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Arya A, Chaudhry S, Yadav K, Tamang S, Meena SS, Matlani M, Pande V, Singh V. Screening Clinical, Laboratory and Host Markers for Diagnosis of Disease Severity in Plasmodium vivax Clinical Samples. Indian J Microbiol 2024; 64:1278-1289. [PMID: 39282159 PMCID: PMC11399495 DOI: 10.1007/s12088-024-01324-4] [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: 12/29/2023] [Accepted: 06/07/2024] [Indexed: 09/18/2024] Open
Abstract
Malaria is one of the most infectious disease that affects lives of million people throughout the world. Recently, there are several reports which indicate Plasmodium vivax (P. vivax) causing severe disease in infected patients from different parts of the world. For P. vivax disease severity, the data related to immunological and inflammatory status in human host is very limited. In the present study clinical parameters, cytokine profile and integrin gene were analyzed in P. vivax clinical patients. A total of 169 P. vivax samples were collected and categorized into severe vivax malaria (SVM; n = 106) and non-severe vivax malaria (NSVM; n = 63) according to WHO severity criteria. We measured host biomarker levels of interferon (IFN-γ), superoxide dismutase (SOD-1), interleukins viz. (IL-6, IL-10), and tumor necrosis factor (TNF-α) in patient plasma samples by ELISA for pro- and anti-inflammatory cytokines in severe malaria. Host integrin gene was genotyped using PCR assay. In our study, thrombocytopenia and anemia were major symptoms in severe P. vivax patients. In analyzed SVM and NSVM groups a significant increase in cytokine levels (IL-10, IL-6, and TNF-α) and anti-oxidant enzyme SOD-1 was found. Our study results also showed a higher pro-inflammatory (TNF-α, IL-6 and IFN-γ) to anti-inflammatory (IL-10) cytokine ratio in severe vivax patients. Integrin gene showed no mutation with respect to thrombocytopenic patients among clinically defined groups. It was observed that severe vivax cases had increased cytokine levels irrespective of age and sex of the patients along with thrombocytopenia and other clinical manifestations. The results of current findings could serve as baseline data for evaluating severe malaria parameters during P. vivax infections and will help in developing an effective biomarker for diagnosis. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s12088-024-01324-4.
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Affiliation(s)
- Aditi Arya
- Cell Biology Laboratory and Malaria Parasite Bank, ICMR-National Institute of Malaria Research, New Delhi, India
- Department of Biotechnology, Kumaun University, Nainital, Uttarakhand 263001 India
| | - Shewta Chaudhry
- Cell Biology Laboratory and Malaria Parasite Bank, ICMR-National Institute of Malaria Research, New Delhi, India
- Department of Biotechnology, Kumaun University, Nainital, Uttarakhand 263001 India
| | - Karmveer Yadav
- Cell Biology Laboratory and Malaria Parasite Bank, ICMR-National Institute of Malaria Research, New Delhi, India
| | - Suman Tamang
- Cell Biology Laboratory and Malaria Parasite Bank, ICMR-National Institute of Malaria Research, New Delhi, India
| | - Shyam Sundar Meena
- Department of Pediatrics VMMC, Safdarjung Hospital Campus, New Delhi, India
| | - Monika Matlani
- Department of Microbiology, VMMC, Safdarjung Hospital Campus, New Delhi, India
| | - Veena Pande
- Department of Biotechnology, Kumaun University, Nainital, Uttarakhand 263001 India
| | - Vineeta Singh
- Cell Biology Laboratory and Malaria Parasite Bank, ICMR-National Institute of Malaria Research, New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh India
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Simião GM, Parreira KS, Klein SG, Ferreira FB, Freitas FDS, Silva EFD, Silva NM, Silva MVD, Lima WR. Involvement of Inflammatory Cytokines, Renal NaPi-IIa Cotransporter, and TRAIL Induced-Apoptosis in Experimental Malaria-Associated Acute Kidney Injury. Pathogens 2024; 13:376. [PMID: 38787228 DOI: 10.3390/pathogens13050376] [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: 02/09/2024] [Revised: 04/24/2024] [Accepted: 04/26/2024] [Indexed: 05/25/2024] Open
Abstract
The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA was used to investigate the relationship among pro-inflammatory cytokines, alterations in renal function biomarkers, and the induction of the TRAIL apoptosis pathway during malaria-associated acute kidney injury (AKI). Renal function was evaluated through the measurement of plasma creatinine and blood urea nitrogen (BUN). The mRNA expression of several cytokines and NaPi-IIa was quantified. Kidney sections were examined and cytokine levels were assessed using cytometric bead array (CBA) assays. The presence of glomerular IgG deposits and apoptosis-related proteins were investigated using in situ immunofluorescence assays and quantitative real-time PCR, respectively. NaPi-IIa downregulation in the kidneys provided novel insights into the pathogenesis of hypophosphatemia during CM. Histopathological analysis revealed characteristic features of severe malaria-associated nephritis, including glomerular collapse and tubular alterations. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, were upregulated. The TRAIL apoptosis pathway was significantly activated, implicating its role in renal apoptosis. The observed alterations in renal biomarkers and the downregulation of NaPi-IIa shed light on potential mechanisms contributing to renal dysfunction in ECM. The intricate balance between pro- and anti-inflammatory cytokines, along with the activation of the TRAIL apoptosis pathway, highlights the complexity of malaria-associated AKI and provides new therapeutic targets.
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Affiliation(s)
- Gustavo Martins Simião
- Faculty of Health Sciences, Federal University of Rondonopolis, Rondonópolis 78736-900, MT, Brazil
| | | | - Sandra Gabriela Klein
- Laboratory of Biotechnology in Experimental Models, Federal University of Uberlandia, Uberlândia 38410-337, MG, Brazil
| | - Flávia Batista Ferreira
- Laboratory of Biotechnology in Experimental Models, Federal University of Uberlandia, Uberlândia 38410-337, MG, Brazil
- Institute of Biomedical Sciences, Federal University of Uberlandia, Uberlândia 38405-318, MG, Brazil
| | | | | | - Neide Maria Silva
- Institute of Biomedical Sciences, Federal University of Uberlandia, Uberlândia 38405-318, MG, Brazil
| | - Murilo Vieira da Silva
- Laboratory of Biotechnology in Experimental Models, Federal University of Uberlandia, Uberlândia 38410-337, MG, Brazil
| | - Wânia Rezende Lima
- Faculty of Health Sciences, Federal University of Rondonopolis, Rondonópolis 78736-900, MT, Brazil
- Institute of Biotechnology, Federal University of Catalao, Catalão 75706-881, GO, Brazil
- Laboratory of Biotechnology in Experimental Models, Federal University of Uberlandia, Uberlândia 38410-337, MG, Brazil
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Sterba G, Sterba Y. Parasitic and Fungal Triggers of Cytokine Storm Syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:293-305. [PMID: 39117823 DOI: 10.1007/978-3-031-59815-9_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
Infections caused by parasites and fungi can trigger the cytokine storm syndrome (CSS). These infections causing CSS can occur together with acquired immunodeficiencies, lymphomas, the use of immunosuppressive medications, transplant recipients, cancer, autoinflammatory, and autoimmune diseases or less frequently in healthy individuals. Histoplasma, Leishmania, Plasmodium, and Toxoplasma are the most frequent organisms associated with a CSS. It is very important to determine a previous travel history when evaluating a patient with a CSS triggered by these organisms as this may be the clue to the causal agent. Even though CSS is treated with specific therapies, an effort to find the causal organism should be carried out since the treatment of the infectious organism may stop the CSS. Diagnosing a CSS in the presence of parasitic or fungal sepsis should also lead to the study of an altered cytotoxic or hemophagocytic response in the susceptible host.
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Prasad R, Patel RS, Mishra SP, Singh A, Abhinay A, Singh TB. Cerebrospinal fluid tumor necrosis factor-alpha (TNF-α) levels in children with cerebral malaria. J Trop Pediatr 2023; 69:fmad032. [PMID: 37805828 DOI: 10.1093/tropej/fmad032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/09/2023]
Abstract
This prospective cross-sectional study evaluated the diagnostic and prognostic role of cerebrospinal fluid (CSF) tumor necrosis factor-alpha (TNF-α) in children with cerebral malaria (CM) and its role in the differentiation of CM from non-cerebral severe malaria. CSF TNF-α was measured using a human TNF-α enzyme-linked immunosorbent assay kit of 39 cases of CM and 19 cases of non-cerebral severe malaria. CSF TNF-α levels were significantly higher in CM (p < 0.001). Based on the receiver operating characteristics curve, a cutoff value of CSF TNF-α was 5.7 pg/ml for diagnosis of CM with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 87.2%, 94.7%, 97.1% and 78.3% respectively. The cutoff value of CSF TNF-α was 13.7 pg/ml for predicting adverse outcomes in CM with sensitivity, specificity, PPV and NPV of 100%, 96.8%, 88.9% and 100%, respectively. However, the cutoff value of CSF TNF-α was 4.96 pg/ml for predicting adverse outcomes in non-cerebral severe malaria with a sensitivity, specificity, PPV and NPV of 100%, 94.1%, 88.9% and 100% respectively. So, CSF TNF-α is an excellent biomarker and can be used as a diagnostic and prognostic tool. More studies are needed to establish CSF TNF-α as a predictor of neurological sequelae.
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Affiliation(s)
- Rajniti Prasad
- Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Raghvendra Singh Patel
- Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - S P Mishra
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Ankur Singh
- Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Abhishek Abhinay
- Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Tej Bali Singh
- Department of Biostatistics, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
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Wideman SK, Frost JN, Richter FC, Naylor C, Lopes JM, Viveiros N, Teh MR, Preston AE, White N, Yusuf S, Draper SJ, Armitage AE, Duarte TL, Drakesmith H. Cellular iron governs the host response to malaria. PLoS Pathog 2023; 19:e1011679. [PMID: 37812650 PMCID: PMC10586691 DOI: 10.1371/journal.ppat.1011679] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/19/2023] [Accepted: 09/11/2023] [Indexed: 10/11/2023] Open
Abstract
Malaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasis TfrcY20H/Y20H mice appear healthy and are not anaemic. However, TfrcY20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that TfrcY20H/Y20H mice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead, P. chabaudi infected TfrcY20H/Y20H mice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production. Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, as ex vivo iron supplementation fully recovered CD4+ T cell and B cell function. Despite the inhibited immune response and increased parasitaemia, TfrcY20H/Y20H mice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria.
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Affiliation(s)
- Sarah K. Wideman
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Joe N. Frost
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Felix C. Richter
- Kennedy Institute of Rheumatology, Roosevelt Drive, Oxford, United Kingdom
| | - Caitlin Naylor
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - José M. Lopes
- Faculty of Medicine (FMUP) and Institute of Molecular Pathology, Immunology (IPATIMUP), University of Porto, Porto, Portugal
- Instituto de Biologia Molecular e Celular & Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
| | - Nicole Viveiros
- Instituto de Biologia Molecular e Celular & Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
| | - Megan R. Teh
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Alexandra E. Preston
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Natasha White
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Shamsideen Yusuf
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Simon J. Draper
- Department of Biochemistry, University of Oxford, South Parks Road, Oxford, United Kingdom
| | - Andrew E. Armitage
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Tiago L. Duarte
- Faculty of Medicine (FMUP) and Institute of Molecular Pathology, Immunology (IPATIMUP), University of Porto, Porto, Portugal
- Instituto de Biologia Molecular e Celular & Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
| | - Hal Drakesmith
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
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Harit K, Bhattacharjee R, Matuschewski K, Becker J, Kalinke U, Schlüter D, Nishanth G. The deubiquitinating enzyme OTUD7b protects dendritic cells from TNF-induced apoptosis by stabilizing the E3 ligase TRAF2. Cell Death Dis 2023; 14:480. [PMID: 37516734 PMCID: PMC10387084 DOI: 10.1038/s41419-023-06014-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 05/19/2023] [Accepted: 07/19/2023] [Indexed: 07/31/2023]
Abstract
The cytokine tumor necrosis factor (TNF) critically regulates the intertwined cell death and pro-inflammatory signaling pathways of dendritic cells (DCs) via ubiquitin modification of central effector molecules, but the intrinsic molecular switches deciding on either pathway are incompletely defined. Here, we uncover that the ovarian tumor deubiquitinating enzyme 7b (OTUD7b) prevents TNF-induced apoptosis of DCs in infection, resulting in efficient priming of pathogen-specific CD8+ T cells. Mechanistically, OTUD7b stabilizes the E3 ligase TNF-receptor-associated factor 2 (TRAF2) in human and murine DCs by counteracting its K48-ubiquitination and proteasomal degradation. TRAF2 in turn facilitates K63-linked polyubiquitination of RIPK1, which mediates activation of NF-κB and MAP kinases, IL-12 production, and expression of anti-apoptotic cFLIP and Bcl-xL. We show that mice with DC-specific OTUD7b-deficiency displayed DC apoptosis and a failure to induce CD8+ T cell-mediated brain pathology, experimental cerebral malaria, in a murine malaria infection model. Together, our data identify the deubiquitinating enzyme OTUD7b as a central molecular switch deciding on survival of human and murine DCs and provides a rationale to manipulate DC responses by targeting their ubiquitin network downstream of the TNF receptor pathway.
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Affiliation(s)
- Kunjan Harit
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany
| | - Rituparna Bhattacharjee
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany
| | - Kai Matuschewski
- Department of Molecular Parasitology, Institute of Biology, Humboldt University, 10115, Berlin, Germany
| | - Jennifer Becker
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany
| | - Dirk Schlüter
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany
| | - Gopala Nishanth
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625, Hannover, Germany.
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Ademola SA, Bamikole OJ, Amodu OK. Is TNF alpha a mediator in the co-existence of malaria and type 2 diabetes in a malaria endemic population? Front Immunol 2023; 14:1028303. [PMID: 37215099 PMCID: PMC10196125 DOI: 10.3389/fimmu.2023.1028303] [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: 08/25/2022] [Accepted: 04/25/2023] [Indexed: 05/24/2023] Open
Abstract
Malaria remains a disease of public health importance globally, especially in sub-Saharan Africa. Malaria deaths reduced globally steadily between 2000-2019, however there was a 10% increase in 2020 due to disruptions in medical service during the COVID-19 pandemic. Globally, about 96% of malaria deaths occurred in 29 countries; out of which, four countries (Nigeria, the Democratic Republic of the Congo, the Niger, and the United Republic of Tanzania) accounted for just over half of the malaria deaths. Nigeria leads the four countries with the highest malaria deaths (accounting for 31% globally). Parallelly, sub-Saharan Africa is faced with a rise in the incidence of Type 2 diabetes (T2D). Until recently, T2D was a disease of adulthood and old age. However, this is changing as T2D in children and adolescents is becoming an increasingly important public health problem. Nigeria has been reported to have the highest burden of diabetes in Africa with a prevalence of 5.77% in the country. Several studies conducted in the last decade investigating the interaction between malaria and T2D in developing countries have led to the emergence of the intra-uterine hypothesis. The hypothesis has arisen as a possible explanation for the rise of T2D in malaria endemic areas; malaria in pregnancy could lead to intra-uterine stress which could contribute to low birth weight and may be a potential cause of T2D later in life. Hence, previous, and continuous exposure to malaria infection leads to a higher risk of T2D. Current and emerging evidence suggests that an inflammation-mediated link exists between malaria and eventual T2D emergence. The inflammatory process thus, is an important link for the co-existence of malaria and T2D because these two diseases are inflammatory-related. A key feature of T2D is systemic inflammation, characterized by the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) which leads to impaired insulin signaling. Malaria infection is an inflammatory disease in which TNF-α also plays a major role. TNF-α plays an important role in the pathogenesis and development of malaria and T2D. We therefore hypothesize that TNF-α is an important link in the increasing co-existence of T2D.
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Modi M, Mahantshetty P, Gandhi P. A Case Of Spontaneous Acute Subdural Hematoma In Plasmodium Falciparum Malaria: A Systematic Review. BRAIN HEMORRHAGES 2023. [DOI: 10.1016/j.hest.2023.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023] Open
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Royo J, Vianou B, Accrombessi M, Kinkpé E, Ayédadjou L, Dossou-Dagba I, Ladipo Y, Alao MJ, Bertin GI, Cot M, Boumédiène F, Houzé S, Faucher JF, Aubouy A, NeuroCM Group AffolabiDissouAjzenbergDanielBiokouBibianeBrissetJosselin10DegbeloJean-Eudes2DeloronPhilippeDramaneLatifouJafari-GuemouriSayehKamaliddinClaireLabrunieAnaïsLathiereThomasMassougbodjiAchille2MowendabekaAudreyPapinJadePipyBernardPreuxPierre-MarieRaymondeauMarieSossouDariusTecherBrigitteWatierLaurence. Elevated plasma interleukin-8 as a risk factor for mortality in children presenting with cerebral malaria. Infect Dis Poverty 2023; 12:8. [PMID: 36759905 PMCID: PMC9909955 DOI: 10.1186/s40249-023-01059-2] [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: 11/16/2022] [Accepted: 01/26/2023] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Cerebral malaria (CM) is a neuropathology which remains one of the deadliest forms of malaria among African children. The kinetics of the pathophysiological mechanisms leading to neuroinflammation and the death or survival of patients during CM are still poorly understood. The increasing production of cytokines, chemokines and other actors of the inflammatory and oxidative response by various local actors in response to neuroinflammation plays a major role during CM, participating in both the amplification of the neuroinflammation phenomenon and its resolution. In this study, we aimed to identify risk factors for CM death among specific variables of inflammatory and oxidative responses to improve our understanding of CM pathogenesis. METHODS Children presenting with CM (n = 70) due to P. falciparum infection were included in southern Benin and divided according to the clinical outcome into 50 children who survived and 20 who died. Clinical examination was complemented by fundoscopic examination and extensive blood biochemical analysis associated with molecular diagnosis by multiplex PCR targeting 14 pathogens in the patients' cerebrospinal fluid to rule out coinfections. Luminex technology and enzyme immunoassay kits were used to measure 17 plasma and 7 urinary biomarker levels, respectively. Data were analysed by univariate analysis using the nonparametric Mann‒Whitney U test and Pearson's Chi2 test. Adjusted and multivariate analyses were conducted separately for plasma and urinary biomarkers to identify CM mortality risk factors. RESULTS Univariate analysis revealed higher plasma levels of tumour necrosis factor (TNF), interleukin-1beta (IL-1β), IL-10, IL-8, C-X-C motif chemokine ligand 9 (CXCL9), granzyme B, and angiopoietin-2 and lower urinary levels of prostanglandine E2 metabolite (PGEM) in children who died compared to those who survived CM (Mann-Whitney U-test, P-values between 0.03 and < 0.0001). The multivariate logistic analysis highlighted elevated plasma levels of IL-8 as the main risk factor for death during CM (adjusted odd ratio = 14.2, P-value = 0.002). Values obtained during follow-up at D3 and D30 revealed immune factors associated with disease resolution, including plasma CXCL5, C-C motif chemokine ligand 17 (CCL17), CCL22, and urinary 15-F2t-isoprostane. CONCLUSIONS The main risk factor of death during CM was thus elevated plasma levels of IL-8 at inclusion. Follow-up of patients until D30 revealed marker profiles of disease aggravation and resolution for markers implicated in neutrophil activation, endothelium activation and damage, inflammatory and oxidative response. These results provide important insight into our understanding of CM pathogenesis and clinical outcome and may have important therapeutic implications.
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Affiliation(s)
- Jade Royo
- grid.508721.9UMR152 PHARMADEV, IRD, UPS, Toulouse University, 35 Chemin Des Maraichers, 31400 Toulouse, France
| | - Bertin Vianou
- grid.508721.9UMR152 PHARMADEV, IRD, UPS, Toulouse University, 35 Chemin Des Maraichers, 31400 Toulouse, France ,Clinical Research Institute of Benin (IRCB), Abomey Calavi, Benin
| | - Manfred Accrombessi
- Clinical Research Institute of Benin (IRCB), Abomey Calavi, Benin ,grid.8991.90000 0004 0425 469XFaculty of Infectious and Tropical Diseases, Disease Control Department, London School of Hygiene and Tropical Medicine, London, UK
| | - Elisée Kinkpé
- Paediatric Department, Calavi Hospital, Calavi, Benin
| | - Linda Ayédadjou
- Paediatric Department, Mother and Child University and Hospital Center (CHU-MEL), Cotonou, Benin
| | | | - Yélé Ladipo
- Paediatric Department, Mother and Child University and Hospital Center (CHU-MEL), Cotonou, Benin
| | - Maroufou Jules Alao
- Paediatric Department, Mother and Child University and Hospital Center (CHU-MEL), Cotonou, Benin
| | | | - Michel Cot
- grid.462420.6UMR261 MERIT, IRD, Paris University, Paris, France
| | - Farid Boumédiène
- grid.9966.00000 0001 2165 4861UMR 1094 EpiMaCT, Inserm, Limoges University Hospital, Limoges University, Limoges, France
| | - Sandrine Houzé
- grid.462420.6UMR261 MERIT, IRD, Paris University, Paris, France ,grid.411119.d0000 0000 8588 831XFrench Malaria Reference Center, APHP, Bichat Hospital, Paris, France ,grid.411119.d0000 0000 8588 831XParasitology Laboratory, APHP, Bichat-Claude-Bernard Hospital, Paris, France
| | - Jean François Faucher
- grid.9966.00000 0001 2165 4861UMR 1094 EpiMaCT, Inserm, Limoges University Hospital, Limoges University, Limoges, France ,grid.411178.a0000 0001 1486 4131Infectious Diseases and Tropical Medicine Department, Limoges University Hospital, Limoges, France
| | - Agnès Aubouy
- UMR152 PHARMADEV, IRD, UPS, Toulouse University, 35 Chemin Des Maraichers, 31400, Toulouse, France. .,Clinical Research Institute of Benin (IRCB), Abomey Calavi, Benin.
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Muppidi P, Wright E, Wassmer SC, Gupta H. Diagnosis of cerebral malaria: Tools to reduce Plasmodium falciparum associated mortality. Front Cell Infect Microbiol 2023; 13:1090013. [PMID: 36844403 PMCID: PMC9947298 DOI: 10.3389/fcimb.2023.1090013] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/24/2023] [Indexed: 02/11/2023] Open
Abstract
Cerebral malaria (CM) is a major cause of mortality in Plasmodium falciparum (Pf) infection and is associated with the sequestration of parasitised erythrocytes in the microvasculature of the host's vital organs. Prompt diagnosis and treatment are key to a positive outcome in CM. However, current diagnostic tools remain inadequate to assess the degree of brain dysfunction associated with CM before the window for effective treatment closes. Several host and parasite factor-based biomarkers have been suggested as rapid diagnostic tools with potential for early CM diagnosis, however, no specific biomarker signature has been validated. Here, we provide an updated review on promising CM biomarker candidates and evaluate their applicability as point-of-care tools in malaria-endemic areas.
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Affiliation(s)
- Pranavi Muppidi
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Emily Wright
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Samuel C. Wassmer
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Himanshu Gupta
- Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Mathura, UP, India
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Adderley J, Grau GE. Host-directed therapies for malaria: possible applications and lessons from other indications. Curr Opin Microbiol 2023; 71:102228. [PMID: 36395572 DOI: 10.1016/j.mib.2022.102228] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/26/2022] [Accepted: 10/11/2022] [Indexed: 11/15/2022]
Abstract
Host-directed therapies (HDT) are rapidly advancing as a new and clinically relevant strategy to treat infectious disease. The application of HDT can be broadly used to (i) inhibit host factors essential for pathogen development, including host protein kinases, (ii) control detrimental immune signalling, resulting from excessive release of cytokines, chemokines and extracellular vesicles and (iii) strengthen host defence mechanisms, such as tight junctions in the endothelium. For malaria and other eukaryotic parasite-causing diseases, HDTs could provide a novel avenue to combat the growing resistance seen across all antimicrobials and provide protection against the severe forms of disease through modulation of the host immune response.
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Affiliation(s)
- Jack Adderley
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia.
| | - Georges E Grau
- Vascular Immunology Unit, School of Medical Sciences, Faculty of Medicine & Health, The University of Sydney, Medical Foundation Building, 92-94 Parramatta Road, Camperdown, NSW 2050, Australia
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12
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Chaturvedi R, Mohan M, Kumar S, Chandele A, Sharma A. Profiles of host immune impairment in Plasmodium and SARS-CoV-2 infections. Heliyon 2022; 8:e11744. [PMID: 36415655 PMCID: PMC9671871 DOI: 10.1016/j.heliyon.2022.e11744] [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: 12/03/2021] [Revised: 07/21/2022] [Accepted: 11/11/2022] [Indexed: 11/19/2022] Open
Abstract
Over the past two decades, many countries have reported a steady decline in reported cases of malaria, and a few countries, like China, have been declared malaria-free by the World Health Organization. In 2020 the number of deaths from malaria has declined since 2000. The COVID-19 pandemic has adversely affected overall public health efforts and thus it is feasible that there might be a resurgence of malaria. COVID-19 and malaria share some similarities in the immune responses of the patient and these two diseases also share overlapping early symptoms such as fever, headache, nausea, and muscle pain/fatigue. In the absence of early diagnostics, there can be a misdiagnosis of the infection(s) that can pose additional challenges due to delayed treatment. In both SARS-CoV-2 and Plasmodium infections, there is a rapid release of cytokines/chemokines that play a key role in disease pathophysiology. In this review, we have discussed the cytokine/chemokine storm observed during COVID-19 and malaria. We observed that: (1) the severity in malaria and COVID-19 is likely a consequence primarily of an uncontrolled 'cytokine storm'; (2) five pro-inflammatory cytokines (IL-6, IL-10, TNF-α, type I IFN, and IFN-γ) are significantly increased in severe/critically ill patients in both diseases; (3) Plasmodium and SARS-CoV-2 share some similar clinical manifestations and thus may result in fatal consequences if misdiagnosed during onset.
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Affiliation(s)
- Rini Chaturvedi
- Molecular Medicine Group, International Center for Genetic Engineering and Biotechnology, New Delhi, Delhi, India
| | - Mradul Mohan
- Parasite-Host Biology Group, National Institute of Malaria Research, New Delhi, Delhi, India,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sanjeev Kumar
- ICGEB-Emory Vaccine Program, International Center for Genetic Engineering and Biotechnology, New Delhi, Delhi, India
| | - Anmol Chandele
- ICGEB-Emory Vaccine Program, International Center for Genetic Engineering and Biotechnology, New Delhi, Delhi, India
| | - Amit Sharma
- Molecular Medicine Group, International Center for Genetic Engineering and Biotechnology, New Delhi, Delhi, India,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India,Corresponding author
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13
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Mahittikorn A, Mala W, Srisuphanunt M, Masangkay FR, Kotepui KU, Wilairatana P, Kotepui M. Tumour necrosis factor-α as a prognostic biomarker of severe malaria: a systematic review and meta-analysis. J Travel Med 2022; 29:6573410. [PMID: 35467747 DOI: 10.1093/jtm/taac053] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/08/2022] [Accepted: 04/13/2022] [Indexed: 11/14/2022]
Abstract
BACKGROUND Tumour necrosis factor-alpha (TNF-α) levels are reportedly altered during malaria. In this systematic review and meta-analysis, we aimed to collect and compare data on TNF-α levels between patients with malaria of varying severity and healthy asymptomatic positive controls. METHODS We searched PubMed, Scopus and Web of Science for studies that reported TNF-α levels in malaria cases of different severity and healthy asymptomatic positive controls using a combination of search terms. The quality of the included studies was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. To compare the TNF-α levels among fatal cases, severe cases, uncomplicated cases and healthy asymptomatic positive controls, we applied the random-effects model that assumed the existence of variations between studies. The effect estimate was pooled mean difference (MD) with a 95% confidence interval (CI). RESULTS From 1694 studies, we included 31 studies that met our eligibility criteria for systematic review and meta-analysis. Patients with severe malaria showed higher mean TNF-α levels than those with uncomplicated malaria (P < 0.001, pooled MD = 79.02 pg/ml, 95% CI: 63.68-94.35 pg/ml, I2: 99.5%, n = 26 studies). Furthermore, fatal cases had no difference in the mean TNF-α levels in comparison with survived cases (P = 0.055, pooled MD = 82.38 pg/ml, 95% CI: -1.93 to 166.69 pg/ml, I2: 99.54%, n = 5 studies). Finally, patients with uncomplicated malaria showed higher mean TNF-α levels than those with asymptomatic malaria (P < 0.001, pooled MD = 45.10 pg/ml, 95% CI: 18.45-71.76 pg/ml, I2: 97.09%, n = 5 studies). CONCLUSION This systematic review and meta-analysis confirmed the increase of TNF-α levels in patients with severe malaria. Therefore, TNF-α may be alternatively used as a prognostic biomarker of severe malaria. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Aongart Mahittikorn
- Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Wanida Mala
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Tha Sala, Nakhon Si Thammarat, Thailand
| | - Mayuna Srisuphanunt
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Tha Sala, Nakhon Si Thammarat, Thailand
| | | | - Kwuntida Uthaisar Kotepui
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Tha Sala, Nakhon Si Thammarat, Thailand
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Manas Kotepui
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Tha Sala, Nakhon Si Thammarat, Thailand
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14
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Matteucci KC, Correa AAS, Costa DL. Recent Advances in Host-Directed Therapies for Tuberculosis and Malaria. Front Cell Infect Microbiol 2022; 12:905278. [PMID: 35669122 PMCID: PMC9163498 DOI: 10.3389/fcimb.2022.905278] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/21/2022] [Indexed: 11/30/2022] Open
Abstract
Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, and malaria, caused by parasites from the Plasmodium genus, are two of the major causes of death due to infectious diseases in the world. Both diseases are treatable with drugs that have microbicidal properties against each of the etiologic agents. However, problems related to treatment compliance by patients and emergence of drug resistant microorganisms have been a major problem for combating TB and malaria. This factor is further complicated by the absence of highly effective vaccines that can prevent the infection with either M. tuberculosis or Plasmodium. However, certain host biological processes have been found to play a role in the promotion of infection or in the pathogenesis of each disease. These processes can be targeted by host-directed therapies (HDTs), which can be administered in conjunction with the standard drug treatments for each pathogen, aiming to accelerate their elimination or to minimize detrimental side effects resulting from exacerbated inflammation. In this review we discuss potential new targets for the development of HDTs revealed by recent advances in the knowledge of host-pathogen interaction biology, and present an overview of strategies that have been tested in vivo, either in experimental models or in patients.
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Affiliation(s)
- Kely C. Matteucci
- Plataforma de Medicina Translacional Fundação Oswaldo Cruz/Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
| | - André A. S. Correa
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
| | - Diego L. Costa
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
- Programa de Pós-Graduação em Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
- *Correspondence: Diego L. Costa,
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15
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Simwela NV, Waters AP. Current status of experimental models for the study of malaria. Parasitology 2022; 149:1-22. [PMID: 35357277 PMCID: PMC9378029 DOI: 10.1017/s0031182021002134] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 01/09/2023]
Abstract
Infection by malaria parasites (Plasmodium spp.) remains one of the leading causes of morbidity and mortality, especially in tropical regions of the world. Despite the availability of malaria control tools such as integrated vector management and effective therapeutics, these measures have been continuously undermined by the emergence of vector resistance to insecticides or parasite resistance to frontline antimalarial drugs. Whilst the recent pilot implementation of the RTS,S malaria vaccine is indeed a remarkable feat, highly effective vaccines against malaria remain elusive. The barriers to effective vaccines result from the complexity of both the malaria parasite lifecycle and the parasite as an organism itself with consequent major gaps in our understanding of their biology. Historically and due to the practical and ethical difficulties of working with human malaria infections, research into malaria parasite biology has been extensively facilitated by animal models. Animals have been used to study disease pathogenesis, host immune responses and their (dys)regulation and further disease processes such as transmission. Moreover, animal models remain at the forefront of pre-clinical evaluations of antimalarial drugs (drug efficacy, mode of action, mode of resistance) and vaccines. In this review, we discuss commonly used animal models of malaria, the parasite species used and their advantages and limitations which hinder their extrapolation to actual human disease. We also place into this context the most recent developments such as organoid technologies and humanized mice.
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Affiliation(s)
- Nelson V. Simwela
- Institute of Infection, Immunity & Inflammation, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow, UK
| | - Andrew P. Waters
- Institute of Infection, Immunity & Inflammation, Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow, UK
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16
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Omar M, Marchionni L, Häcker G, Badr MT. Host Blood Gene Signatures Can Detect the Progression to Severe and Cerebral Malaria. Front Cell Infect Microbiol 2021; 11:743616. [PMID: 34746025 PMCID: PMC8569259 DOI: 10.3389/fcimb.2021.743616] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/23/2021] [Indexed: 11/16/2022] Open
Abstract
Malaria is a major international public health problem that affects millions of patients worldwide especially in sub-Saharan Africa. Although many tests have been developed to diagnose malaria infections, we still lack reliable diagnostic biomarkers for the identification of disease severity, especially in endemic areas where the diagnosis of cerebral malaria is very difficult and requires the exclusion of all other possible causes. Previous host and pathogen transcriptomic studies have not yielded homogenous results that can be harnessed into a reliable diagnostic tool. Here we utilized a multi-cohort analysis approach using machine-learning algorithms to identify blood gene signatures that can distinguish severe and cerebral malaria from moderate and non-cerebral cases. Using a Regularized Random Forest model, we identified 28-gene and 32-gene signatures that can reliably distinguish severe and cerebral malaria, respectively. We tested the specificity of both signatures against other common infectious diseases to ensure the signatures reliability and suitability as diagnostic markers. The severe and cerebral malaria gene-signatures were further integrated through k-top scoring pairs classifiers into ten and nine gene pairs that could distinguish severe and cerebral malaria, respectively. These signatures have various implications that can be utilized as blood diagnostic tools for malaria severity in endemic countries.
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Affiliation(s)
- Mohamed Omar
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Luigi Marchionni
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Georg Häcker
- Institute of Medical Microbiology and Hygiene, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.,BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany
| | - Mohamed Tarek Badr
- Institute of Medical Microbiology and Hygiene, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.,IMM-PACT-Program, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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17
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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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18
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Mandala WL, Harawa V, Dzinjalamala F, Tembo D. The role of different components of the immune system against Plasmodium falciparum malaria: Possible contribution towards malaria vaccine development. Mol Biochem Parasitol 2021; 246:111425. [PMID: 34666102 PMCID: PMC8655617 DOI: 10.1016/j.molbiopara.2021.111425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 08/10/2021] [Accepted: 10/08/2021] [Indexed: 12/24/2022]
Abstract
Plasmodium falciparum malaria still remains a major global public health challenge with over 220 million new cases and well over 400,000 deaths annually. Most of the deaths occur in sub-Saharan Africa which bears 90 % of the malaria cases. Such high P. falciparum malaria-related morbidity and mortality rates pose a huge burden on the health and economic wellbeing of the countries affected. Lately, substantial gains have been made in reducing malaria morbidity and mortality through intense malaria control initiatives such as use of effective antimalarials, intensive distribution and use of insecticide-treated nets (ITNs), and implementation of massive indoor residual spraying (IRS) campaigns. However, these gains are being threatened by widespread resistance of the parasite to antimalarials, and the vector to insecticides. Over the years the use of vaccines has proven to be the most reliable, cost-effective and efficient method for controlling the burden and spread of many infectious diseases, especially in resource poor settings with limited public health infrastructure. Nonetheless, this had not been the case with malaria until the most promising malaria vaccine candidate, RTS,S/AS01, was approved for pilot implementation programme in three African countries in 2015. This was regarded as the most important breakthrough in the fight against malaria. However, RTS,S/AS01 has been found to have some limitations, the main ones being low efficacy in certain age groups, poor immunogenicity and need for almost three boosters to attain a reasonable efficacy. Thus, the search for a more robust and effective malaria vaccine still continues and a better understanding of naturally acquired immune responses to the various stages, including the transmissible stages of the parasite, could be crucial in rational vaccine design. This review therefore compiles what is currently known about the basic biology of P. falciparum and the natural malaria immune response against malaria and progress made towards vaccine development.
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Affiliation(s)
- Wilson L Mandala
- Academy of Medical Sciences, Malawi University of Science and Technology, Thyolo, Malawi; Malawi Liverpool Wellcome Trust, Blantyre, Malawi.
| | | | - Fraction Dzinjalamala
- Academy of Medical Sciences, Malawi University of Science and Technology, Thyolo, Malawi
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19
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Ghazanfari N, Gregory JL, Devi S, Fernandez-Ruiz D, Beattie L, Mueller SN, Heath WR. CD8 + and CD4 + T Cells Infiltrate into the Brain during Plasmodium berghei ANKA Infection and Form Long-Term Resident Memory. THE JOURNAL OF IMMUNOLOGY 2021; 207:1578-1590. [PMID: 34400523 DOI: 10.4049/jimmunol.2000773] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 07/18/2021] [Indexed: 12/31/2022]
Abstract
In the Plasmodium berghei ANKA mouse model of malaria, accumulation of CD8+ T cells and infected RBCs in the brain promotes the development of experimental cerebral malaria (ECM). In this study, we used malaria-specific transgenic CD4+ and CD8+ T cells to track evolution of T cell immunity during the acute and memory phases of P. berghei ANKA infection. Using a combination of techniques, including intravital multiphoton and confocal microscopy and flow cytometric analysis, we showed that, shortly before onset of ECM, both CD4+ and CD8+ T cell populations exit the spleen and begin infiltrating the brain blood vessels. Although dominated by CD8+ T cells, a proportion of both T cell subsets enter the brain parenchyma, where they are largely associated with blood vessels. Intravital imaging shows these cells moving freely within the brain parenchyma. Near the onset of ECM, leakage of RBCs into areas of the brain can be seen, implicating severe damage. If mice are cured before ECM onset, brain infiltration by T cells still occurs, but ECM is prevented, allowing development of long-term resident memory T cell populations within the brain. This study shows that infiltration of malaria-specific T cells into the brain parenchyma is associated with cerebral immunopathology and the formation of brain-resident memory T cells. The consequences of these resident memory populations is unclear but raises concerns about pathology upon secondary infection.
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Affiliation(s)
- Nazanin Ghazanfari
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia; and.,The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Julia L Gregory
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia; and.,The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Sapna Devi
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia; and.,The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Daniel Fernandez-Ruiz
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia; and.,The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Lynette Beattie
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia; and.,The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Scott N Mueller
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia; and.,The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - William R Heath
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria, Australia; and .,The Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
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20
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Bioengineered 3D Microvessels for Investigating Plasmodium falciparum Pathogenesis. Trends Parasitol 2021; 37:401-413. [PMID: 33485788 DOI: 10.1016/j.pt.2020.12.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/15/2020] [Accepted: 12/25/2020] [Indexed: 12/18/2022]
Abstract
Plasmodium falciparum pathogenesis is complex and intimately connected to vascular physiology. This is exemplified by cerebral malaria (CM), a neurovascular complication that accounts for most of the malaria deaths worldwide. P. falciparum sequestration in the brain microvasculature is a hallmark of CM and is not replicated in animal models. Numerous aspects of the disease are challenging to fully understand from clinical studies, such as parasite binding tropism or causal pathways in blood-brain barrier breakdown. Recent bioengineering approaches allow for the generation of 3D microvessels and organ-specific vasculature that provide precise control of vessel architecture and flow dynamics, and hold great promise for malaria research. Here, we discuss recent and future applications of bioengineered microvessels in malaria pathogenesis research.
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21
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Abstract
Cerebral malaria (CM) remains a major problem of public health at the world level (Idro et al. 2010; WHO 2009), in spite of numerous efforts from various disciplines to improve our knowledge of disease mechanisms (Hunt and Grau 2003; Schofield and Grau 2005; van der Heyde et al. 2006). Our approach to a better understanding of CM pathogenesis has involved the dissection of immunopathological pathways which, in addition to direct changes caused by malaria parasite-infected erythrocytes (IE), lead to neurovascular lesions. We posited that immunopathology is important in CM because a role for cells and soluble mediators of the immune system has been widely recognised as contributing to the complications of viral, bacterial, fungal and many parasitic infections. As detailed earlier, it would be extraordinary if malaria did not conform to this general pattern. As a matter of fact, there now is strong evidence to support immune mechanisms in malarial pathogenesis (Grau and Hunt 2014).Extracellular vesicles (EV) and their subtypes have been described and reviewed by a number of investigators (Hosseini-Beheshti and Grau 2018, 2019; Raposo and Stahl 2019; Witwer et al. 2017; Zijlstra and Di Vizio 2018) and in others chapters of the present book.
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Affiliation(s)
- Georges Emile Raymond Grau
- Vascular Immunology Unit, Discipline of Pathology, School of Medical Sciences; Marie Bashir Institute and The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, Camperdown, NSW, Australia.
| | - Elham Hosseini-Beheshti
- Vascular Immunology Unit, Discipline of Pathology, School of Medical Sciences; Marie Bashir Institute and The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, Camperdown, NSW, Australia
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22
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Patel H, Dunican C, Cunnington AJ. Predictors of outcome in childhood Plasmodium falciparum malaria. Virulence 2020; 11:199-221. [PMID: 32063099 PMCID: PMC7051137 DOI: 10.1080/21505594.2020.1726570] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 01/16/2020] [Accepted: 01/20/2020] [Indexed: 12/16/2022] Open
Abstract
Plasmodium falciparum malaria is classified as either uncomplicated or severe, determining clinical management and providing a framework for understanding pathogenesis. Severe malaria in children is defined by the presence of one or more features associated with adverse outcome, but there is wide variation in the predictive value of these features. Here we review the evidence for the usefulness of these features, alone and in combination, to predict death and other adverse outcomes, and we consider the role that molecular biomarkers may play in augmenting this prediction. We also examine whether a more personalized approach to predicting outcome for specific presenting syndromes of severe malaria, particularly cerebral malaria, has the potential to be more accurate. We note a general need for better external validation in studies of outcome predictors and for the demonstration that predictors can be used to guide clinical management in a way that improves survival and long-term health.
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Affiliation(s)
- Harsita Patel
- Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, UK
| | - Claire Dunican
- Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, UK
| | - Aubrey J. Cunnington
- Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, London, UK
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Bucşan AN, Williamson KC. Setting the stage: The initial immune response to blood-stage parasites. Virulence 2020; 11:88-103. [PMID: 31900030 PMCID: PMC6961725 DOI: 10.1080/21505594.2019.1708053] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/05/2019] [Accepted: 12/09/2019] [Indexed: 01/22/2023] Open
Abstract
Individuals growing up in malaria endemic areas gradually develop protection against clinical malaria and passive transfer experiments in humans have demonstrated that this protection is mediated in part by protective antibodies. However, neither the target antigens, specific effector mechanisms, nor the role of continual parasite exposure have been elucidated, which complicates vaccine development. Progress has been made in defining the innate signaling pathways activated by parasite components, including DNA, RNA, hemozoin, and phospholipids, which initiate the immune response and will be the focus of this review. The challenge that remains within the field is to understand the role of these early responses in the development of protective adaptive responses that clear iRBC and block merozoite invasion so that optimal vaccines and therapeutics may be produced.
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Affiliation(s)
- Allison N. Bucşan
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Kim C. Williamson
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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24
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Hayat Z, Ullah I, Hayat K, Khan HA, Raziq F, Khan H. REFRACTORY ANEMIA AND PANCYTOPENIA AS PRESENTATIONS OF FALCIPARUM MALARIA IN POPULATION OF KHYBER PAKHTUNKHWA, PAKISTAN. GOMAL JOURNAL OF MEDICAL SCIENCES 2020. [DOI: 10.46903/gjms/17.03.2027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
Background: Falciparum malaria is a common disease in our area. Apart from its classical presentation, at times it may present with refractory anemia or pancytopenia. The aim of this study was to determine the refractory anemia and pancytopenia as complications of falciparum malaria and apart from peripheral blood smears the significance of rapid antigen tests and bone marrow examination in the diagnosis of falciparum malaria. Material & Methods: The descriptive study included 200 consecutive cases of fever and refractory anemia or pancytopenia from 2011 to 2014. Stratification of patients according to the clinical scenario included Group-A having fever with refractory anemia and Group-B with fever and pancytopenia. A detailed history, thorough clinical examination, and pertinent laboratory tests were performed. All patients were treated with antimalarial drugs and followed-up for eight weeks. The pre and post treatment hematologic parameters were compared. Results: Among the 200 patients, 85 were males and 115 females. The age ranged from 15 to 55 years. Stratification of patients on clinical scenario revealed 175(87.5%) patients with fever and refractory anemia (Group-A). Among these, 125(62.5%) patients were reported smear positive for P. falciparum. In the remaining 50 smear negative patients rapid antigen tests were performed and all were reported positive. In 25 patients of Group B with fever and pancytopenia, the peripheral smear for malaria was positive only in 5 patients. In the remaining 20 cases both the peripheral blood smears and rapid antigen tests were reported negative. Bone marrow examination was planned to confirm the bone marrow suppression as the cause of peripheral pancytopenia, to exclude leukemia and to identify P. falciparum. The bone marrow examination revealed P. falciparum in all these cases. All the patients had a dramatic response to treatment with antimalarials in terms of disappearance of fever and correction of anemia and bone marrow rescue with reversal of pancytopenia to normal counts. Conclusion: Plasmodium falciparum should be considered in all cases of prolonged fever with refractory anemia or pancytopenia in malaria endemic areas, even with negative smear and rapid antigen tests. Bone examination is mandatory for the diagnosis in such cases. There is dramatic response of such patients to treatment with antimalarial drugs and hematinics.
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25
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Leão L, Puty B, Dolabela MF, Povoa MM, Né YGDS, Eiró LG, Fagundes NCF, Maia LC, Lima RR. Association of cerebral malaria and TNF-α levels: a systematic review. BMC Infect Dis 2020; 20:442. [PMID: 32576141 PMCID: PMC7310527 DOI: 10.1186/s12879-020-05107-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023] Open
Abstract
Background Cerebral malaria is the most severe form of infection with Plasmodium falciparum characterized by a highly inflammatory response. This systematic review aimed to investigate the association between TNF-α levels and cerebral malaria. Methods This review followed the Preferred Reporting of Systematic Review and Meta-analyses (PRISMA) guidelines. The search was performed at PubMed, LILACS, Scopus, Web of Science, The Cochrane Library, OpenGrey and Google Scholar. We have included studies of P. falciparum-infected humans with or without cerebral malaria and TNF-α dosage level. All studies were evaluated using a risk of bias tool and the GRADE approach. Results Our results have identified 2338 studies, and 8 articles were eligible according to this systematic review inclusion criteria. Among the eight articles, five have evaluated TNF- α plasma dosage, while two have evaluated at the blood and one at the brain (post-Morten). Among them, only five studies showed higher TNF-α levels in the cerebral malaria group compared to the severe malaria group. Methodological problems were identified regarding sample size, randomization and blindness, but no risk of bias was detected. Conclusion Although the results suggested that that TNF-α level is associated with cerebral malaria, the evidence is inconsistent and imprecise. More observational studies evaluating the average TNF-alpha are needed.
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Affiliation(s)
- Luana Leão
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Correa Street, Guama, Belem, PA, 66075-900, Brazil
| | - Bruna Puty
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Correa Street, Guama, Belem, PA, 66075-900, Brazil
| | - Maria Fâni Dolabela
- Postgraduate Program in Pharmaceutical Sciences, Institute of Health Sciences, Federal University of Pará, Belém, Brazil
| | | | - Yago Gecy De Sousa Né
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Correa Street, Guama, Belem, PA, 66075-900, Brazil
| | - Luciana Guimarães Eiró
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Correa Street, Guama, Belem, PA, 66075-900, Brazil
| | | | - Lucianne Cople Maia
- Department of Pediatric Dentistry and Orthodontics, School of Dentistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rafael Rodrigues Lima
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, 01 Augusto Correa Street, Guama, Belem, PA, 66075-900, Brazil.
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26
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Manda-Taylor L, Liomba A, Taylor TE, Elwell K. Barriers and Facilitators to Obtaining Informed Consent in a Critical Care Pediatric Research Ward in Southern Malawi. J Empir Res Hum Res Ethics 2020; 14:152-168. [PMID: 30866724 DOI: 10.1177/1556264619830859] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Informed consent is an ethical requirement in clinical research. Obtaining informed consent is challenging in resource-constrained settings. We report results of a formative qualitative study that examined factors that facilitate and hinder informed consent for clinical research among critically ill children in Malawi. We argue that truly informed consent in a pediatric intensive care unit (PICU) is challenged by parental distress, time constraints when balancing care for critically ill patients with research-related tasks, and social hierarchies and community mistrust toward certain research procedures. We interviewed health care providers and parents of children attending a critical care unit to identify potential challenges and solicit strategies for addressing them. Providers and caregivers suggested practical solutions to enhance research participant understanding of clinical trial research, including the use of visual materials, community engagement strategies, and using patients as advocates in promoting understanding of research procedures.
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27
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Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction. Mediators Inflamm 2020; 2020:3280689. [PMID: 32801995 PMCID: PMC7327554 DOI: 10.1155/2020/3280689] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 05/08/2020] [Indexed: 12/26/2022] Open
Abstract
Background Cerebral malaria (CM), a reversible encephalopathy affecting young children, is a medical emergency requiring rapid clinical assessment and treatment. However, understanding of the genes/proteins and the biological pathways involved in the disease outcome is still limited. Methods We have performed a whole transcriptomic analysis of blood samples from Malian children with CM or uncomplicated malaria (UM). Hierarchical clustering and pathway, network, and upstream regulator analyses were performed to explore differentially expressed genes (DEGs). We validated gene expression for 8 genes using real-time quantitative PCR (RT-qPCR). Plasma levels were measured for IP-10/CXCL10 and IL-18. Results A blood RNA signature including 538 DEGs (∣FC | ≥2.0, adjusted P value ≤ 0.01) allowed to discriminate between CM and UM. Ingenuity Pathway Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed novel genes and biological pathways related to immune/inflammatory responses, erythrocyte alteration, and neurodegenerative disorders. Gene expressions of CXCL10, IL12RB2, IL18BP, IL2RA, AXIN2, and NET were significantly lower in CM whereas ARG1 and SLC6A9 were higher in CM compared to UM. Plasma protein levels of IP-10/CXCL10 were significantly lower in CM than in UM while levels of IL-18 were higher. Interestingly, among children with CM, those who died from a complication of malaria tended to have higher concentrations of IP-10/CXCL10 and IFN-γ than those who recovered. Conclusions This study identified some new factors and mechanisms that play crucial roles in CM and characterized their respective biological pathways as well as some upstream regulators.
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28
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Jensen AR, Adams Y, Hviid L. Cerebral Plasmodium falciparum malaria: The role of PfEMP1 in its pathogenesis and immunity, and PfEMP1-based vaccines to prevent it. Immunol Rev 2020; 293:230-252. [PMID: 31562653 PMCID: PMC6972667 DOI: 10.1111/imr.12807] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/04/2019] [Accepted: 09/09/2019] [Indexed: 12/13/2022]
Abstract
Malaria, a mosquito-borne infectious disease caused by parasites of the genus Plasmodium continues to be a major health problem worldwide. The unicellular Plasmodium-parasites have the unique capacity to infect and replicate within host erythrocytes. By expressing variant surface antigens Plasmodium falciparum has evolved to avoid protective immune responses; as a result in endemic areas anti-malaria immunity develops gradually over many years of multiple and repeated infections. We are studying the role of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed by asexual stages of P. falciparum responsible for the pathogenicity of severe malaria. The immunopathology of falciparum malaria has been linked to cyto-adhesion of infected erythrocytes to specific host receptors. A greater appreciation of the PfEMP1 molecules important for the development of protective immunity and immunopathology is a prerequisite for the rational discovery and development of a safe and protective anti-disease malaria vaccine. Here we review the role of ICAM-1 and EPCR receptor adhering falciparum-parasites in the development of severe malaria; we discuss our current research to understand the factors involved in the pathogenesis of cerebral malaria and the feasibility of developing a vaccine targeted specifically to prevent this disease.
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Affiliation(s)
- Anja Ramstedt Jensen
- Centre for Medical Parasitology at Department of Immunology and MicrobiologyFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Yvonne Adams
- Centre for Medical Parasitology at Department of Immunology and MicrobiologyFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Lars Hviid
- Centre for Medical Parasitology at Department of Immunology and MicrobiologyFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Department of Infectious DiseasesRigshospitaletCopenhagenDenmark
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29
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Chin SS, Chorro L, Chan J, Lauvau G. Splenic Innate B1 B Cell Plasmablasts Produce Sustained Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-3 Cytokines during Murine Malaria Infections. Infect Immun 2019; 87:e00482-19. [PMID: 31591168 PMCID: PMC6867857 DOI: 10.1128/iai.00482-19] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 09/24/2019] [Indexed: 12/14/2022] Open
Abstract
The physiopathology of malaria, one of the most deadly human parasitic diseases worldwide, is complex, as it is a systemic disease involving multiple parasitic stages and hosts and leads to the activation of numerous immune cells and release of inflammatory mediators. While some cytokines increased in the blood of patients infected with Plasmodium falciparum have been extensively studied, others, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), have not received much attention. GM-CSF and IL-3 belong to the β common (βc/CD131) chain family of cytokines, which exhibit pleiotropic functions, including the regulation of myeloid cell growth, differentiation, and activation. GM-CSF can be secreted by multiple cell types, whereas IL-3 is mostly restricted to T cells, yet innate response activator (IRA) B cells, a subset of innate B1 B cells, also produce significant amounts of these cytokines during bacterial sepsis via Toll-like receptor 4 (TLR4)/MyD88 sensing of lipopolysaccharides. Herein, using murine models of malaria, we report a sustained production of GM-CSF and IL-3 from IgM+ and IgM-/IgG+ CD138+ Blimp-1+ innate B1b B cell plasmablasts. IgM+ B1b B cells include IRA-like and non-IRA B cells and express higher levels of both cytokines than do their IgG+ counterparts. Interestingly, as infection progresses, the relative proportion of IgM+ B1 B cells decreases while that of IgG+ plasmablasts increases, correlating with potential isotype switching of GM-CSF- and IL-3-producing IgM+ B1 B cells. GM-CSF/IL-3+ B1 B cells originate in the spleen of infected mice and are partially dependent on type I and type II interferon signaling to produce both cytokines. These data reveal that GM-CSF and IL-3 are produced during malaria infections, initially from IgM+ and then from IgG+ B1b B cell plasmablasts, which may represent important emergency cellular sources of these cytokines. These results further highlight the phenotypic heterogeneity of innate B1 B cell subsets and of their possible fates in a relevant murine model of parasitic infection in vivo.
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Affiliation(s)
- Shu Shien Chin
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Laurent Chorro
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - John Chan
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Grégoire Lauvau
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
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30
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Nallandhighal S, Park GS, Ho YY, Opoka RO, John CC, Tran TM. Whole-Blood Transcriptional Signatures Composed of Erythropoietic and NRF2-Regulated Genes Differ Between Cerebral Malaria and Severe Malarial Anemia. J Infect Dis 2019; 219:154-164. [PMID: 30060095 DOI: 10.1093/infdis/jiy468] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 07/24/2018] [Indexed: 02/03/2023] Open
Abstract
Background Among the severe malaria syndromes, severe malarial anemia (SMA) is the most common, whereas cerebral malaria (CM) is the most lethal. However, the mechanisms that lead to CM and SMA are unclear. Methods We compared transcriptomic profiles of whole blood obtained from Ugandan children with acute CM (n = 17) or SMA (n = 17) and community children without Plasmodium falciparum infection (n = 12) and determined the relationships among gene expression, hematological indices, and relevant plasma biomarkers. Results Both CM and SMA demonstrated predominantly upregulated enrichment of dendritic cell activation, inflammatory/Toll-like receptor/chemokines, and monocyte modules, but downregulated enrichment of lymphocyte modules. Nuclear factor, erythroid 2 like 2 (Nrf2)-regulated genes were overexpressed in children with SMA relative to CM, with the highest expression in children with both SMA and sickle cell disease (HbSS), corresponding with elevated plasma heme oxygenase-1 in this group. Erythroid and reticulocyte-specific signatures were markedly decreased in CM relative to SMA despite higher hemoglobin levels and appropriate increases in erythropoietin. Viral sensing/interferon-regulatory factor 2 module expression and plasma interferon-inducible protein-10/CXCL10 negatively correlated with reticulocyte-specific signatures. Conclusions Compared with SMA, CM is associated with downregulation of Nrf2-related and erythropoiesis signatures by whole-blood transcriptomics. Future studies are needed to confirm these findings and assess pathways that may be amenable to interventions to ameliorate CM and SMA.
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Affiliation(s)
- Srinivas Nallandhighal
- Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis
| | - Gregory S Park
- Division of Global Pediatrics, Department of Pediatrics, University of Minnesota Medical School, Minneapolis
| | - Yen-Yi Ho
- Department of Statistics, College of Arts and Sciences, University of South Carolina, Columbia
| | - Robert O Opoka
- Department of Paediatrics and Child Health, Makerere University, Kampala, Uganda
| | - Chandy C John
- Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis.,Division of Global Pediatrics, Department of Pediatrics, University of Minnesota Medical School, Minneapolis.,Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis
| | - Tuan M Tran
- Division of Infectious Diseases, Department of Medicine, Indiana University School of Medicine, Indianapolis.,Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis
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31
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Penha-Gonçalves C. Genetics of Malaria Inflammatory Responses: A Pathogenesis Perspective. Front Immunol 2019; 10:1771. [PMID: 31417551 PMCID: PMC6682681 DOI: 10.3389/fimmu.2019.01771] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 07/15/2019] [Indexed: 12/27/2022] Open
Abstract
Despite significant progress in combating malaria in recent years the burden of severe disease and death due to Plasmodium infections remains a global public health concern. Only a fraction of infected people develops severe clinical syndromes motivating a longstanding search for genetic determinants of malaria severity. Strong genetic effects have been repeatedly ascribed to mutations and allelic variants of proteins expressed in red blood cells but the role of inflammatory response genes in disease pathogenesis has been difficult to discern. We revisited genetic evidence provided by inflammatory response genes that have been repeatedly associated to malaria, namely TNF, NOS2, IFNAR1, HMOX1, TLRs, CD36, and CD40LG. This highlighted specific genetic variants having opposing roles in the development of distinct malaria clinical outcomes and unveiled diverse levels of genetic heterogeneity that shaped the complex association landscape of inflammatory response genes with malaria. However, scrutinizing genetic effects of individual variants corroborates a pathogenesis model where pro-inflammatory genetic variants acting in early infection stages contribute to resolve infection but at later stages confer increased vulnerability to severe organ dysfunction driven by tissue inflammation. Human genetics studies are an invaluable tool to find genes and molecular pathways involved in the inflammatory response to malaria but their precise roles in disease pathogenesis are still unexploited. Genome editing in malaria experimental models and novel genotyping-by-sequencing techniques are promising approaches to delineate the relevance of inflammatory response gene variants in the natural history of infection thereby will offer new rational angles on adjuvant therapeutics for prevention and clinical management of severe malaria.
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32
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Cui A, Li Y, Zhou X, Wang L, Luo E. Characterization of Plasmodium berghei Homologues of T-cell Immunomodulatory Protein as a New Potential Candidate for Protecting against Experimental Cerebral Malaria. THE KOREAN JOURNAL OF PARASITOLOGY 2019; 57:101-115. [PMID: 31104402 PMCID: PMC6526220 DOI: 10.3347/kjp.2019.57.2.101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 04/14/2019] [Accepted: 04/16/2019] [Indexed: 11/27/2022]
Abstract
The pathogenesis of cerebral malaria is biologically complex and involves multi-factorial mechanisms such as microvascular congestion, immunopathology by the pro-inflammatory cytokine and endothelial dysfunction. Recent data have suggested that a pleiotropic T-cell immunomodulatory protein (TIP) could effectively mediate inflammatory cytokines of mammalian immune response against acute graft-versus-host disease in animal models. In this study, we identified a conserved homologue of TIP in Plasmodium berghei (PbTIP) as a membrane protein in Plasmodium asexual stage. Compared with PBS control group, the pathology of experimental cerebral malaria (ECM) in rPbTIP intravenous injection (i.v.) group was alleviated by the downregulation of pro-inflammatory responses, and rPbTIP i.v. group elicited an expansion of regulatory T-cell response. Therefore, rPbTIP i.v. group displayed less severe brain pathology and feverish mice in rPbTIP i.v. group died from ECM. This study suggested that PbTIP may be a novel promising target to alleviate the severity of ECM.
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Affiliation(s)
- Ai Cui
- Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Yucen Li
- Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Xia Zhou
- Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Lin Wang
- Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Enjie Luo
- Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110122, P.R. China
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33
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Harawa V, Njie M, Kessler A, Choko A, Kumwenda B, Kampondeni S, Potchen M, Kim K, Jaworowski A, Taylor T, Mandala W, Seydel K, Rogerson S. Brain swelling is independent of peripheral plasma cytokine levels in Malawian children with cerebral malaria. Malar J 2018; 17:435. [PMID: 30477519 PMCID: PMC6260579 DOI: 10.1186/s12936-018-2590-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/22/2018] [Indexed: 11/26/2022] Open
Abstract
Background Cerebral malaria (CM) is often fatal, and severe brain swelling is a predictor of CM-related mortality. CM is characterized by elevated circulating pro-inflammatory cytokines TNF and IFN-γ and anti-inflammatory cytokine IL-10, however whether cytokine levels correlate with brain swelling severity is unknown. This study therefore was conducted to investigate the relationship between cytokine levels and brain swelling severity in children presenting with CM. Methods A total of 195 Malawian children presenting with CM were recruited and had the concentrations of plasma cytokines determined and compared to brain swelling severity, determined by MRI examination, and graded as severe, moderate, mild or none. Results Levels of IL-1β, IL-6, IL-8 and IL-10 did not differ between CM patients with and without severe brain swelling. Compared to children without brain swelling, IL-12 levels were higher in children with severe swelling (p < 0.01, no swelling 1 pg/mL, IQR [1] vs. severe swelling 18.7 pg/mL, IQR [1–27]), whereas TNF concentrations were higher in children with moderate brain swelling compared to children with no swelling (p < 0.01, no swelling 3 pg/mL, IQR [1–20] vs. moderate swelling 24 pg/mL, IQR [8–58]. Multivariate analysis showed that no single cytokine independently predicted brain swelling. Conclusion Severe brain swelling in paediatric CM was independent of tested blood pro-inflammatory and anti-inflammatory cytokines which are markers of systemic inflammation. Electronic supplementary material The online version of this article (10.1186/s12936-018-2590-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Visopo Harawa
- Biomedical Sciences Department, College of Medicine, University of Malawi, Blantyre, Malawi. .,Malawi-Liverpool Wellcome Trust Clinical Programme, Blantyre, Malawi.
| | - Madi Njie
- Department of Medicine at the Doherty Institute, University of Melbourne, Melbourne, Australia
| | - Anne Kessler
- Albert Einstein College of Medicine, Bronx, NY, USA
| | - Augustine Choko
- Biomedical Sciences Department, College of Medicine, University of Malawi, Blantyre, Malawi.,London School of Hygiene & Tropical Medicine, London, UK
| | - Benjamin Kumwenda
- Biomedical Sciences Department, College of Medicine, University of Malawi, Blantyre, Malawi.,Malawi-Liverpool Wellcome Trust Clinical Programme, Blantyre, Malawi
| | - Sam Kampondeni
- Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi
| | | | - Kami Kim
- Albert Einstein College of Medicine, Bronx, NY, USA.,University of South Florida, Tampa, FL, USA
| | - Anthony Jaworowski
- Life Sciences Program, Burnet Institute, Melbourne, Australia.,Health and Biomedical Sciences, RMIT University, Melbourne, Australia
| | - Terrie Taylor
- Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.,Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, E. Lansing, MI, USA
| | - Wilson Mandala
- Biomedical Sciences Department, College of Medicine, University of Malawi, Blantyre, Malawi. .,Malawi-Liverpool Wellcome Trust Clinical Programme, Blantyre, Malawi. .,Academy of Medical Sciences, Malawi University of Science and Technology, Thyolo, Malawi.
| | - Karl Seydel
- Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.,Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, E. Lansing, MI, USA
| | - Stephen Rogerson
- Department of Medicine at the Doherty Institute, University of Melbourne, Melbourne, Australia
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Reuterswärd P, Bergström S, Orikiiriza J, Lindquist E, Bergström S, Andersson Svahn H, Ayoglu B, Uhlén M, Wahlgren M, Normark J, Ribacke U, Nilsson P. Levels of human proteins in plasma associated with acute paediatric malaria. Malar J 2018; 17:426. [PMID: 30442134 PMCID: PMC6238294 DOI: 10.1186/s12936-018-2576-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 11/09/2018] [Indexed: 02/07/2023] Open
Abstract
Background The intimate interaction between the pathophysiology of the human host and the biology of the Plasmodium falciparum parasite results in a wide spectrum of disease outcomes in malaria. Development of severe disease is associated with a progressively augmented imbalance in pro- and anti-inflammatory responses to high parasite loads and sequestration of parasitized erythrocytes. Although these phenomena collectively constitute common denominators for the wide variety of discrete severe malaria manifestations, the mechanistic rationales behind discrepancies in outcome are poorly understood. Exploration of the human pathophysiological response by variations in protein profiles in plasma presents an excellent opportunity to increase the understanding. This is ultimately required for better prediction, prevention and treatment of malaria, which is essential for ongoing elimination and eradication efforts. Results An affinity proteomics approach was used to analyse 541 paediatric plasma samples collected from community controls and patients with mild or severe malaria in Rwanda. Protein profiles were generated with an antibody-based suspension bead array containing 255 antibodies targetting 115 human proteins. Here, 57 proteins were identified with significantly altered levels (adjusted p-values < 0.001) in patients with malaria compared to controls. From these, the 27 most significant proteins (adjusted p-values < 10−14) were selected for a stringent analysis approach. Here, 24 proteins showed elevated levels in malaria patients and included proteins involved in acute inflammatory response as well as cell adhesion. The remaining three proteins, also implicated in immune regulation and cellular adhesivity, displayed lower abundance in malaria patients. In addition, 37 proteins (adjusted p-values < 0.05) were identified with increased levels in patients with severe compared to mild malaria. This set includes, proteins involved in tissue remodelling and erythrocyte membrane proteins. Collectively, this approach has been successfully used to identify proteins both with known and unknown association with different stages of malaria. Conclusion In this study, a high-throughput affinity proteomics approach was used to find protein profiles in plasma linked to P. falciparum infection and malaria disease progression. The proteins presented herein are mainly involved in inflammatory response, cellular adhesion and as constituents of erythrocyte membrane. These findings have a great potential to provide increased conceptual understanding of host-parasite interaction and malaria pathogenesis. Electronic supplementary material The online version of this article (10.1186/s12936-018-2576-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Philippa Reuterswärd
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden.
| | - Sofia Bergström
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Judy Orikiiriza
- Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda
| | | | - Sven Bergström
- Department of Molecular Biology, Umeå University, Umeå, Sweden
| | - Helene Andersson Svahn
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Burcu Ayoglu
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden.,Department of Medicine, Division of Immunology and Rheumatology, School of Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Mathias Uhlén
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Mats Wahlgren
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Johan Normark
- Department of Molecular Biology, Umeå University, Umeå, Sweden
| | - Ulf Ribacke
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Peter Nilsson
- Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
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Stanisic DI, Fink J, Mayer J, Coghill S, Gore L, Liu XQ, El-Deeb I, Rodriguez IB, Powell J, Willemsen NM, De SL, Ho MF, Hoffman SL, Gerrard J, Good MF. Vaccination with chemically attenuated Plasmodium falciparum asexual blood-stage parasites induces parasite-specific cellular immune responses in malaria-naïve volunteers: a pilot study. BMC Med 2018; 16:184. [PMID: 30293531 PMCID: PMC6174572 DOI: 10.1186/s12916-018-1173-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 09/11/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The continuing morbidity and mortality associated with infection with malaria parasites highlights the urgent need for a vaccine. The efficacy of sub-unit vaccines tested in clinical trials in malaria-endemic areas has thus far been disappointing, sparking renewed interest in the whole parasite vaccine approach. We previously showed that a chemically attenuated whole parasite asexual blood-stage vaccine induced CD4+ T cell-dependent protection against challenge with homologous and heterologous parasites in rodent models of malaria. METHODS In this current study, we evaluated the immunogenicity and safety of chemically attenuated asexual blood-stage Plasmodium falciparum (Pf) parasites in eight malaria-naïve human volunteers. Study participants received a single dose of 3 × 107 Pf pRBC that had been treated in vitro with the cyclopropylpyrolloindole analogue, tafuramycin-A. RESULTS We demonstrate that Pf asexual blood-stage parasites that are completely attenuated are immunogenic, safe and well tolerated in malaria-naïve volunteers. Following vaccination with a single dose, species and strain transcending Plasmodium-specific T cell responses were induced in recipients. This included induction of Plasmodium-specific lymphoproliferative responses, T cells secreting the parasiticidal cytokines, IFN-γ and TNF, and CD3+CD45RO+ memory T cells. Pf-specific IgG was not detected. CONCLUSIONS This is the first clinical study evaluating a whole parasite blood-stage malaria vaccine. Following administration of a single dose of completely attenuated Pf asexual blood-stage parasites, Plasmodium-specific T cell responses were induced while Pf-specific antibodies were not detected. These results support further evaluation of this chemically attenuated vaccine in humans. TRIAL REGISTRATION Trial registration: ACTRN12614000228684 . Registered 4 March 2014.
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Affiliation(s)
- Danielle I Stanisic
- Institute for Glycomics, Griffith University, Parklands Drive, Southport, Queensland, Australia.
| | - James Fink
- Gold Coast University Hospital, 1 Hospital Blvd, Southport, Queensland, Australia
| | - Johanna Mayer
- Gold Coast University Hospital, 1 Hospital Blvd, Southport, Queensland, Australia
| | - Sarah Coghill
- Gold Coast University Hospital, 1 Hospital Blvd, Southport, Queensland, Australia
| | - Letitia Gore
- Gold Coast University Hospital, 1 Hospital Blvd, Southport, Queensland, Australia
| | - Xue Q Liu
- Institute for Glycomics, Griffith University, Parklands Drive, Southport, Queensland, Australia
| | - Ibrahim El-Deeb
- Institute for Glycomics, Griffith University, Parklands Drive, Southport, Queensland, Australia
| | - Ingrid B Rodriguez
- Institute for Glycomics, Griffith University, Parklands Drive, Southport, Queensland, Australia
| | - Jessica Powell
- Institute for Glycomics, Griffith University, Parklands Drive, Southport, Queensland, Australia
| | - Nicole M Willemsen
- Institute for Glycomics, Griffith University, Parklands Drive, Southport, Queensland, Australia
| | - Sai Lata De
- Institute for Glycomics, Griffith University, Parklands Drive, Southport, Queensland, Australia
| | - Mei-Fong Ho
- Institute for Glycomics, Griffith University, Parklands Drive, Southport, Queensland, Australia
| | | | - John Gerrard
- Gold Coast University Hospital, 1 Hospital Blvd, Southport, Queensland, Australia
| | - Michael F Good
- Institute for Glycomics, Griffith University, Parklands Drive, Southport, Queensland, Australia.
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36
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Glennon EKK, Dankwa S, Smith JD, Kaushansky A. Opportunities for Host-targeted Therapies for Malaria. Trends Parasitol 2018; 34:843-860. [PMID: 30122551 PMCID: PMC6168423 DOI: 10.1016/j.pt.2018.07.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/20/2018] [Accepted: 07/23/2018] [Indexed: 12/19/2022]
Abstract
Despite the recent successes of artemisinin-based antimalarial drugs, many still die from severe malaria, and eradication efforts are hindered by the limited drugs currently available to target transmissible gametocyte parasites and liver-resident dormant Plasmodium vivax hypnozoites. Host-targeted therapy is a new direction for infectious disease drug development and aims to interfere with host molecules, pathways, or networks that are required for infection or that contribute to disease. Recent advances in our understanding of host pathways involved in parasite development and pathogenic mechanisms in severe malaria could facilitate the development of host-targeted interventions against Plasmodium infection and malaria disease. This review discusses new opportunities for host-targeted therapeutics for malaria and the potential to harness drug polypharmacology to simultaneously target multiple host pathways using a single drug intervention.
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Affiliation(s)
- Elizabeth K K Glennon
- Center for Infectious Disease Research, 307 Westlake Ave N Suite 500, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Harris Hydraulics Laboratory, Box 357965, Seattle, WA 98195, USA; These authors made an equal contribution
| | - Selasi Dankwa
- Center for Infectious Disease Research, 307 Westlake Ave N Suite 500, Seattle, WA 98109, USA; These authors made an equal contribution
| | - Joseph D Smith
- Center for Infectious Disease Research, 307 Westlake Ave N Suite 500, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Harris Hydraulics Laboratory, Box 357965, Seattle, WA 98195, USA
| | - Alexis Kaushansky
- Center for Infectious Disease Research, 307 Westlake Ave N Suite 500, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Harris Hydraulics Laboratory, Box 357965, Seattle, WA 98195, USA.
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37
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Ghazanfari N, Mueller SN, Heath WR. Cerebral Malaria in Mouse and Man. Front Immunol 2018; 9:2016. [PMID: 30250468 PMCID: PMC6139318 DOI: 10.3389/fimmu.2018.02016] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 08/15/2018] [Indexed: 12/18/2022] Open
Abstract
Cerebral malaria (CM) is an acute encephalopathy caused by the malaria parasite Plasmodium falciparum, which develops in a small minority of infected patients and is responsible for the majority of deaths in African children. Despite decades of research on CM, the pathogenic mechanisms are still relatively poorly defined. Nevertheless, many studies in recent years, using a combination of animal models, in vitro cell culture work, and human patients, provide significant insight into the pathologic mechanisms leading to CM. In this review, we summarize recent findings from mouse models and human studies on the pathogenesis of CM, understanding of which may enable development of novel therapeutic approaches.
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Affiliation(s)
- Nazanin Ghazanfari
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.,The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia
| | - Scott N Mueller
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.,The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia
| | - William R Heath
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.,The ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC, Australia
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38
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Titov A, Petukhov A, Staliarova A, Motorin D, Bulatov E, Shuvalov O, Soond SM, Piacentini M, Melino G, Zaritskey A, Barlev NA. The biological basis and clinical symptoms of CAR-T therapy-associated toxicites. Cell Death Dis 2018; 9:897. [PMID: 30181581 PMCID: PMC6123453 DOI: 10.1038/s41419-018-0918-x] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 06/15/2018] [Accepted: 06/21/2018] [Indexed: 12/11/2022]
Abstract
Currently, immunotherapy is attracting a lot of attention and may potentially become a leading approach in the treatment of cancer. One emerging therapeutic, the chimeric-antigen receptor T-cell adoptive immunotherapy (CAR-T) is showing remarkable efficacy in the treatment of several B-cell malignancies. The popularity of CAR-T has been founded on two CAR T-cell products recently approved by FDA (during 2017) in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia and B-cell lymphoma. However, their toxicities observed in clinical trials were extremely significant and in some cases even fatal with no approved algorithms for toxicity prediction being available to date. A deeper understanding of the biological basis of such complications is the key to prompt and comprehensive clinical management. Here we review the wide spectrum of effects associated with CAR T cell therapy with a major focus on the pathogenesis of cytokine release syndrome and neurotoxicity as the most common, potentially life-threatening effects of this treatment. We discuss the basis of clinical management and the existing models that predict the severity of toxicity, as well as the key factors that modulate this event. Finally, we will summarize the literature detailing universal allogenic CAR T-cells and their toxicity profile.
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Affiliation(s)
- Aleksei Titov
- Almazov National Medical Research Centre, St. Petersburg, Russia, 197341
| | - Alexey Petukhov
- Almazov National Medical Research Centre, St. Petersburg, Russia, 197341.,Institute of Cytology of the Russian Academy of Science, St. Petersburg, Russia, 194064.,Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia, 420008
| | - Alena Staliarova
- Belarussian Research Center for Pediatric Oncology, Hematology and Immunology, 223053, Borovliani, Republic of Belarus
| | - Dmitriy Motorin
- Almazov National Medical Research Centre, St. Petersburg, Russia, 197341
| | - Emil Bulatov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia, 420008
| | - Oleg Shuvalov
- Institute of Cytology of the Russian Academy of Science, St. Petersburg, Russia, 194064
| | - Surinder M Soond
- Institute of Cytology of the Russian Academy of Science, St. Petersburg, Russia, 194064
| | - Mauro Piacentini
- Institute of Cytology of the Russian Academy of Science, St. Petersburg, Russia, 194064.,University of Rome Tor Vergata, 00173, Rome, Italy
| | - Gerry Melino
- Institute of Cytology of the Russian Academy of Science, St. Petersburg, Russia, 194064.,University of Rome Tor Vergata, 00173, Rome, Italy
| | - Andrey Zaritskey
- Almazov National Medical Research Centre, St. Petersburg, Russia, 197341
| | - Nickolai A Barlev
- Institute of Cytology of the Russian Academy of Science, St. Petersburg, Russia, 194064. .,Moscow Institute of Physics and Technology, Dolgoprudny, Moscow, Russia, 141701.
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Hosseini-Beheshti E, Grau GER. Extracellular vesicles as mediators of immunopathology in infectious diseases. Immunol Cell Biol 2018; 96:694-703. [PMID: 29577413 DOI: 10.1111/imcb.12044] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 03/19/2018] [Accepted: 03/19/2018] [Indexed: 12/12/2022]
Abstract
In the last decades, extracellular vesicles have emerged as important elements in cell-cell communication and as key players in disease pathogenesis via transmission of their cargo between different cells. Various works have described different subpopulations of these membrane structures, based on their cell of origin, biogenesis, size, biophysical properties and cargo. In addition to their pathophysiological role in the development and progression of different diseases including infectious diseases, neurodegenerative disorders and cancer, extracellular vesicles are now recognized for their potential as novel therapeutic targets and intelligent drug delivery system. Here, we have reviewed the most recent data on different subtypes of extracellular vesicles, focusing on microvesicles and exosomes and their subpopulations, their involvement in immune-mediated pathogenesis of various infectious diseases and their role as potential therapeutic targets.
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Affiliation(s)
- Elham Hosseini-Beheshti
- Vascular Immunology Unit, Department of Pathology, School of Medical Sciences, Marie Bashir Institute and The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, Camperdown, NSW, Australia
| | - Georges Emile Raymond Grau
- Vascular Immunology Unit, Department of Pathology, School of Medical Sciences, Marie Bashir Institute and The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, Camperdown, NSW, Australia
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40
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Plewes K, Turner GD, Dondorp AM. Pathophysiology, clinical presentation, and treatment of coma and acute kidney injury complicating falciparum malaria. Curr Opin Infect Dis 2018; 31:69-77. [PMID: 29206655 PMCID: PMC5768231 DOI: 10.1097/qco.0000000000000419] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE OF REVIEW Cerebral impairment and acute kidney injury (AKI) are independent predictors of mortality in both adults and children with severe falciparum malaria. In this review, we present recent advances in understanding the pathophysiology, clinical features, and management of these complications of severe malaria, and discuss future areas of research. RECENT FINDINGS Cerebral malaria and AKI are serious and well recognized complications of severe malaria. Common pathophysiological pathways include impaired microcirculation, due to sequestration of parasitized erythrocytes, systemic inflammatory responses, and endothelial activation. Recent MRI studies show significant brain swelling in both adults and children with evidence of posterior reversible encephalopathy syndrome-like syndrome although targeted interventions including mannitol and dexamethasone are not beneficial. Recent work shows association of cell-free hemoglobin oxidation stress involved in the pathophysiology of AKI in both adults and children. Paracetamol protected renal function likely by inhibiting cell-free-mediated oxidative stress. It is unclear if heme-mediated endothelial activation or oxidative stress is involved in cerebral malaria. SUMMARY The direct causes of cerebral and kidney dysfunction remain incompletely understood. Optimal treatment involves prompt diagnosis and effective antimalarial treatment with artesunate. Renal replacement therapy reduces mortality in AKI but delayed diagnosis is an issue.
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Affiliation(s)
- Katherine Plewes
- Faculty of Tropical Medicine, Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
- Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Gareth D.H. Turner
- Department of Cellular Pathology, John Radcliffe Hospital
- Nuffield Department of Clinical Medicine, Center for Tropical Medicine and Global Health, University of Oxford, Oxford, UK
| | - Arjen M. Dondorp
- Faculty of Tropical Medicine, Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
- Nuffield Department of Clinical Medicine, Center for Tropical Medicine and Global Health, University of Oxford, Oxford, UK
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41
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Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia. Blood 2017; 130:2585-2593. [PMID: 29051184 DOI: 10.1182/blood-2017-06-788935] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Accepted: 08/18/2017] [Indexed: 11/20/2022] Open
Abstract
Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416.
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42
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Nash SD, Prevots DR, Kabyemela E, Khasa YP, Lee KL, Fried M, Duffy PE. A Malaria-Resistant Phenotype with Immunological Correlates in a Tanzanian Birth Cohort Exposed to Intense Malaria Transmission. Am J Trop Med Hyg 2017; 96:1190-1196. [PMID: 28500801 DOI: 10.4269/ajtmh.16-0554] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
AbstractMalaria incidence is highly heterogeneous even in areas of high transmission, although no conclusive evidence exists that innate or naturally acquired resistance can prevent infection over an extended period of time. This longitudinal study examined immunoparasitological evidence for a malaria-resistant phenotype in which children do not develop malaria despite an extended period of exposure to parasites. Within a birth cohort followed from 2002 to 2006 in Muheza, Tanzania, an area of intense transmission, children (N = 687) provided blood smears biweekly during infancy and monthly thereafter. Maternal and childhood characteristics were obtained, cord-blood cytokines were measured, and antibody responses were assayed as measures of stage-specific exposure. Sixty-three (9.2%) children had no blood smear-positive slides over 2 years of follow-up (range: 1-3.5 years) and were identified as malaria resistant. Malaria-resistant children were similar to other children with respect to completeness of follow-up and all maternal and childhood characteristics except residence area. Antibody seroprevalence was similar for two sporozoite antigens, but malaria-resistant children had a lower antibody seroprevalence to merozoite antigens merozoite surface protein 1 (5.4% versus 30.2%; P < 0.0001) and apical membrane antigen 1 (7.2% versus 33.3%; P < 0.0001). Malaria-resistant children had higher cytokine levels in cord blood, particularly interleukin-1β. In summary, a subset of children living in an area of intense transmission was exposed to malaria parasites, but never developed patent parasitemia; this phenotype was associated with a distinct cytokine profile at birth and antibody profile during infancy. Further research with malaria-resistant children may identify mechanisms for naturally acquired immunity.
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Affiliation(s)
- Scott D Nash
- Epidemiology Unit, Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.,Laboratory of Malaria Immunology and Vaccinology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland
| | - D Rebecca Prevots
- Epidemiology Unit, Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | | | - Yogender P Khasa
- Department of Microbiology, University of Delhi South Campus, New Delhi, India
| | - Kun-Lin Lee
- Laboratory of Malaria Immunology and Vaccinology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland
| | - Michal Fried
- Laboratory of Malaria Immunology and Vaccinology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland
| | - Patrick E Duffy
- Laboratory of Malaria Immunology and Vaccinology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland
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Nguyen TN, Baaklini S, Koukouikila-Koussounda F, Ndounga M, Torres M, Pradel L, Ntoumi F, Rihet P. Association of a functional TNF variant with Plasmodium falciparum parasitaemia in a congolese population. Genes Immun 2017; 18:152-157. [DOI: 10.1038/gene.2017.13] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 05/08/2017] [Accepted: 05/10/2017] [Indexed: 11/09/2022]
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Sibiya H, Musabayane CT, Mabandla MV. Transdermal delivery of oleanolic acid attenuates pro-inflammatory cytokine release and ameliorates anaemia in P. berghei malaria. Acta Trop 2017; 171:24-29. [PMID: 28283442 DOI: 10.1016/j.actatropica.2017.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 02/28/2017] [Accepted: 03/06/2017] [Indexed: 12/13/2022]
Abstract
Malaria remains a major health problem in many tropical areas. Severe malaria infection is associated with secondary complications including anaemia leading to a need for the search of affordable antimalarial agents that can clear the parasitaemia and ameliorate anaemia during infection. The current study investigated the effects of transdermally delivered OA on malaria parasites, HCT and selected plasma cytokine concentrations in P. berghei-infected male Sprague-Dawley rats. The study was carried out over a period of 21days, divided into pre-treatment (day 0-7), treatment (day 8-12) and post-treatment (day 13-21) periods. Parasitaemia, HCT, RBC count, Hgb, plasma TNF-α, IL-6 and IL-10 concentrations were monitored in non-infected and infected rats following a once-off application of an OA-pectin patch (34mg/kg). Animals treated with drug-free pectin and CHQ (30mg/kg, p.o) twice daily for 5 consecutive days acted as negative and positive controls respectively. Infected control animals exhibited increased percentage parasitaemia, TNF-α, IL-6, IL-10 and a reduction in HCT. Interestingly, OA-pectin patch application cleared the malaria parasites and increased HCT values back to normalcy. Furthermore, TNF-α, IL-6 and IL-10 were reduced by day 12 of the study. These findings suggest that the OA-pectin patch delivers therapeutic doses of OA which are able to attenuate cytokine release and ameliorate anaemia during malaria infection. Therefore, transdermally delivered OA may be a potent therapeutic agent for malaria and amelioration of anaemia.
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Punsawad C, Viriyavejakul P. Reduction in serum sphingosine 1-phosphate concentration in malaria. PLoS One 2017; 12:e0180631. [PMID: 28666023 PMCID: PMC5493422 DOI: 10.1371/journal.pone.0180631] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 06/19/2017] [Indexed: 11/29/2022] Open
Abstract
Sphingosine 1-phosphate (S1P) is a lipid mediator formed by the metabolism of sphingomyelin which is involved in the endothelial permeability and inflammation. Although the plasma S1P concentration is reportedly decreased in patients with cerebral malaria, the role of S1P in malaria is still unclear. The purpose of this study was to examine the impact of malaria on circulating S1P concentration and its relationship with clinical data in malaria patients. Serum S1P levels were measured in 29 patients with P. vivax, 30 patients with uncomplicated P. falciparum, and 13 patients with complicated P. falciparum malaria on admission and on day 7, compared with healthy subjects (n = 18) as control group. The lowest level of serum S1P concentration was found in the complicated P. falciparum malaria group, compared with P. vivax, uncomplicated P. falciparum patients and healthy controls (all p < 0.001). In addition, serum S1P level was positively correlated with platelet count, hemoglobin and hematocrit levels in malaria patients. In conclusions, low levels of S1P are associated with the severity of malaria, and are correlated with thrombocytopenia and anemia. These findings highlight a role of S1P in the severity of malaria and support the use of S1P and its analogue as a novel adjuvant therapy for malaria complications.
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Affiliation(s)
- Chuchard Punsawad
- School of Medicine, Walailak University, Nakhon Si Thammarat, Thailand
- Tropical Diseases and Parasitic Infectious Diseases Research Group, Walailak University, Nakhon Si Thammarat, Thailand
| | - Parnpen Viriyavejakul
- Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
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Shabani E, Ouma BJ, Idro R, Bangirana P, Opoka RO, Park GS, Conroy AL, John CC. Elevated cerebrospinal fluid tumour necrosis factor is associated with acute and long-term neurocognitive impairment in cerebral malaria. Parasite Immunol 2017; 39. [PMID: 28453871 DOI: 10.1111/pim.12438] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 04/24/2017] [Indexed: 12/25/2022]
Abstract
Systemic tumour necrosis factor-α (TNF-α) may contribute to the pathogenesis of cerebral malaria (CM) by promoting endothelial activation and parasite sequestration. However, less is known about the role of central nervous system (CNS) TNF-α in CM. We assessed plasma (n=249) and cerebrospinal fluid (CSF) (n=167) TNF-α levels in Ugandan children with CM, plasma TNF-α in Ugandan community control children (n=198) and CSF TNF-α in North American control children who had recovered from leukaemia (n=13). Plasma and CSF TNF-α were measured by magnetic bead assay. We compared plasma and CSF TNF-α levels in children with CM to mortality, acute and chronic neurologic deficits and long-term neurocognitive impairment. Plasma and CSF TNF-α levels were higher in CM than control children (P<.0001 for both). CSF TNF-α levels were higher in children who had neurologic deficits at discharge or 6-month follow-up (P≤.05 for both). Elevated CSF but not plasma TNF-α was associated with longer coma duration (Spearman's rho .18, P=.02) and deficits in overall cognition in children 5 years and older (β coefficient -.74, 95% CI -1.35 to -0.13, P=.02). The study findings suggest that CNS TNF-α may be involved in the development of acute and chronic neurologic and cognitive sequelae in children with CM.
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Affiliation(s)
- E Shabani
- Department of Pediatrics, Division of Global Pediatrics, University of Minnesota, Minneapolis, MN, USA.,Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University, Indianapolis, IN, USA
| | - B J Ouma
- Department of Microbiology, Makerere University, Kampala, Uganda
| | - R Idro
- Department of Pediatrics and Child Health, Makerere University, Kampala, Uganda
| | - P Bangirana
- Department of Psychiatry, Makerere University, Kampala, Uganda
| | - R O Opoka
- Department of Pediatrics and Child Health, Makerere University, Kampala, Uganda
| | - G S Park
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
| | - A L Conroy
- Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University, Indianapolis, IN, USA
| | - C C John
- Department of Pediatrics, Division of Global Pediatrics, University of Minnesota, Minneapolis, MN, USA.,Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University, Indianapolis, IN, USA
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47
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Cytokine Profiles in Malawian Children Presenting with Uncomplicated Malaria, Severe Malarial Anemia, and Cerebral Malaria. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2017; 24:CVI.00533-16. [PMID: 28122790 PMCID: PMC5382826 DOI: 10.1128/cvi.00533-16] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 01/18/2017] [Indexed: 01/05/2023]
Abstract
Proinflammatory cytokines are involved in clearance of Plasmodium falciparum, and very high levels of these cytokines have been implicated in the pathogenesis of severe malaria. In order to determine how cytokines vary with disease severity and syndrome, we enrolled Malawian children presenting with cerebral malaria (CM), severe malarial anemia (SMA), and uncomplicated malaria (UCM) and healthy controls. We analyzed serum cytokine concentrations in acute infection and in convalescence. With the exception of interleukin 5 (IL-5), cytokine concentrations were highest in acute CM, followed by SMA, and were only mildly elevated in UCM. Cytokine concentrations had fallen to control levels when remeasured at 1 month of convalescence in all three clinical malaria groups. Ratios of IL-10 to tumor necrosis factor alpha (TNF-α) and of IL-10 to IL-6 followed a similar pattern. Children presenting with acute CM had significantly higher concentrations of TNF-α (P < 0.001), interferon gamma (IFN-γ) (P = 0.0019), IL-2 (P = 0.0004), IL-6 (P < 0.001), IL-8 (P < 0.001), and IL-10 (P < 0.001) in sera than healthy controls. Patients with acute CM had significantly higher concentrations of IL-6 (P < 0.001) and IL-10 (P = 0.0003) than those presenting with acute SMA. Our findings are consistent with the concept that high levels of proinflammatory cytokines, despite high levels of the anti-inflammatory cytokine IL-10, could contribute to the pathogenesis of CM.
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48
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Seki T, Obata-Ninomiya K, Shimogawara-Furushima R, Arai T, Akao N, Hoshino T, Ohta N. IL-33/ST2 contributes to severe symptoms in Plasmodium chabaudi-infected BALB/c mice. Parasitol Int 2017; 67:64-69. [PMID: 28359899 DOI: 10.1016/j.parint.2017.03.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Revised: 03/22/2017] [Accepted: 03/27/2017] [Indexed: 02/07/2023]
Abstract
It has been reported that IL-33 contributes to potentiation of Th2 inflammatory diseases and protection against helminth infection. Increased plasma IL-33 levels have been observed in patients with severe falciparum malaria, however, the role of IL-33 in malaria remains unclear. Here we report that IL-33 enhances inflammatory responses in malaria infection. ST2-deficiency altered severity of inflammation in the liver and serum levels of pro-inflammatory cytokines such as TNF-α and IL-6, and IL-13 that is a Th2 cytokine during Plasmodium chabaudi infection. IL-13-deficient mice have similar phenotype with ST2-deficient mice during P. chabaudi infection. Furthermore, ST2- and IL-13-deficiency reduced mortality from P. chabaudi infection. These results indicate that IL-33/ST2 can induce production of proinflammatory cytokines, such as TNF-α and IL-6, through production of IL-13 in P. chabaudi-infected BALB/c mice, suggesting that IL-33/ST2 play a critical role in inflammatory responses to malaria infection. Thus, these findings may define a novel therapeutic target for patients with severe malaria.
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Affiliation(s)
- Takenori Seki
- Department of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazushige Obata-Ninomiya
- Department of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo, Japan; Department of Immune Regulation, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | | | - Toshio Arai
- Department of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Nobuaki Akao
- Department of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomoaki Hoshino
- Division of Respirology, Neurology, and Rheumatology, Department of Medicine 1, Kurume University School of Medicine, Fukuoka, Japan
| | - Nobuo Ohta
- Department of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo, Japan.
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49
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Barker KR, Lu Z, Kim H, Zheng Y, Chen J, Conroy AL, Hawkes M, Cheng HS, Njock MS, Fish JE, Harlan JM, López JA, Liles WC, Kain KC. miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria. Mol Med 2017; 23:24-33. [PMID: 28182191 DOI: 10.2119/molmed.2016.00139] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 01/26/2017] [Indexed: 12/17/2022] Open
Abstract
miR-155 has been shown to participate in host response to infection and neuro-inflammation via negative regulation of blood-brain-barrier (BBB) integrity and T cell function. We hypothesized that miR-155 may contribute to the pathogenesis of cerebral malaria (CM). To test this hypothesis, we used a genetic approach to modulate miR-155 expression in an experimental model of cerebral malaria (ECM). In addition, an engineered endothelialized microvessel system and serum samples from Ugandan children with CM were used to examine an anti-miR-155 as a potential adjunctive therapeutic for severe malaria. Despite higher parasitemia, survival was significantly improved in miR-155-/- mice vs. wild-type littermate mice in ECM. Improved survival was associated with preservation of BBB integrity and reduced endothelial activation, despite increased levels of pro-inflammatory cytokines. Pre-treatment with antagomir-155 reduced vascular leak induced by human CM sera in an ex vivo endothelial microvessel model. These data provide evidence supporting a mechanistic role for miR-155 in host response to malaria via regulation of endothelial activation, microvascular leak and BBB dysfunction in CM.
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Affiliation(s)
- Kevin Richard Barker
- Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.,Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada
| | - Ziyue Lu
- Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada
| | - Hani Kim
- Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada
| | - Ying Zheng
- Department of Bioengineering, University of Washington, Seattle, WA, USA; Center of Cardiovascular Biology, Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
| | - Junmei Chen
- Bloodworks Northwest Research Institute, Seattle, WA, USA
| | - Andrea L Conroy
- Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada
| | - Michael Hawkes
- Division of Infectious Diseases, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Henry S Cheng
- Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.,Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada
| | - Makon-Sébastien Njock
- Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada
| | - Jason E Fish
- Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.,Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada
| | - John M Harlan
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Jose A López
- Bloodworks Northwest Research Institute, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA
| | - W Conrad Liles
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Kevin C Kain
- Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.,Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, and the Tropical Disease Unit, Department of Medicine, University of Toronto, ON, Canada
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50
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Gillrie MR, Ho M. Dynamic interactions of Plasmodium spp. with vascular endothelium. Tissue Barriers 2017; 5:e1268667. [PMID: 28452684 PMCID: PMC5362994 DOI: 10.1080/21688370.2016.1268667] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 11/24/2016] [Accepted: 11/30/2016] [Indexed: 12/18/2022] Open
Abstract
Plasmodial species are protozoan parasites that infect erythrocytes. As such, they are in close contact with microvascular endothelium for most of the life cycle in the mammalian host. The host-parasite interactions of this stage of the infection are responsible for the clinical manifestations of the disease that range from a mild febrile illness to severe and frequently fatal syndromes such as cerebral malaria and multi-organ failure. Plasmodium falciparum, the causative agent of the most severe form of malaria, is particularly predisposed to modulating endothelial function through either direct adhesion to endothelial receptor molecules, or by releasing potent host and parasite products that can stimulate endothelial activation and/or disrupt barrier function. In this review, we provide a critical analysis of the current clinical and laboratory evidence for endothelial dysfunction during severe P. falciparum malaria. Future investigations using state-of-the-art technologies such as mass cytometry and organs-on-chips to further delineate parasite-endothelial cell interactions are also discussed.
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Affiliation(s)
- Mark R. Gillrie
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - May Ho
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
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