.
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Affiliation(s)
- Opeyemi O Ojueromi
- Functional Foods and Nutraceuticals Unit, Department of Biochemistry, Federal University of Technology, Akure, Nigeria
- Department of Pure and Applied Sciences, Precious Cornerstone University, Ibadan, Nigeria
| | - Ganiyu Oboh
- Functional Foods and Nutraceuticals Unit, Department of Biochemistry, Federal University of Technology, Akure, Nigeria
| | - Ayokunle O Ademosun
- Functional Foods and Nutraceuticals Unit, Department of Biochemistry, Federal University of Technology, Akure, Nigeria
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16
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Feng X, Yu JL, Sun YF, Du CY, Shen Y, Zhang L, Kong WZ, Han S, Cheng Y. Plasmodium yoelii surface-related antigen (PySRA) modulates the host pro-inflammatory responses via binding to CD68 on macrophage membrane. Infect Immun 2024; 92:e0011324. [PMID: 38624215 PMCID: PMC11075460 DOI: 10.1128/iai.00113-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 04/17/2024] Open
Abstract
Malaria, one of the major infectious diseases in the world, is caused by the Plasmodium parasite. Plasmodium antigens could modulate the inflammatory response by binding to macrophage membrane receptors. As an export protein on the infected erythrocyte membrane, Plasmodium surface-related antigen (SRA) participates in the erythrocyte invasion and regulates the immune response of the host. This study found that the F2 segment of P. yoelii SRA activated downstream MAPK and NF-κB signaling pathways by binding to CD68 on the surface of the macrophage membrane and regulating the inflammatory response. The anti-PySRA-F2 antibody can protect mice against P. yoelii, and the pro-inflammatory responses such as IL-1β, TNF-α, and IL-6 after infection with P. yoelii are attenuated. These findings will be helpful for understanding the involvement of the pathogenic mechanism of malaria with the exported protein SRA.
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MESH Headings
- Animals
- Female
- Humans
- Mice
- Antigens, CD/metabolism
- Antigens, CD/immunology
- Antigens, Differentiation, Myelomonocytic/metabolism
- Antigens, Differentiation, Myelomonocytic/immunology
- Antigens, Protozoan/immunology
- Antigens, Protozoan/metabolism
- Antigens, Surface/immunology
- Antigens, Surface/metabolism
- Cell Membrane/metabolism
- Cell Membrane/immunology
- Inflammation/immunology
- Inflammation/metabolism
- Macrophages/immunology
- Macrophages/metabolism
- Macrophages/parasitology
- Malaria/immunology
- Malaria/parasitology
- NF-kappa B/metabolism
- NF-kappa B/immunology
- Plasmodium yoelii/immunology
- Protein Binding
- Signal Transduction
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Affiliation(s)
- Xin Feng
- Department of Public Health and Preventive Medicine, Laboratory of Pathogen Infection and Immunity, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Jia-Li Yu
- Department of Public Health and Preventive Medicine, Laboratory of Pathogen Infection and Immunity, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yi-Fan Sun
- Department of Public Health and Preventive Medicine, Laboratory of Pathogen Infection and Immunity, Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Chen-Yan Du
- Department of Public Health and Preventive Medicine, Laboratory of Pathogen Infection and Immunity, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yao Shen
- Department of Food Quality and Safety, School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Lu Zhang
- Department of General Practice, Rongxiang Street Community Health Service Center, Binhu District, Wuxi, China
| | - Wei-Zhong Kong
- Department of Public Health and Preventive Medicine, Laboratory of Pathogen Infection and Immunity, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Su Han
- Department of Public Health and Preventive Medicine, Laboratory of Pathogen Infection and Immunity, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yang Cheng
- Department of Public Health and Preventive Medicine, Laboratory of Pathogen Infection and Immunity, Wuxi School of Medicine, Jiangnan University, Wuxi, China
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17
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Uribe-Querol E, Rosales C. Neutrophils versus Protozoan Parasites: Plasmodium, Trichomonas, Leishmania, Trypanosoma, and Entameoba. Microorganisms 2024; 12:827. [PMID: 38674770 PMCID: PMC11051968 DOI: 10.3390/microorganisms12040827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/04/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Neutrophils are the most abundant polymorphonuclear granular leukocytes in human blood and are an essential part of the innate immune system. Neutrophils are efficient cells that eliminate pathogenic bacteria and fungi, but their role in dealing with protozoan parasitic infections remains controversial. At sites of protozoan parasite infections, a large number of infiltrating neutrophils is observed, suggesting that neutrophils are important cells for controlling the infection. Yet, in most cases, there is also a strong inflammatory response that can provoke tissue damage. Diseases like malaria, trichomoniasis, leishmaniasis, Chagas disease, and amoebiasis affect millions of people globally. In this review, we summarize these protozoan diseases and describe the novel view on how neutrophils are involved in protection from these parasites. Also, we present recent evidence that neutrophils play a double role in these infections participating both in control of the parasite and in the pathogenesis of the disease.
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Affiliation(s)
- Eileen Uribe-Querol
- Laboratorio de Biología del Desarrollo, División de Estudios de Posgrado e Investigación, Facultad de Odontología, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Carlos Rosales
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
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18
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Sharma I, Kataria P, Das J. Cerebral malaria pathogenesis: Dissecting the role of CD4 + and CD8 + T-cells as major effectors in disease pathology. Int Rev Immunol 2024; 43:309-325. [PMID: 38618863 DOI: 10.1080/08830185.2024.2336539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 03/22/2024] [Accepted: 03/24/2024] [Indexed: 04/16/2024]
Abstract
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum (P. falciparum) infection, with complex pathogenesis involving multiple factors, including the host's immunological response. T lymphocytes, specifically CD4+ T helper cells and CD8+ cytotoxic T cells, are crucial in controlling parasite growth and activating cells for parasite clearance via cytokine secretion. Contrary to this, reports also suggest the pathogenic nature of T lymphocytes as they are often involved in disease progression and severity. CD8+ cytotoxic T cells migrate to the host's brain vasculature, disrupting the blood-brain barrier and causing neurological manifestations. CD4+ T helper cells on the other hand play a variety of functions as they differentiate into different subtypes which may function as pro-inflammatory or anti-inflammatory. The excessive pro-inflammatory response in CM can lead to multi-organ failure, necessitating a check mechanism to maintain immune homeostasis. This is achieved by regulatory T cells and their characteristic cytokines, which counterbalance the pro-inflammatory immune response. Maintaining a critical balance between pro and anti-inflammatory responses is crucial for determining disease outcomes in CM. A slight change in this balance may contribute to a disease severity owing to an extreme inflammatory response or unrestricted parasite growth, a potential target for designing immunotherapeutic treatment approaches. The review briefly discusses the pathogenesis of CM and various mechanisms responsible for the disruption of the blood-brain barrier. It also highlights the role of different T cell subsets during infection and emphasizes the importance of balance between pro and anti-inflammatory T cells that ultimately decides the outcome of the disease.
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Affiliation(s)
- Indu Sharma
- Academy of Scientific and Innovative Research (AcSIR), Noida, India
- Division of Immunology, National Institute of Malaria Research, Dwarka, New Delhi, India
| | - Poonam Kataria
- Academy of Scientific and Innovative Research (AcSIR), Noida, India
- Division of Immunology, National Institute of Malaria Research, Dwarka, New Delhi, India
| | - Jyoti Das
- Academy of Scientific and Innovative Research (AcSIR), Noida, India
- Division of Immunology, National Institute of Malaria Research, Dwarka, New Delhi, India
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19
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Dey S, Mohapatra S, Khokhar M, Hassan S, Pandey RK. Extracellular Vesicles in Malaria: Shedding Light on Pathogenic Depths. ACS Infect Dis 2024; 10:827-844. [PMID: 38320272 PMCID: PMC10928723 DOI: 10.1021/acsinfecdis.3c00649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 02/08/2024]
Abstract
Malaria, a life-threatening infectious disease caused by Plasmodium falciparum, remains a significant global health challenge, particularly in tropical and subtropical regions. The epidemiological data for 2021 revealed a staggering toll, with 247 million reported cases and 619,000 fatalities attributed to the disease. This formidable global health challenge continues to perplex researchers seeking a comprehensive understanding of its pathogenesis. Recent investigations have unveiled the pivotal role of extracellular vesicles (EVs) in this intricate landscape. These tiny, membrane-bound vesicles, secreted by diverse cells, emerge as pivotal communicators in malaria's pathogenic orchestra. This Review delves into the multifaceted roles of EVs in malaria pathogenesis, elucidating their impact on disease progression and immune modulation. Insights into EV involvement offer potential therapeutic and diagnostic strategies. Integrating this information identifies targets to mitigate malaria's global impact. Moreover, this Review explores the potential of EVs as diagnostic biomarkers and therapeutic targets in malaria. By deciphering the intricate dialogue facilitated by these vesicles, new avenues for intervention and novel strategies for disease management may emerge.
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Affiliation(s)
- Sangita Dey
- CSO
Department, Cellworks Research India Pvt
Ltd, Bengaluru 560066, Karnataka, India
| | - Salini Mohapatra
- Department
of Biotechnology, Chandigarh University, Punjab 140413, India
| | - Manoj Khokhar
- Department
of Biochemistry, All India Institute of
Medical Sciences Jodhpur, Rajasthan 342005, India
| | - Sana Hassan
- Department
of Life Sciences, Manipal Academy of Higher
Education, Dubai 345050, United Arab Emirates
| | - Rajan Kumar Pandey
- Department
of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177, Sweden
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20
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Ramalho T, Assis PA, Ojelabi O, Tan L, Carvalho B, Gardinassi L, Campos O, Lorenzi PL, Fitzgerald KA, Haynes C, Golenbock DT, Gazzinelli RT. Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells. Cell Metab 2024; 36:484-497.e6. [PMID: 38325373 PMCID: PMC10940217 DOI: 10.1016/j.cmet.2024.01.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 10/27/2023] [Accepted: 01/14/2024] [Indexed: 02/09/2024]
Abstract
Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.
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Affiliation(s)
- Theresa Ramalho
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
| | - Patricia A Assis
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Ogooluwa Ojelabi
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Lin Tan
- Department of Bioinformatics and Computational Biology, University of Texas MD Cancer Center, Houston, TX, USA
| | - Brener Carvalho
- Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - Luiz Gardinassi
- Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil
| | - Osvaldo Campos
- Plataforma de Medicina Translacional, Fundação Oswaldo Cruz/Faculdade de Medicina de Ribeirao Preto, Ribeirao Preto, Sao Paulo, Brazil
| | - Philip L Lorenzi
- Department of Bioinformatics and Computational Biology, University of Texas MD Cancer Center, Houston, TX, USA
| | - Katherine A Fitzgerald
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Cole Haynes
- Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Douglas T Golenbock
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Ricardo T Gazzinelli
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil; Centro de Tecnologia de Vacinas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
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21
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Jeje TO, Bando H, Azad MTA, Fukuda Y, Oluwafemi IE, Kato K. Antiplasmodial and interferon-gamma-modulating activities of the aqueous extract of stone breaker (Phyllanthus niruri Linn.) in malaria infection. Parasitol Int 2023; 97:102789. [PMID: 37473798 DOI: 10.1016/j.parint.2023.102789] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 07/14/2023] [Accepted: 07/15/2023] [Indexed: 07/22/2023]
Abstract
Plasmodium falciparum parasites are the primary cause of malaria across Africa. The problem of drug resistance to malaria is ever growing and novel therapeutic strategies need to be developed, particularly those targeting the parasite and also the host or host-pathogen interaction. Previous studies have shown that the development of cerebral malaria (CM) is related to dysregulation of the immune system in a murine malaria model of experimental cerebral malaria. It involves a complex interaction of events and interferon-gamma seems to be the unifying factor. Therefore, the antiplasmodial activity targeting the parasite and immunomodulatory strategies that reduce overall host inflammation, with IFN-γ in focus, could delay CM onset and prove beneficial in malaria infection therapy. Phyllanthus niruri is used to treat fever and other symptoms of malaria in Nigeria. Its modes of action as an anti-malarial remedy have not been exhaustively investigated. This study therefore examined the aqueous extract of P. niruri (PE) for its antiplasmodial activity in vitro using the Plasmodium falciparum HB3 strain. Furthermore, in vivo murine malaria model using the Plasmodium berghei ANKA strain was used to investigate its anti-malarial effects. We showed that PE has multiple anti-malarial effects, including anti-parasitic and host immunomodulatory activities. Co-culture of P. falciparum with PE and some of its phytoconstituents drastically reduced parasite number. PE also decreased parasitemia, and increased the survival of infected mice. We also observed that the integrity of the blood-brain barrier was maintained in the PE-treated mice. The results confirmed that PE showed moderate antiplasmodial activity. In vivo murine malaria model using P. berghei ANKA for experimental cerebral malaria revealed that PE suppressed parasite growth, and modulate the production of interferon-gamma. The findings demonstrate that PE affects malaria progression, targeting parasites and host cells.
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Affiliation(s)
- Temitope Olawale Jeje
- Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi 989-6711, Japan; Department of Biochemistry, Faculty of Science, Federal University Oye-Ekiti, Nigeria; Department of Biochemistry, School of Science, Federal University of Technology, Akure, Nigeria
| | - Hironori Bando
- Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi 989-6711, Japan
| | - Md Thoufic Anam Azad
- Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi 989-6711, Japan; Department of Veterinary and Animal Sciences, Faculty of Veterinary and Animal Sciences, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Yasuhiro Fukuda
- Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi 989-6711, Japan
| | | | - Kentaro Kato
- Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University, 232-3 Yomogida, Naruko-onsen, Osaki, Miyagi 989-6711, Japan.
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22
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Patel D, Lin R, Majumder B, Ganusov VV. Brain-localized CD4 and CD8 T cells perform correlated random walks and not Levy walks. F1000Res 2023; 12:87. [PMID: 37811200 PMCID: PMC10556561 DOI: 10.12688/f1000research.129923.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/20/2023] [Indexed: 10/10/2023] Open
Abstract
Background. For survival of the organism, T cells must efficiently control pathogens invading different peripheral tissues. Whether or not such control is achieved by utilizing different movement strategies in different tissues remains poorly understood. Liver-localized CD8 T cells perform correlated random walks --- a type of a Brownian walk -- in liver sinusoids but in some condition these T cells may also perform Levy flights -- rapid and large displacements by floating with the blood flow. CD8 T cells in lymph nodes or skin also undergo Brownian walks. A recent study suggested that brain-localized CD8 T cells, specific to Toxoplasma gondii, perform generalized Levy walks -- a walk type in which T cells alternate pausing and displacing long distances --- which may indicate that brain is a unique organ where T cells exhibit movement strategies different from other tissues. Methods. We quantified movement patterns of brain-localized Plasmodium berghei-specific CD4 and CD8 T cells by using well-established statistical and computational methods. Results. We found that T cells change their movement pattern with time since infection and that CD4 T cells move faster and turn less than CD8 T cells. Importantly, both CD4 and CD8 T cells move in the brain by correlated random walks without long displacements challenging previous observations. We have also re-analyzed the movement data of brain-localized CD8 T cells in T. gondii-infected mice and found no evidence of Levy walks. We hypothesize that the previous conclusion of Levy walks of T. gondii-specific CD8 T cells in the brain was reached due to missing time-frames in the data that create an impression of large movement lengths between assumed-to-be-sequential movements. Conclusion. Our results suggests that movement strategies of CD8 T cells are largely similar between LNs, liver, and the brain and consistent with correlated random walks and not Levy walks.
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Affiliation(s)
- Dhruv Patel
- Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee Knoxville, Knoxville, TN, 37996, USA
| | - Raymond Lin
- Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee Knoxville, Knoxville, TN, 37996, USA
| | - Barun Majumder
- Department of Microbiology, Universitiy of Tennessee, Knoxville, TN, 37996, USA
| | - Vitaly V. Ganusov
- Department of Microbiology, Universitiy of Tennessee, Knoxville, TN, 37996, USA
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23
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Musrati MA, De Baetselier P, Movahedi K, Van Ginderachter JA. Ontogeny, functions and reprogramming of Kupffer cells upon infectious disease. Front Immunol 2023; 14:1238452. [PMID: 37691953 PMCID: PMC10485603 DOI: 10.3389/fimmu.2023.1238452] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 08/11/2023] [Indexed: 09/12/2023] Open
Abstract
The liver is a vital metabolic organ that also performs important immune-regulatory functions. In the context of infections, the liver represents a target site for various pathogens, while also having an outstanding capacity to filter the blood from pathogens and to contain infections. Pathogen scavenging by the liver is primarily performed by its large and heterogeneous macrophage population. The major liver-resident macrophage population is located within the hepatic microcirculation and is known as Kupffer cells (KCs). Although other minor macrophages reside in the liver as well, KCs remain the best characterized and are the best well-known hepatic macrophage population to be functionally involved in the clearance of infections. The response of KCs to pathogenic insults often governs the overall severity and outcome of infections on the host. Moreover, infections also impart long-lasting, and rarely studied changes to the KC pool. In this review, we discuss current knowledge on the biology and the various roles of liver macrophages during infections. In addition, we reflect on the potential of infection history to imprint long-lasting effects on macrophages, in particular liver macrophages.
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Affiliation(s)
- Mohamed Amer Musrati
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
| | - Patrick De Baetselier
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
| | - Kiavash Movahedi
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
- Lab of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Jo A. Van Ginderachter
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium
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24
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Chinna P, Bratl K, Lambarey H, Blumenthal MJ, Schäfer G. The Impact of Co-Infections for Human Gammaherpesvirus Infection and Associated Pathologies. Int J Mol Sci 2023; 24:13066. [PMID: 37685871 PMCID: PMC10487760 DOI: 10.3390/ijms241713066] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/18/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
The two oncogenic human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause significant disease burden, particularly in immunosuppressed individuals. Both viruses display latent and lytic phases of their life cycle with different outcomes for their associated pathologies. The high prevalence of infectious diseases in Sub-Saharan Africa (SSA), particularly HIV/AIDS, tuberculosis, malaria, and more recently, COVID-19, as well as their associated inflammatory responses, could potentially impact either virus' infectious course. However, acute or lytically active EBV and/or KSHV infections often present with symptoms mimicking these predominant diseases leading to misdiagnosis or underdiagnosis of oncogenic herpesvirus-associated pathologies. EBV and/or KSHV infections are generally acquired early in life and remain latent until lytic reactivation is triggered by various stimuli. This review summarizes known associations between infectious agents prevalent in SSA and underlying EBV and/or KSHV infection. While presenting an overview of both viruses' biphasic life cycles, this review aims to highlight the importance of co-infections in the correct identification of risk factors for and diagnoses of EBV- and/or KSHV-associated pathologies, particularly in SSA, where both oncogenic herpesviruses as well as other infectious agents are highly pervasive and can lead to substantial morbidity and mortality.
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Affiliation(s)
- Prishanta Chinna
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Katrin Bratl
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Humaira Lambarey
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Melissa J. Blumenthal
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Georgia Schäfer
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
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Rankawat S, Kundal K, Chakraborty S, Kumar R, Ray S. A comprehensive rhythmicity analysis of host proteins and immune factors involved in malaria pathogenesis to decipher the importance of host circadian clock in malaria. Front Immunol 2023; 14:1210299. [PMID: 37638001 PMCID: PMC10449258 DOI: 10.3389/fimmu.2023.1210299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 07/17/2023] [Indexed: 08/29/2023] Open
Abstract
Background Circadian rhythms broadly impact human health by regulating our daily physiological and metabolic processes. The circadian clocks substantially regulate our immune responses and susceptibility to infections. Malaria parasites have intrinsic molecular oscillations and coordinate their infection cycle with host rhythms. Considering the cyclical nature of malaria, a clear understanding of the circadian regulations in malaria pathogenesis and host responses is of immense importance. Methods We have thoroughly investigated the transcript level rhythmic patterns in blood proteins altered in falciparum and vivax malaria and malaria-related immune factors in mice, baboons, and humans by analyzing datasets from published literature and comprehensive databases. Using the Metascape and DAVID platforms, we analyzed Gene Ontology terms and physiological pathways associated with the rhythmic malaria-associated host immune factors. Results We observed that almost 50% of the malaria-associated host immune factors are rhythmic in mice and humans. Overlapping rhythmic genes identified in mice, baboons, and humans, exhibited enrichment (Q < 0.05, fold-enrichment > 5) of multiple physiological pathways essential for host immune and defense response, including cytokine production, leukocyte activation, cellular defense, and response, regulation of kinase activity, B-cell receptor signaling pathway, and cellular response to cytokine stimulus. Conclusions Our analysis indicates a robust circadian regulation on multiple interconnected host response pathways and immunological networks in malaria, evident from numerous rhythmic genes involved in those pathways. Host immune rhythms play a vital role in the temporal regulation of host-parasite interactions and defense machinery in malaria.
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Affiliation(s)
| | | | | | | | - Sandipan Ray
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana, India
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Deshmukh R. Exploring the potential of antimalarial nanocarriers as a novel therapeutic approach. J Mol Graph Model 2023; 122:108497. [PMID: 37149980 DOI: 10.1016/j.jmgm.2023.108497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 03/31/2023] [Accepted: 04/17/2023] [Indexed: 05/09/2023]
Abstract
Malaria is a life-threatening parasitic disease that affects millions of people worldwide, especially in developing countries. Despite advances in conventional therapies, drug resistance in malaria parasites has become a significant concern. Hence, there is a need for a new therapeutic approach. To combat the disease effectively means eliminating vectors and discovering potent treatments. The nanotechnology research efforts in nanomedicine show promise by exploring the potential use of nanomaterials that can surmount these limitations occurring with antimalarial drugs, which include multidrug resistance or lack of specificity when targeting parasites directly. Utilizing nanomaterials would possess unique advantages over conventional chemotherapy systems by increasing the efficacy levels while reducing side effects significantly by delivering medications precisely within the diseased area. It also provides cheap yet safe measures against Malaria infections worldwide-ultimately improving treatment efficiency holistically without reinventing new methods therapeutically. This review is an effort to provide an overview of the various stages of malaria parasites, pathogenesis, and conventional therapies, as well as the treatment gap existing with available formulations. It explores different types of nanocarriers, such as liposomes, ethosomal cataplasm, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanocarriers, and metallic nanoparticles, which are frequently employed to boost the efficiency of antimalarial drugs to overcome the challenges and develop effective and safe therapies. The study also highlights the improved pharmacokinetics, enhanced drug bioavailability, and reduced toxicity associated with nanocarriers, making them a promising therapeutic approach for treating malaria.
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Affiliation(s)
- Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, 281406, India.
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Jamil SNH, Ali AH, Feroz SR, Lam SD, Agustar HK, Mohd Abd Razak MR, Latip J. Curcumin and Its Derivatives as Potential Antimalarial and Anti-Inflammatory Agents: A Review on Structure-Activity Relationship and Mechanism of Action. Pharmaceuticals (Basel) 2023; 16:609. [PMID: 37111366 PMCID: PMC10146798 DOI: 10.3390/ph16040609] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/31/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Curcumin, one of the major ingredients of turmeric (Curcuma longa), has been widely reported for its diverse bioactivities, including against malaria and inflammatory-related diseases. However, curcumin's low bioavailability limits its potential as an antimalarial and anti-inflammatory agent. Therefore, research on the design and synthesis of novel curcumin derivatives is being actively pursued to improve the pharmacokinetic profile and efficacy of curcumin. This review discusses the antimalarial and anti-inflammatory activities and the structure-activity relationship (SAR), as well as the mechanisms of action of curcumin and its derivatives in malarial treatment. This review provides information on the identification of the methoxy phenyl group responsible for the antimalarial activity and the potential sites and functional groups of curcumin for structural modification to improve its antimalarial and anti-inflammatory actions, as well as potential molecular targets of curcumin derivatives in the context of malaria and inflammation.
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Affiliation(s)
- Siti Nur Hidayah Jamil
- Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi 43600, Selangor, Malaysia
| | - Amatul Hamizah Ali
- Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi 43600, Selangor, Malaysia
| | - Shevin Rizal Feroz
- Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi 43600, Selangor, Malaysia
| | - Su Datt Lam
- Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi 43600, Selangor, Malaysia
| | - Hani Kartini Agustar
- Department of Earth Sciences and Environment, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi 43600, Selangor, Malaysia
| | - Mohd Ridzuan Mohd Abd Razak
- Herbal Medicine Research Centre, Institute for Medical Research, National Institute of Health (NIH) Complex, Ministry of Health Malaysia, Shah Alam 40170, Selangor, Malaysia
| | - Jalifah Latip
- Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia (UKM), Bangi 43600, Selangor, Malaysia
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Coelho KF, Neves JCF, Ibiapina HNS, Magalhães-Gama F, Barbosa FBA, Silva FS, Wellmann IAM, Sachett JAG, Tarragô AM, Ferreira LCL, Malheiro A, Monteiro WM, Costa AG. Exploring the Profile of Cell Populations and Soluble Immunological Mediators in Bothrops atrox Envenomations. Toxins (Basel) 2023; 15:196. [PMID: 36977086 PMCID: PMC10051854 DOI: 10.3390/toxins15030196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/18/2023] [Accepted: 02/20/2023] [Indexed: 03/08/2023] Open
Abstract
Bothrops atrox envenomations are common in the Brazilian Amazon. The venom of B. atrox is highly inflammatory, which results in severe local complications, including the formation of blisters. Moreover, there is little information on the immune mechanisms associated with this condition. Thus, a longitudinal study was carried out to characterize the profile of the cell populations and soluble immunological mediators in the peripheral blood and blisters in B. atrox patients s according to their clinical manifestations (mild and severe). A similar response in both B. atrox patient groups (MILD and SEV) was observed, with an increase in inflammatory monocytes, NKT, and T and B cells, as well as CCL2, CCL5, CXCL9, CXCL10, IL-1β and IL-10, when compared with the group of healthy blood donors. After the administration of antivenom, the participation of patrolling monocytes and IL-10 in the MILD group was observed. In the SEV group, the participation of B cells was observed, with high levels of CCL2 and IL-6. In the blister exudate, a hyperinflammatory profile was observed. In conclusion, we revealed the involvement of cell populations and soluble mediators in the immune response to B. atrox envenomation at the local and peripheral level, which is related to the onset and extent of the inflammation/clinical manifestation.
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Affiliation(s)
- Kerolaine Fonseca Coelho
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus 69040-000, AM, Brazil
| | - Juliana Costa Ferreira Neves
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus 69040-000, AM, Brazil
| | - Hiochelson Najibe Santos Ibiapina
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus 69040-000, AM, Brazil
| | - Fábio Magalhães-Gama
- Programa de Pós-Graduação em Ciências da Saúde, Instituto René Rachou-Fundação Oswaldo Cruz (FIOCRUZ Minas), Belo Horizonte 30190-002, MG, Brazil
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus 69050-001, AM, Brazil
| | - Fabiane Bianca Albuquerque Barbosa
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus 69040-000, AM, Brazil
| | - Flavio Souza Silva
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus 69050-001, AM, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus 69067-005, AM, Brazil
| | - Irmgardt Alicia María Wellmann
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus 69040-000, AM, Brazil
| | - Jacqueline Almeida Gonçalves Sachett
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus 69040-000, AM, Brazil
- Departamento de Ensino e Pesquisa, Fundação Alfredo da Matta (FUAM), Manaus 69065-130, AM, Brazil
| | - Andréa Monteiro Tarragô
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus 69050-001, AM, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus 69067-005, AM, Brazil
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69050-001, AM, Brazil
| | - Luiz Carlos Lima Ferreira
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus 69040-000, AM, Brazil
| | - Adriana Malheiro
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus 69050-001, AM, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus 69067-005, AM, Brazil
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69050-001, AM, Brazil
| | - Wuelton Marcelo Monteiro
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus 69040-000, AM, Brazil
| | - Allyson Guimarães Costa
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus 69040-000, AM, Brazil
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus 69040-000, AM, Brazil
- Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus 69050-001, AM, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus 69067-005, AM, Brazil
- Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus 69050-001, AM, Brazil
- Escola de Enfermagem de Manaus, Universidade Federal do Amazonas (UFAM), Manaus 69057-070, AM, Brazil
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Altered gastrointestinal tract structure and microbiome following cerebral malaria infection. Parasitol Res 2023; 122:789-799. [PMID: 36602586 DOI: 10.1007/s00436-022-07775-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 12/20/2022] [Indexed: 01/06/2023]
Abstract
Cerebral malaria (CM) is the most severe form of malaria with the highest mortality rate and can result in life-long neurological deficits and ongoing comorbidities. Factors contributing to severity of infection and development of CM are not fully elucidated. Recent studies have indicated a key role of the gut microbiome in a range of health conditions that affect the brain, but limited microbiome research has been conducted in the context of malaria. To address this knowledge gap, the impact of CM on the gut microbiome was investigated in mice. C57BL/6J mice were infected with Plasmodium berghei ANKA (PbA) parasites and compared to non-infected controls. Microbial DNA from faecal pellets collected daily for 6-days post-infection were extracted, and microbiome comparisons conducted using 16S rRNA profiling. We identified significant differences in the composition of bacterial communities between the infected and the non-infected groups, including a higher abundance of the genera Akkermansia, Alistipes and Alloprevotella in PbA-infected mice. Furthermore, intestinal samples were collected post-cull for morphological analysis. We determined that the caecal weight was significantly lower, and the small intestine was significantly longer in PbA-infected mice than in the non-infected controls. We concluded that changes in microbial community composition were primarily driven by the infection protocol and, to a lesser extent, by the time of infection. Our findings pave the way for a new area of research and novel intervention strategies to modulate the severity of cerebral malaria disease.
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van Zyl E, Leisewitz AL, Atkinson BK, Goddard A, Rautenbach Y, Thompson PN, Schoeman JP. Serial changes in the concentrations of cortisol and thyroid hormones in Beagle dogs infected with Babesia rossi. Ticks Tick Borne Dis 2023; 14:102107. [PMID: 36535203 DOI: 10.1016/j.ttbdis.2022.102107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/13/2022] [Accepted: 11/13/2022] [Indexed: 12/14/2022]
Abstract
An experimental infection using Babesia (B.) rossi was performed in healthy male Beagle dogs to assess the changes in endocrine variables during disease. Two dogs were infected with a low dose (LD) of parasite inoculum (104 parasites) and three dogs were infected with a high dose (HD) (108 parasites). Basal serum cortisol, thyroxine (T4), and thyrotropin (TSH) concentrations were measured every second day. Samples were analyzed using a solid- phase, competitive chemiluminescent enzyme immunoassay (Immulyte® 2000, Siemens). Variables were compared between groups and timepoints using linear mixed models. In both groups, the median cortisol concentration increased, whilst the median T4 concentration decreased after infection, with a return towards baseline concentration post treatment. The highest cortisol and the lowest T4 concentrations were reached at 96 h and 108 h post infection, respectively, in the HD group and slightly later at 108 and 144 h post-infection, respectively, in the LD group. A higher cortisol concentration with a more rapid increase, and a lower T4 concentration with a more rapid decline, were associated with disease severity and a higher dose of parasite inoculum. The TSH concentration remained within the reference interval throughout the study period. This study illustrated the temporal changes in endocrine parameters during experimental B. rossi infection and demonstrated that cortisol and T4 tracked the severity of disease, albeit in opposite directions.
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Affiliation(s)
- E van Zyl
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, 175 Bryanston drive, Bryanston, Onderstepoort, Johannesburg 2021, South Africa.
| | - A L Leisewitz
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, 175 Bryanston drive, Bryanston, Onderstepoort, Johannesburg 2021, South Africa
| | - B K Atkinson
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, 175 Bryanston drive, Bryanston, Onderstepoort, Johannesburg 2021, South Africa
| | - A Goddard
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, 175 Bryanston drive, Bryanston, Onderstepoort, Johannesburg 2021, South Africa
| | - Y Rautenbach
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, 175 Bryanston drive, Bryanston, Onderstepoort, Johannesburg 2021, South Africa
| | - P N Thompson
- Department of Production Animal Studies, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, South Africa
| | - J P Schoeman
- Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, 175 Bryanston drive, Bryanston, Onderstepoort, Johannesburg 2021, South Africa
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Li JX, Liao WZ, Huang ZM, Yin X, Ouyang S, Gu B, Guo XG. Identifying effective diagnostic biomarkers for childhood cerebral malaria in Africa integrating coexpression analysis with machine learning algorithm. Eur J Med Res 2023; 28:76. [PMID: 36782344 PMCID: PMC9926768 DOI: 10.1186/s40001-022-00980-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 12/30/2022] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Cerebral malaria (CM) is a manifestation of malaria caused by plasmodium infection. It has a high mortality rate and severe neurological sequelae, existing a significant research gap and requiring further study at the molecular level. METHODS We downloaded the GSE117613 dataset from the Gene Expression Omnibus (GEO) database to determine the differentially expressed genes (DEGs) between the CM group and the control group. Weighted gene coexpression network analysis (WGCNA) was applied to select the module and hub genes most relevant to CM. The common genes of the key module and DEGs were selected to perform further analysis. The least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine recursive feature elimination (SVM-RFE) were applied to screen and verify the diagnostic markers of CM. Eventually, the hub genes were validated in the external dataset. Gene set enrichment analysis (GSEA) was applied to investigate the possible roles of the hub genes. RESULTS The GO and KEGG results showed that DEGs were enriched in some neutrophil-mediated pathways and associated with some lumen structures. Combining LASSO and the SVM-RFE algorithms, LEF1 and IRAK3 were identified as potential hub genes in CM. Through the GSEA enrichment results, we found that LEF1 and IRAK3 participated in maintaining the integrity of the blood-brain barrier (BBB), which contributed to improving the prognosis of CM. CONCLUSIONS This study may help illustrate the pathophysiology of CM at the molecular level. LEF1 and IRAK3 can be used as diagnostic biomarkers, providing new insight into the diagnosis and prognosis prediction in pediatric CM.
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Affiliation(s)
- Jia-Xin Li
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The First Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Wan-Zhe Liao
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The Nanshan College of Guangzhou Medical University, Guangzhou, 511436, China
| | - Ze-Min Huang
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Xin Yin
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
- Department of Pediatrics, The Pediatrics School of Guangzhou Medical University, Guangzhou, 511436, China
| | - Shi Ouyang
- Department of Infectious Disease, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Bing Gu
- Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510000, China.
| | - Xu-Guang Guo
- Department of Clinical Laboratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
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Pathogenesis of Anemia in Canine Babesiosis: Possible Contribution of Pro-Inflammatory Cytokines and Chemokines-A Review. Pathogens 2023; 12:pathogens12020166. [PMID: 36839438 PMCID: PMC9962459 DOI: 10.3390/pathogens12020166] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
Canine babesiosis is a tick-borne protozoan disease caused by intraerythrocytic parasites of the genus Babesia. The infection may lead to anemia in infected dogs. However, anemia is not directly caused by the pathogen. The parasite's developmental stages only have a marginal role in contributing to a decreased red blood cell (RBC) count. The main cause of anemia in affected dogs is the immune response to the infection. This response includes antibody production, erythrophagocytosis, oxidative damage of RBCs, complement activation, and antibody-dependent cellular cytotoxicity. Moreover, both infected and uninfected erythrocytes are retained in the spleen and sequestered in micro-vessels. All these actions are driven by pro-inflammatory cytokines and chemokines, especially IFN-γ, TNF-α, IL-6, and IL-8. Additionally, imbalance between the actions of pro- and anti-inflammatory cytokines plays a role in patho-mechanisms leading to anemia in canine babesiosis. This article is a review of the studies on the pathogenesis of anemia in canine babesiosis and related diseases, such as bovine or murine babesiosis and human or murine malaria, and the role of pro-inflammatory cytokines and chemokines in the mechanisms leading to anemia in infected dogs.
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Investigation of Plasma-Derived Lipidome Profiles in Experimental Cerebral Malaria in a Mouse Model Study. Int J Mol Sci 2022; 24:ijms24010501. [PMID: 36613941 PMCID: PMC9820457 DOI: 10.3390/ijms24010501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Cerebral malaria (CM), a fatal complication of Plasmodium infection that affects children, especially under the age of five, in sub-Saharan Africa and adults in South-East Asia, results from incompletely understood pathogenetic mechanisms. Increased release of circulating miRNA, proteins, lipids and extracellular vesicles has been found in CM patients and experimental mouse models. We compared lipid profiles derived from the plasma of CBA mice infected with Plasmodium berghei ANKA (PbA), which causes CM, to those from Plasmodium yoelii (Py), which does not. We previously showed that platelet-free plasma (18k fractions enriched from plasma) contains a high number of extracellular vesicles (EVs). Here, we found that this fraction produced at the time of CM differed dramatically from those of non-CM mice, despite identical levels of parasitaemia. Using high-resolution liquid chromatography-mass spectrometry (LCMS), we identified over 300 lipid species within 12 lipid classes. We identified 45 and 75 lipid species, mostly including glycerolipids and phospholipids, with significantly altered concentrations in PbA-infected mice compared to Py-infected and uninfected mice, respectively. Total lysophosphatidylethanolamine (LPE) levels were significantly lower in PbA infection compared to Py infection and controls. These results suggest that experimental CM could be characterised by specific changes in the lipid composition of the 18k fraction containing circulating EVs and can be considered an appropriate model to study the role of lipids in the pathophysiology of CM.
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Ntenda PAM, Chirambo AC, Nkoka O, El-Meidany WM, Goupeyou-Youmsi J. Implication of asymptomatic and clinical Plasmodium falciparum infections on biomarkers of iron status among school-aged children in Malawi. Malar J 2022; 21:278. [PMID: 36183114 PMCID: PMC9526385 DOI: 10.1186/s12936-022-04297-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 09/17/2022] [Indexed: 12/03/2022] Open
Abstract
Background Iron status is considered as a continuum from an iron deficiency with anaemia, without anaemia, varying amounts of stored iron to iron overload. The burden of Plasmodium falciparum infections is typically high among school-aged children (SAC). Nonetheless, SAC are often less likely to be covered by malaria interventions, making them a group with an untreated reservoir of parasite transmission. This study aimed to assess the effects of asymptomatic and clinical malaria infections on biochemical markers of iron status among SAC in Malawi. Methods Data from the 2015–2016 Malawi Micronutrient Survey (MNS) was used and multivariable logistic regression models using a generalized estimating equation to account for the complex cluster survey design were constructed. Blood samples of 684 children aged 5 to 14 years old were evaluated for clinical and asymptomatic malaria infections. Furthermore, blood samples were used to estimate haemoglobin (Hb), serum ferritin (SF) and, soluble transferrin receptors (sTfR) concentrations. Results Of the 684 SAC analysed, approximately 42% had asymptomatic malaria, while 41.0% had clinical malaria. Anaemia (low Hb levels), iron deficiency (low SF concentration), and functional iron deficiency (high sTfR levels) were found in 20%, 5%, and 30% of the children, respectively. School-aged children with asymptomatic malaria had increased odds of being anaemic (adjusted odds ratio [aOR]: 3.71, 95% confidence interval [CI]: 2.29–5.99) and increased levels of sTfR (aOR: 3.00, 95% CI 2.01–4.47). Similarly, SAC with clinical malaria had increased odds of being anaemic (aOR: 3.54, 95% CI 2.19–5.72) and increased levels of sTfR (aOR: 3.02, 95% CI 2.02–4.52). Conclusions Both asymptomatic and clinical malaria were independent risk factors for anaemia and functional iron deficiency (FID). The notion that asymptomatic and clinical malaria were associated with both anaemia and FID underscores the need for public health programmers to consider adding mass screening and treatment for malaria to existing school-based health programmes. Supplementary Information The online version contains supplementary material available at 10.1186/s12936-022-04297-1.
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Affiliation(s)
- Peter A M Ntenda
- Malaria Alert Centre, Kamuzu University of Health Sciences, Private Bag 360, Chichiri, Blantyre 3, Malawi.
| | - Angeziwa C Chirambo
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, P.O. Box 30096, Mahatma Ghandhi Road, Chichiri, Blantyre, Malawi
| | - Owen Nkoka
- Institute of Health and Wellbeing, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Walaa M El-Meidany
- Department of Nutrition, High Institute of Public Health, Alexandria University, Hiph 65 El-Horreya Avenue, El-Ibrahimia, Alexandria, Egypt
| | - Jessy Goupeyou-Youmsi
- Malaria Alert Centre, Kamuzu University of Health Sciences, Private Bag 360, Chichiri, Blantyre 3, Malawi
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Salazar-Castañón VH, Juárez-Avelar I, Legorreta-Herrera M, Rodriguez-Sosa M. Macrophage migration inhibitory factor contributes to immunopathogenesis during Plasmodium yoelii 17XL infection. Front Cell Infect Microbiol 2022; 12:968422. [PMID: 36093199 PMCID: PMC9449124 DOI: 10.3389/fcimb.2022.968422] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/08/2022] [Indexed: 01/04/2023] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a cytokine recognized regulator of the inflammatory immune response associated with several immune cells that produce inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-18, and TNF-α. This study aimed to understand the effect of MIF on the immune response and pathogenesis during Plasmodium infection. Wild-type (Wt) and MIF knockout (Mif -/-) mice were intravenously infected with 1×103 Plasmodium yoelii (Py) 17XL-parasitized red blood cells. Our data showed that Py17XL-infected Wt mice died 11 days postinfection, while Mif -/- mice showed reduced parasitemia and an increase in their survival at day 11 up to 58%, importantly they succumb up to day 21 postinfection. The increased survival rate in Mif -/- mice was associated with less severe cachexia and anemia as a result of a mixed Th1/Th2 cytokine profile, high levels of IL-12, IL-17/IL-4, and IL-10 in serum; and high levels of IL-4 and IL-10, and low levels of IFN-γ in spleen cells compared to Py17XL infected Wt mice. Moreover, macrophages (Mφs) from Mif -/- mice exhibited higher concentrations of IL-10 and IL-12 and reduced levels of TNF-α and nitric oxide (NO) compared to Py17XL-infected Wt mice. These results demonstrate that MIF has an important role in regulating the immune response associated with host pathogenesis and lethality, which is relevant to consider in preventing/reducing complications in Plasmodium infections.
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Affiliation(s)
- Víctor H. Salazar-Castañón
- Laboratorio de Inmunología Molecular, Unidad de Investigación Química Computacional, Síntesis y Farmacología en Moléculas de Interés Biológico, División de Estudios de Posgrado e Investigación, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - Imelda Juárez-Avelar
- Laboratorio de Inmunidad Innata, Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Estado de México, Mexico
| | - Martha Legorreta-Herrera
- Laboratorio de Inmunología Molecular, Unidad de Investigación Química Computacional, Síntesis y Farmacología en Moléculas de Interés Biológico, División de Estudios de Posgrado e Investigación, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico,*Correspondence: Miriam Rodriguez-Sosa, ; Martha Legorreta-Herrera,
| | - Miriam Rodriguez-Sosa
- Laboratorio de Inmunidad Innata, Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Estado de México, Mexico,*Correspondence: Miriam Rodriguez-Sosa, ; Martha Legorreta-Herrera,
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Ibraheem Y, Bayarsaikhan G, Inoue SI. Host immunity to Plasmodium infection: Contribution of Plasmodium berghei to our understanding of T cell-related immune response to blood-stage malaria. Parasitol Int 2022; 92:102646. [PMID: 35998816 DOI: 10.1016/j.parint.2022.102646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 10/15/2022]
Abstract
Malaria is a life-threatening disease caused by infection with Plasmodium parasites. The goal of developing an effective malaria vaccine is yet to be reached despite decades of massive research efforts. CD4+ helper T cells, CD8+ cytotoxic T cells, and γδ T cells are associated with immune responses to both liver-stage and blood-stage Plasmodium infection. The immune responses of T cell-lineages to Plasmodium infection are associated with both protection and immunopathology. Studies with mouse model of malaria contribute to our understanding of host immune response. In this paper, we focus primarily on mouse malaria model with blood-stage Plasmodium berghei infection and review our knowledge of T cell immune responses against Plasmodium infection. Moreover, we also discuss findings of experimental human studies. Uncovering the precise mechanisms of T cell-mediated immunity to Plasmodium infection can be accomplished through further investigations using mouse models of malaria with rodent Plasmodium parasites. Those findings would be invaluable to advance the efforts for development of an effective malaria vaccine.
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Affiliation(s)
- Yarob Ibraheem
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki-city, Nagasaki 852-8523, Japan
| | - Ganchimeg Bayarsaikhan
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki-city, Nagasaki 852-8523, Japan
| | - Shin-Ichi Inoue
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki-city, Nagasaki 852-8523, Japan.
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Chen C, Chen A, Yang Y. A diversified role for γδT cells in vector-borne diseases. Front Immunol 2022; 13:965503. [PMID: 36052077 PMCID: PMC9424759 DOI: 10.3389/fimmu.2022.965503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/28/2022] [Indexed: 11/17/2022] Open
Abstract
Vector-borne diseases have high morbidity and mortality and are major health threats worldwide. γδT cells represent a small but essential subpopulation of T cells. They reside in most human tissues and exert important functions in both natural and adaptive immune responses. Emerging evidence have shown that the activation and expansion of γδT cells invoked by pathogens play a diversified role in the regulation of host-pathogen interactions and disease progression. A better understanding of such a role for γδT cells may contribute significantly to developing novel preventative and therapeutic strategies. Herein, we summarize recent exciting findings in the field, with a focus on the role of γδT cells in the infection of vector-borne pathogens.
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Affiliation(s)
- Chen Chen
- Department of Microbiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- *Correspondence: Chen Chen, ; Yanan Yang,
| | - Aibao Chen
- Department of Cell Biology, School of Life Sciences, Anhui Medical University, Hefei, China
| | - Yanan Yang
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- *Correspondence: Chen Chen, ; Yanan Yang,
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Babatunde KA, Adenuga OF. Neutrophils in malaria: A double-edged sword role. Front Immunol 2022; 13:922377. [PMID: 35967409 PMCID: PMC9367684 DOI: 10.3389/fimmu.2022.922377] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 07/01/2022] [Indexed: 11/16/2022] Open
Abstract
Neutrophils are the most abundant leukocytes in human peripheral blood. They form the first line of defense against invading foreign pathogens and might play a crucial role in malaria. According to World Health Organization (WHO), malaria is a globally significant disease caused by protozoan parasites from the Plasmodium genus, and it's responsible for 627,000 deaths in 2020. Neutrophils participate in the defense response against the malaria parasite via phagocytosis and reactive oxygen species (ROS) production. Neutrophils might also be involved in the pathogenesis of malaria by the release of toxic granules and the release of neutrophil extracellular traps (NETs). Intriguingly, malaria parasites inhibit the anti-microbial function of neutrophils, thus making malaria patients more susceptible to secondary opportunistic Salmonella infections. In this review, we will provide a summary of the role of neutrophils during malaria infection, some contradicting mouse model neutrophil data and neutrophil-related mechanisms involved in malaria patients' susceptibility to bacterial infection.
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Affiliation(s)
- Kehinde Adebayo Babatunde
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
- Department of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI, United States
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Barateiro A, Junior ARC, Epiphanio S, Marinho CRF. Homeostasis Maintenance in Plasmodium-Infected Placentas: Is There a Role for Placental Autophagy During Malaria in Pregnancy? Front Immunol 2022; 13:931034. [PMID: 35898514 PMCID: PMC9309427 DOI: 10.3389/fimmu.2022.931034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/20/2022] [Indexed: 11/24/2022] Open
Abstract
Malaria represents a significant public health burden to populations living in developing countries. The disease takes a relevant toll on pregnant women, who are more prone to developing severe clinical manifestations. Inflammation triggered in response to P. falciparum sequestration inside the placenta leads to physiological and structural changes in the organ, reflecting locally disrupted homeostasis. Altogether, these events have been associated with poor gestational outcomes, such as intrauterine growth restriction and premature delivery, contributing to the parturition of thousands of African children with low birth weight. Despite significant advances in the field, the molecular mechanisms that govern these outcomes are still poorly understood. Herein, we discuss the idea of how some housekeeping molecular mechanisms, such as those related to autophagy, might be intertwined with the outcomes of malaria in pregnancy. We contextualize previous findings suggesting that placental autophagy is dysregulated in P. falciparum-infected pregnant women with complementary research describing the importance of autophagy in healthy pregnancies. Since the functional role of autophagy in pregnancy outcomes is still unclear, we hypothesize that autophagy might be essential for circumventing inflammation-induced stress in the placenta, acting as a cytoprotective mechanism that attempts to ensure local homeostasis and better gestational prognosis in women with malaria in pregnancy.
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Affiliation(s)
- André Barateiro
- Institute of Biomedical Sciences, Department of Parasitology, University of São Paulo, São Paulo, Brazil
| | | | - Sabrina Epiphanio
- School of Pharmaceutical Sciences, Department of Clinical and Toxicological Analysis, University of São Paulo, São Paulo, Brazil
| | - Claudio Romero Farias Marinho
- Institute of Biomedical Sciences, Department of Parasitology, University of São Paulo, São Paulo, Brazil
- *Correspondence: Claudio Romero Farias Marinho,
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Zoia M, Yesodha Subramanian B, Eriksson KK, Ravi MS, Yaghmaei S, Fellay I, Scolari B, Walch M, Mantel PY. Validation of Effective Extracellular Vesicles Isolation Methods Adapted to Field Studies in Malaria Endemic Regions. Front Cell Dev Biol 2022; 10:812244. [PMID: 35652104 PMCID: PMC9149222 DOI: 10.3389/fcell.2022.812244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 04/13/2022] [Indexed: 11/13/2022] Open
Abstract
Malaria affects the poorer regions of the world and is of tremendous health and economic burden for developing countries. Extracellular vesicles (EVs) are small vesicles released by almost any cells in the human body, including malaria infected red blood cells. Recent evidence shows that EVs might contribute to the pathogenesis of malaria. In addition, EVs hold considerable value in biomarker discovery. However, there are still significant gaps in our understanding of EV biology. So far most of our knowledge about EVs in malaria comes from in vitro work. More field studies are required to gain insight into their contribution to the disease and pathogenesis under physiological conditions. However, to perform research on EVs in low-income regions might be challenging due to the lack of appropriate equipment to isolate EVs. Therefore, there is a need to develop and validate EV extraction protocols applicable to poorly equipped laboratories. We established and validated two protocols for EV isolation from cell culture supernatants, rodent and human plasma. We compared polyethylene glycol (PEG) and salting out (SA) with sodium acetate for precipitation of EVs. We then characterized the EVs by Transmission Electron Microscopy (TEM), Western Blot, Size-exclusion chromatography (SEC), bead-based flow cytometry and protein quantification. Both protocols resulted in efficient purification of EVs without the need of expensive material or ultracentrifugation. Furthermore, the procedure is easily scalable to work with large and small sample volumes. Here, we propose that both of our approaches can be used in resource limited countries, therefore further helping to close the gap in knowledge of EVs during malaria.
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Affiliation(s)
- Matteo Zoia
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland.,Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Bibin Yesodha Subramanian
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Klara Kristin Eriksson
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Meera Sruthi Ravi
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Shekoofeh Yaghmaei
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Isabelle Fellay
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Brigitte Scolari
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Michael Walch
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
| | - Pierre-Yves Mantel
- Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, Anatomy Unit, University of Fribourg, Fribourg, Switzerland
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Crabtree JN, Caffrey DR, de Souza Silva L, Kurt-Jones EA, Dobbs K, Dent A, Fitzgerald KA, Golenbock DT. Lymphocyte crosstalk is required for monocyte-intrinsic trained immunity to Plasmodium falciparum. J Clin Invest 2022; 132:e139298. [PMID: 35642634 PMCID: PMC9151696 DOI: 10.1172/jci139298] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 04/21/2022] [Indexed: 01/16/2023] Open
Abstract
Plasmodium falciparum (P. falciparum) induces trained innate immune responses in vitro, where initial stimulation of adherent PBMCs with P. falciparum-infected RBCs (iRBCs) results in hyperresponsiveness to subsequent ligation of TLR2. This response correlates with the presence of T and B lymphocytes in adherent PBMCs, suggesting that innate immune training is partially due to adaptive immunity. We found that T cell-depleted PBMCs and purified monocytes alone did not elicit hyperproduction of IL-6 and TNF-α under training conditions. Analysis of P. falciparum-trained PBMCs showed that DCs did not develop under control conditions, and IL-6 and TNF-α were primarily produced by monocytes and DCs. Transwell experiments isolating purified monocytes from either PBMCs or purified CD4+ T cells, but allowing diffusion of secreted proteins, enabled monocytes trained with iRBCs to hyperproduce IL-6 and TNF-α after TLR restimulation. Purified monocytes stimulated with IFN-γ hyperproduced IL-6 and TNF-α, whereas blockade of IFN-γ in P. falciparum-trained PBMCs inhibited trained responses. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) on monocytes from patients with malaria showed persistently open chromatin at genes that appeared to be trained in vitro. Together, these findings indicate that the trained immune response of monocytes to P. falciparum is not completely cell intrinsic but depends on soluble signals from lymphocytes.
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Affiliation(s)
- Juliet N. Crabtree
- Program in Innate Immunity and
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Daniel R. Caffrey
- Program in Innate Immunity and
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Leandro de Souza Silva
- Program in Innate Immunity and
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Evelyn A. Kurt-Jones
- Program in Innate Immunity and
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | | | - Arlene Dent
- Case Western University, Cleveland, Ohio, USA
| | - Katherine A. Fitzgerald
- Program in Innate Immunity and
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Douglas T. Golenbock
- Program in Innate Immunity and
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
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Leleu I, Alloo J, Cazenave PA, Roland J, Pied S. Autophagy Pathways in the Genesis of Plasmodium-Derived Microvesicles: A Double-Edged Sword? Life (Basel) 2022; 12:life12030415. [PMID: 35330166 PMCID: PMC8955828 DOI: 10.3390/life12030415] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/02/2022] [Accepted: 03/08/2022] [Indexed: 11/16/2022] Open
Abstract
Malaria, caused by Plasmodium species (spp.), is a deadly parasitic disease that results in approximately 400,000 deaths per year globally. Autophagy pathways play a fundamental role in the developmental stages of the parasite within the mammalian host. They are also involved in the production of Plasmodium-derived extracellular vesicles (EVs), which play an important role in the infection process, either by providing nutrients for parasite growth or by contributing to the immunopathophysiology of the disease. For example, during the hepatic stage, Plasmodium-derived EVs contribute to parasite virulence by modulating the host immune response. EVs help in evading the different autophagy mechanisms deployed by the host for parasite clearance. During cerebral malaria, on the other hand, parasite-derived EVs promote an astrocyte-mediated inflammatory response, through the induction of a non-conventional host autophagy pathway. In this review, we will discuss the cross-talk between Plasmodium-derived microvesicles and autophagy, and how it influences the outcome of infection.
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Piao X, Ma Y, Liu S, Hou N, Chen Q. A Novel Thioredoxin-Like Protein of Babesia microti Involved in Parasite Pathogenicity. Front Cell Infect Microbiol 2022; 12:826818. [PMID: 35252036 PMCID: PMC8892138 DOI: 10.3389/fcimb.2022.826818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/26/2022] [Indexed: 11/13/2022] Open
Abstract
Babesiosis poses a serious threat to immunocompromised individuals and the major etiological species of Babesia for human babesiosis is Babesia microti. Merozoites are a critical stage in the life cycle of Babesia microti. Several merozoite proteins have been demonstrated to play important roles in this process; however, most of the merozoite proteins of B. microti remain unknown. In the present study, we identified a novel merozoite protein of B. microti with similar structure to the thioredoxin (Trx)-like domain of the Trx family, which was named as B. microti Trx-like protein (BmTLP). Western blot assays demonstrated that this protein was expressed by B. microti during the erythrocytic infection process, and its expression peaked on day 7 post-infection in vivo. Immunofluorescence assay further showed that this protein is mainly expressed in B. microti merozoites. BmTLP hold both heparin- and erythrocyte-binding properties, which are critical functions of invasion-related proteins. Immunization with recombinant BmTLP imparted significant protection against B. microti infection in mice. Taken together, these results suggest that the novel merozoite protein, BmTLP, is an important pathogenic molecule of B. microti and may be a possible target for the design of babesiosis control strategy.
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Affiliation(s)
- Xianyu Piao
- National Health Commission of the People’s Republic of China (NHC) Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yu Ma
- National Health Commission of the People’s Republic of China (NHC) Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shuai Liu
- National Health Commission of the People’s Republic of China (NHC) Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Nan Hou
- National Health Commission of the People’s Republic of China (NHC) Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- *Correspondence: Nan Hou, ; Qijun Chen,
| | - Qijun Chen
- National Health Commission of the People’s Republic of China (NHC) Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Key Laboratory of Livestock Infectious Diseases in Northeast China, Ministry of Education, Key Laboratory of Zoonosis, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
- The Research Unit for Pathogenic Mechanisms of Zoonotic Parasites, Chinese Academy of Medical Sciences, Shenyang, China
- *Correspondence: Nan Hou, ; Qijun Chen,
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Pollenus E, Gouwy M, Van den Steen PE. Neutrophils in malaria: the good, the bad or the ugly? Parasite Immunol 2022; 44:e12912. [PMID: 35175636 DOI: 10.1111/pim.12912] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/09/2022] [Accepted: 02/13/2022] [Indexed: 11/30/2022]
Abstract
Neutrophils are the most abundant circulating leukocytes in human peripheral blood. They are often the first cells to respond to an invading pathogen and might therefore play an important role in malaria. Malaria is a globally important disease caused by Plasmodium parasites, responsible for more than 400 000 deaths each year. Most of these deaths are caused by complications, including cerebral malaria, severe malarial anemia, placental malaria, renal injury, metabolic problems and malaria-associated acute respiratory distress syndrome. Neutrophils contribute in the immune defense against malaria, through clearance of parasites via phagocytosis, production of reactive oxygen species and release of neutrophil extracellular traps (NETs). However, Plasmodium parasites diminish antibacterial functions of neutrophils, making patients more susceptible to other infections. Neutrophils might also be involved in the development of malaria complications, for example via the release of toxic granules and NETs. However, technical pitfalls in the determination of the roles of neutrophils have caused contradicting results. Further investigations need to consider these pitfalls, in order to elucidate the role of neutrophils in malaria complications.
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Affiliation(s)
- Emilie Pollenus
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, University of Leuven, Leuven, Belgium
| | - Mieke Gouwy
- Laboratory of Molecular immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, University of Leuven, Leuven, Belgium
| | - Philippe E Van den Steen
- Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, University of Leuven, Leuven, Belgium
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45
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Rutin ameliorates malaria pathogenesis by modulating inflammatory mechanism: an in vitro and in vivo study. Inflammopharmacology 2022; 30:159-171. [DOI: 10.1007/s10787-021-00920-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/25/2021] [Indexed: 12/19/2022]
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46
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Georgiev V, Avalos-Padilla Y, Fernàndez-Busquets X, Dimova R. Femtoliter Injection of ESCRT-III Proteins into Adhered Giant Unilamellar Vesicles. Bio Protoc 2022; 12:e4328. [DOI: 10.21769/bioprotoc.4328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 11/12/2021] [Accepted: 01/06/2022] [Indexed: 11/02/2022] Open
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47
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Mohanty S, Gupta AC, Maurya AK, Shanker K, Pal A, Bawankule DU. Ameliorative Effects of Dietary Ellagic Acid Against Severe Malaria Pathogenesis by Reducing Cytokine Storms and Oxidative Stress. Front Pharmacol 2021; 12:777400. [PMID: 34975479 PMCID: PMC8717919 DOI: 10.3389/fphar.2021.777400] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/11/2021] [Indexed: 11/24/2022] Open
Abstract
Ellagic acid (EA), a fruit- and vegetable-derived flavonoid, has been reported for multiple pharmacological activities, which encouraged us to examine its useful effect in severe malaria pathogenesis, especially malaria-induced cytokine storms and oxidative stress linked to damage in major organs. Malaria was induced by injecting Plasmodium berghei–infected RBCs intraperitoneally into the mice. EA was given orally (5, 10, and 20 mg/kg) following Peter’s 4-day suppression test. EA exhibited the suppression of parasitemia, production of inflammatory cytokine storms and oxidative stress marker level quantified from vital organs significantly and an increase in hemoglobin, blood glucose, and mean survival time compared to the vehicle-treated infected group. EA administration also restored the blood–brain barrier integrity evidenced through Evans blue staining. Furthermore, we demonstrated the protecting effect of EA in LPS-induced inflammatory cytokine storms and oxidative stress in glial cells. The present study conclude that ellagic acid is able to alleviate severe malaria pathogenesis by reducing cytokine storms and oxidative stress–induced by malarial parasites. It also attributed promising antimalarial activity and afforded to improve the blood glucose and hemoglobin levels in treated mice. These research findings suggested the suitability of ellagic acid as a useful bioflavonoid for further study for the management of severe malaria pathogenesis.
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Affiliation(s)
- Shilpa Mohanty
- In-vivo Testing Laboratory, Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Amit Chand Gupta
- In-vivo Testing Laboratory, Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
| | - Anil Kumar Maurya
- In-vivo Testing Laboratory, Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
| | - Karuna Shanker
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- Analytical Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
| | - Anirban Pal
- In-vivo Testing Laboratory, Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Dnyaneshwar Umrao Bawankule
- In-vivo Testing Laboratory, Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
- *Correspondence: Dnyaneshwar Umrao Bawankule,
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48
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Leleu I, Genete D, Desnoulez SS, Saidi N, Brodin P, Lafont F, Tomavo S, Pied S. A noncanonical autophagy is involved in the transfer of Plasmodium-microvesicles to astrocytes. Autophagy 2021; 18:1583-1598. [PMID: 34747313 DOI: 10.1080/15548627.2021.1993704] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Cerebral malaria is a neuroinflammatory disease induced by P. falciparum infection. In animal models, the neuro-pathophysiology of cerebral malaria results from the sequestration of infected red blood cells (iRBCs) in microvessels that promotes the activation of glial cells in the brain. This activation provokes an exacerbated inflammatory response characterized by the secretion of proinflammatory cytokines and chemokines, leading to brain infiltration by pathogenic CD8+ T lymphocytes. Astrocytes are a major subtype of brain glial cells that play an important role in maintaining the homeostasis of the central nervous system, the integrity of the brain-blood barrier and in mounting local innate immune responses. We have previously shown that parasitic microvesicles (PbA-MVs) are transferred from iRBCs to astrocytes. The present study shows that an unconventional LC3-mediated autophagy pathway independent of ULK1 is involved in the transfer and degradation of PbA-MVs inside the astrocytes. We further demonstrate that inhibition of the autophagy process by treatment with 3-methyladenine blocks the transfer of PbA-MVs, which remain localized in the astrocytic cell membrane and are not internalized. Moreover, bafilomycin A1, another drug against autophagy promotes the accumulation of PbA-MVs inside the astrocytes by inhibiting the fusion with lysosomes, and prevents ECM in mice infected with PbA. Finally, we establish that RUBCN/rubicon or ATG5 silencing impede astrocyte production in CCL2 and CXCL10 chemokines induced by PbA stimulation. Altogether, our data suggest that a non-canonical autophagy-lysosomal pathway may play a key role in cerebral malaria through regulation of brain neuro-inflammation by astrocytes.
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Affiliation(s)
- Inès Leleu
- Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France
| | - Delphine Genete
- Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France
| | | | - Nasreddine Saidi
- Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France
| | - Priscille Brodin
- Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France
| | - Frank Lafont
- Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France.,Institut Pasteur De Lille, Univ. Lille, Cnrs, Inserm, Chu Lille, Lille, France
| | - Stanislas Tomavo
- Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif-sur-Yvette, France
| | - Sylviane Pied
- Center for Infection and Immunity of Lille-CIIL, Institut Pasteur De Lille, Univ. Lille, Lille, France
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49
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Longoni SS, Tiberti N, Bisoffi Z, Piubelli C. Monoclonal Antibodies for Protozoan Infections: A Future Reality or a Utopic Idea? Front Med (Lausanne) 2021; 8:745665. [PMID: 34712683 PMCID: PMC8545981 DOI: 10.3389/fmed.2021.745665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/17/2021] [Indexed: 12/15/2022] Open
Abstract
Following the SARS-CoV-2 pandemic, several clinical trials have been approved for the investigation of the possible use of mAbs, supporting the potential of this technology as a therapeutic approach for infectious diseases. The first monoclonal antibody (mAb), Muromonab CD3, was introduced for the prevention of kidney transplant rejection more than 30 years ago; since then more than 100 mAbs have been approved for therapeutic purposes. Nonetheless, only four mAbs are currently employed for infectious diseases: Palivizumab, for the prevention of respiratory syncytial virus (RSV) infections, Raxibacumab and Obiltoxaximab, for the prophylaxis and treatment against anthrax toxin and Bezlotoxumab, for the prevention of Clostridium difficile recurrence. Protozoan infections are often neglected diseases for which effective and safe chemotherapies are generally missing. In this context, drug resistance and drug toxicity are two crucial problems. The recent advances in bioinformatics, parasite genomics, and biochemistry methodologies are contributing to better understand parasite biology, which is essential to guide the development of new therapies. In this review, we present the efforts that are being made in the evaluation of mAbs for the prevention or treatment of leishmaniasis, Chagas disease, malaria, and toxoplasmosis. Particular emphasis will be placed on the potential strengths and weaknesses of biological treatments in the control of these protozoan diseases that are still affecting hundreds of thousands of people worldwide.
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Affiliation(s)
- Silvia Stefania Longoni
- Department of Infectious-Tropical Diseases and Microbiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Sacro Cuore Don Calabria Hospital, Verona, Italy
| | - Natalia Tiberti
- Department of Infectious-Tropical Diseases and Microbiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Sacro Cuore Don Calabria Hospital, Verona, Italy
| | - Zeno Bisoffi
- Department of Infectious-Tropical Diseases and Microbiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Sacro Cuore Don Calabria Hospital, Verona, Italy.,Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Chiara Piubelli
- Department of Infectious-Tropical Diseases and Microbiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Sacro Cuore Don Calabria Hospital, Verona, Italy
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50
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Scheunemann JF, Reichwald JJ, Korir PJ, Kuehlwein JM, Jenster LM, Hammerschmidt-Kamper C, Lewis MD, Klocke K, Borsche M, Schwendt KE, Soun C, Thiebes S, Limmer A, Engel DR, Mueller AK, Hoerauf A, Hübner MP, Schumak B. Eosinophils Suppress the Migration of T Cells Into the Brain of Plasmodium berghei-Infected Ifnar1-/- Mice and Protect Them From Experimental Cerebral Malaria. Front Immunol 2021; 12:711876. [PMID: 34659202 PMCID: PMC8514736 DOI: 10.3389/fimmu.2021.711876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 09/13/2021] [Indexed: 11/29/2022] Open
Abstract
Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA (PbAAma1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1-/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8+ T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1-/- mice and wild type mice suffering from ECM. Importantly, CD8+ T cells were increased in the spleens of ECM-protected Ifnar1-/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8+ T cell infiltration into the brain and increased ECM induction in PbAAma1OVA-infected Ifnar1-/- mice. However, eosinophil-depletion did not reduce the CD8+ T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8+ T cell migration and proliferation during PbAAma1OVA-infection in Ifnar1-/- mice and thereby are contributing to the protection from ECM.
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Affiliation(s)
- Johanna F Scheunemann
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Julia J Reichwald
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Patricia Jebett Korir
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Janina M Kuehlwein
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Lea-Marie Jenster
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | | | - Matthew D Lewis
- Parasitology Unit, Centre for Infectious Diseases, Heidelberg University Hospital, Heidelberg, Germany
| | - Katrin Klocke
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Max Borsche
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Kim E Schwendt
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
| | - Camille Soun
- Institute for Experimental Immunology and Imaging, University Hospital Essen, Essen, Germany
| | - Stephanie Thiebes
- Institute for Experimental Immunology and Imaging, University Hospital Essen, Essen, Germany
| | - Andreas Limmer
- Clinic for Anesthesiology and Intensive Care, University Hospital Essen, Essen, Germany
| | - Daniel R Engel
- Institute for Experimental Immunology and Imaging, University Hospital Essen, Essen, Germany
| | - Ann-Kristin Mueller
- Parasitology Unit, Centre for Infectious Diseases, Heidelberg University Hospital, Heidelberg, Germany.,German Center for Infection Research (DZIF), Heidelberg, Germany
| | - Achim Hoerauf
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.,German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany
| | - Marc P Hübner
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.,German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Bonn, Germany
| | - Beatrix Schumak
- Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
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