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Carrera Silva EA, Puyssegur J, Errasti AE. Coevolutionary interplay: Helminths-trained immunity and its impact on the rise of inflammatory diseases. eLife 2025; 14:e105393. [PMID: 40231720 PMCID: PMC12002795 DOI: 10.7554/elife.105393] [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: 11/27/2024] [Accepted: 04/01/2025] [Indexed: 04/16/2025] Open
Abstract
The gut biome, a complex ecosystem of micro- and macro-organisms, plays a crucial role in human health. A disruption in this evolutive balance, particularly during early life, can lead to immune dysregulation and inflammatory disorders. 'Biome repletion' has emerged as a potential therapeutic approach, introducing live microbes or helminth-derived products to restore immune balance. While helminth therapy has shown some promise, significant challenges remain in optimizing clinical trials. Factors such as patient genetics, disease status, helminth species, and the optimal timing and dosage of their products or metabolites must be carefully considered to train the immune system effectively. We aim to discuss how helminths and their products induce trained immunity as prospective to treat inflammatory and autoimmune diseases. The molecular repertoire of helminth excretory/secretory products (ESPs), which includes proteins, peptides, lipids, and RNA-carrying extracellular vesicles (EVs), underscores their potential to modulate innate immune cells and hematopoietic stem cell precursors. Mimicking natural delivery mechanisms like synthetic exosomes could revolutionize EV-based therapies and optimizing production and delivery of ESP will be crucial for their translation into clinical applications. By deciphering and harnessing helminth-derived products' diverse modes of action, we can unleash their full therapeutic potential and pave the way for innovative treatments.
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Affiliation(s)
- Eugenio Antonio Carrera Silva
- EACS and JP Institute of Experimental Medicine, National Scientific and Technical Research Council, National Academy of Medicine (IMEX-CONICET-ANM)Buenos AiresArgentina
| | - Juliana Puyssegur
- EACS and JP Institute of Experimental Medicine, National Scientific and Technical Research Council, National Academy of Medicine (IMEX-CONICET-ANM)Buenos AiresArgentina
| | - Andrea Emilse Errasti
- AEE Institute of Pharmacology, School of Medicine, University of Buenos AiresBuenos AiresArgentina
- National Scientific and Technical Research Council (CONICET)Buenos AiresArgentina
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Della Bella C, Medici C, D'Elios S, Benagiano M, Ludovisi A, Gomez-Morales MA, D'Elios MM, Bruschi F. Interleukin 17 producing T cell responses in human chronic trichinellosis-insight from a case study. Cytokine 2024; 184:156795. [PMID: 39492146 DOI: 10.1016/j.cyto.2024.156795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
INTRODUCTION We studied the cellular immune response in a patient infected since 10 months (along with other 51 people) during a trichinellosis outbreak caused by Trichinella spp. METHODS A 46 years old female resulted serologically positive for trichinellosis. We isolated peripheral blood mononuclear cells (PBMCs) and incubated them with excretory/secretory antigens (ESA) of Trichinella spiralis (T1) or Trichinella pseudospiralis (T4) to produce antigen specific T cell lines and clones, analysed for the phenotype (T helper or cytotoxic cells), for their T4 or T1 antigens specificity and for their cytokine profile (IFNγ, IL-17A, IL-4) by flow cytometry, thymidine incorporation assay and ELISpot. RESULTS The test performed using ESA from T1 or T4 has identified the species responsible for infection as T. pseudospiralis since the proliferative responses (evaluated by CFSE, Carboxyfluorescein succinimidyl ester, FACS analysis) was higher for T4 (72,8%) than T1 (23.6 %) antigen. The cell lines produced significant levels of IFNγ, IL-4 and IL-17A after stimulation. From the T cell line obtained in response to T1 ESA, as regards CD4 + cells, 12 % Th2, 22.8 % Th1, 6.6 % Th17, 6 % Th0, 2.2 % Th1/Th17 and 0.7 % Th2/Th17, were obtained. From the T1-specific TCL we generated 15 clones. From the TCL specific for T4 ESA, as regards CD4+, 15.2 % Th2, 27.1 % Th1, 3 % Th17, 10.3 %Th0, 1.9 % Th1/Th17 and 1 % Th2/ Th17 were obtained. From such TCL 4 clones were isolated, 1Th2, 1 Th1, 1 Th17, 1 Th1/Th17 and no Th0 nor Th2/Th17. CONCLUSIONS By cellular immunology techniques the species responsible of the infection resulted T. pseudospiralis, confirming the results previously obtained by serology. For the first time it was revealed in a human chronic infection the presence of Th17 cells.
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Affiliation(s)
- Chiara Della Bella
- Department of Molecular and Developmental Medicine, University of Siena, Italy; Department of Experimental and Clinical Medicine, University of Firenze, Italy
| | - Chiara Medici
- Department of Translational Research, N.T.M.S., Università di Pisa, Pisa, Italy
| | - Sofia D'Elios
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Marisa Benagiano
- Department of Experimental and Clinical Medicine, University of Firenze, Italy
| | - Alessandra Ludovisi
- Department of Infectious Diseases, Istituto Superiore di Sanità, European Union Reference Laboratory for Parasites, Rome, Italy
| | - Maria Angeles Gomez-Morales
- Department of Infectious Diseases, Istituto Superiore di Sanità, European Union Reference Laboratory for Parasites, Rome, Italy
| | - Mario M D'Elios
- Department of Molecular and Developmental Medicine, University of Siena, Italy; Department of Experimental and Clinical Medicine, University of Firenze, Italy
| | - Fabrizio Bruschi
- Department of Translational Research, N.T.M.S., Università di Pisa, Pisa, Italy.
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Minervini G. Feature Paper in Oral Physiology and Pathology. Life (Basel) 2024; 14:895. [PMID: 39063647 PMCID: PMC11278310 DOI: 10.3390/life14070895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
In the realm of life sciences, the journal 'Life' has consistently served as a beacon for groundbreaking research and scientific discovery [...].
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Affiliation(s)
- Giuseppe Minervini
- Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 602105, Tamil Nadu, India;
- Multidisciplinary Department of Medical-Surgical and Odontostomatological Specialties, University of Campania “Luigi Vanvitelli”, 80121 Naples, Italy
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Singh I, Hoti SL, Chauhan N, Joshi RK, Prasad TSK, Sarikhani M, Kaushik M, Unger BS, Jadhav P, Modi PK. Immunomodulation of streptozotocin induced Type 1 diabetes mellitus in mouse model by Macrophage migration inhibitory factor-2 (MIF-2) homologue of human lymphatic filarial parasite, Wuchereria bancrofti. Acta Trop 2024; 252:107142. [PMID: 38331083 DOI: 10.1016/j.actatropica.2024.107142] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 02/05/2024] [Accepted: 02/05/2024] [Indexed: 02/10/2024]
Abstract
Helminth parasites modulate the host immune system to ensure a long-lasting asymptomatic form of infection generally, mediated by the secretion of immunomodulatory molecules and one such molecule is a homologue of human host cytokine, Macrophage migratory Inhibitory Factor (hMIF). In this study, we sought to understand the role of homologue of hMIF from the lymphatic filarial parasite, Wuchereria bancrofti (Wba-MIF2), in the immunomodulation of the Streptozotocin (STZ)-induced Type1 Diabetes Mellitus (T1DM) animal model. Full-length recombinant Wba-MIF2 was expressed and found to have both oxidoreductase and tautomerase activities. Wba-MIF2 recombinant protein was treated to STZ induced T1DM animals, and after 5 weeks pro-inflammatory (IL-1, IL-2, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4, IL-10) cytokines and gene expressions were determined in sera samples and spleen respectively. Pro-inflammatory and anti-inflammatory cytokine levels were significantly (p<0.05) up-regulated and down-regulated respectively, in the STZ-T1DM animals, as compared to treated groups. Histopathology showed macrophage infiltration and greater damage of islets of beta cells in the pancreatic tissue of STZ-T1DM animals, than Wba-MIF2 treated STZ-T1DM animals. The present study clearly showed the potential of Wba-MIF2 as an immunomodulatory molecule, which could modulate the host immune system in the STZ-T1DM mice model from a pro-inflammatory to anti-inflammatory milieu.
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Affiliation(s)
- Ishwar Singh
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India; KLE Academy of Higher Education and Research, Belagavi 590010, India Karnataka, India
| | - S L Hoti
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India.
| | - Nikhil Chauhan
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India
| | - R K Joshi
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India
| | - T S Keshava Prasad
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575007, Karnataka, India
| | | | - Meenakshi Kaushik
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India
| | - Banappa S Unger
- ICMR-National Institute of Traditional Medicine, Belagavi 590010, India Karnataka, India
| | - Pankaj Jadhav
- Indian Institute of Science, Bangalore 560012, Karnataka, India
| | - Prashant Kumar Modi
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575007, Karnataka, India
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Palkumbura PGAS, Mahakapuge TAN, Wijesundera RRMKK, Wijewardana V, Kangethe RT, Rajapakse RPVJ. Mucosal Immunity of Major Gastrointestinal Nematode Infections in Small Ruminants Can Be Harnessed to Develop New Prevention Strategies. Int J Mol Sci 2024; 25:1409. [PMID: 38338687 PMCID: PMC10855138 DOI: 10.3390/ijms25031409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/19/2024] [Accepted: 01/21/2024] [Indexed: 02/12/2024] Open
Abstract
Gastrointestinal parasitic nematode (GIN) infections are the cause of severe losses to farmers in countries where small ruminants such as sheep and goat are the mainstay of livestock holdings. There is a need to develop effective and easy-to-administer anti-parasite vaccines in areas where anthelmintic resistance is rapidly rising due to the inefficient use of drugs currently available. In this review, we describe the most prevalent and economically significant group of GIN infections that infect small ruminants and the immune responses that occur in the host during infection with an emphasis on mucosal immunity. Furthermore, we outline the different prevention strategies that exist with a focus on whole and purified native parasite antigens as vaccine candidates and their possible oral-nasal administration as a part of an integrated parasite control toolbox in areas where drug resistance is on the rise.
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Affiliation(s)
- P. G. Ashani S. Palkumbura
- Department of Veterinary Pathobiology, Faculty of Veterinary Medicine and Animal Science, University of Peradeniya, Kandy 20400, Sri Lanka
| | - Thilini A. N. Mahakapuge
- Department of Veterinary Pathobiology, Faculty of Veterinary Medicine and Animal Science, University of Peradeniya, Kandy 20400, Sri Lanka
| | - R. R. M. K. Kavindra Wijesundera
- Department of Veterinary Pathobiology, Faculty of Veterinary Medicine and Animal Science, University of Peradeniya, Kandy 20400, Sri Lanka
| | - Viskam Wijewardana
- Animal Production and Health Laboratory, Joint FAO/IAEA Centre of Nuclear Techniques in Food and Agriculture, International Atomic Energy Agency, 2444 Seibersdorf, Austria
| | - Richard Thiga Kangethe
- Animal Production and Health Laboratory, Joint FAO/IAEA Centre of Nuclear Techniques in Food and Agriculture, International Atomic Energy Agency, 2444 Seibersdorf, Austria
| | - R. P. V. Jayanthe Rajapakse
- Department of Veterinary Pathobiology, Faculty of Veterinary Medicine and Animal Science, University of Peradeniya, Kandy 20400, Sri Lanka
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Salama MA, Alabiad MA, Saleh AA. Impact of resveratrol and zinc on biomarkers of oxidative stress induced by Trichinella spiralis infection. J Helminthol 2023; 97:e100. [PMID: 38099459 DOI: 10.1017/s0022149x23000810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Trichinellosis is a re-emerging worldwide foodborne zoonosis. Oxidative stress is one of the most common detrimental effects caused by trichinellosis. In addition, Trichinella infection poses an infinite and major challenge to the host's immune system. Resistance and side effects limit the efficiency of the existing anti-trichinella medication. Given that concern, this work aimed to investigate the anti-helminthic, antioxidant, anti-inflammatory and immunomodulatory effects of resveratrol and zinc during both phases of Trichinella spiralis infection. Sixty-four Swiss albino mice were divided into four equal groups: non-infected control, infected control, infected and treated with resveratrol, and infected and treated with zinc. Animals were sacrificed on the 7th and 35th days post-infection for intestinal and muscular phase assessments. Drug efficacy was assessed by biochemical, parasitological, histopathological, immunological, and immunohistochemical assays. Resveratrol and zinc can be promising antiparasitic, antioxidant, anti-inflammatory, and immunomodulatory agents, as evidenced by the significant decrease in parasite burden, the significant improvement of liver and kidney function parameters, the increase in total antioxidant capacity (TAC), the reduction of malondialdehyde (MDA) level, the increase in nuclear factor (erythroid-derived 2)-like-2 factor expression, and the improvement in histopathological findings. Moreover, both drugs enhanced the immune system and restored the disturbed immune balance by increasing the interleukin 12 (IL-12) level. In conclusion, resveratrol and zinc provide protection for the host against oxidative harm and the detrimental effects produced by the host's defense response during Trichinella spiralis infection, making them promising natural alternatives for the treatment of trichinellosis.
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Affiliation(s)
- M A Salama
- Department of Medical Parasitology, Faculty of Medicine, Zagazig University, Egypt
| | - M A Alabiad
- Pathology Department, Faculty of Medicine, Zagazig University, Egypt
| | - A A Saleh
- Department of Medical Parasitology, Faculty of Medicine, Zagazig University, Egypt
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7
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Szczykutowicz J. Ligand Recognition by the Macrophage Galactose-Type C-Type Lectin: Self or Non-Self?-A Way to Trick the Host's Immune System. Int J Mol Sci 2023; 24:17078. [PMID: 38069400 PMCID: PMC10707269 DOI: 10.3390/ijms242317078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
The cells and numerous macromolecules of living organisms carry an array of simple and complex carbohydrates on their surface, which may be recognized by many types of proteins, including lectins. Human macrophage galactose-type lectin (MGL, also known as hMGL/CLEC10A/CD301) is a C-type lectin receptor expressed on professional antigen-presenting cells (APCs) specific to glycans containing terminal GalNAc residue, such as Tn antigen or LacdiNAc but also sialylated Tn antigens. Macrophage galactose-type lectin (MGL) exhibits immunosuppressive properties, thus facilitating the maintenance of immune homeostasis. Hence, MGL is exploited by tumors and some pathogens to trick the host immune system and induce an immunosuppressive environment to escape immune control. The aims of this article are to discuss the immunological outcomes of human MGL ligand recognition, provide insights into the molecular aspects of these interactions, and review the MGL ligands discovered so far. Lastly, based on the human fetoembryonic defense system (Hu-FEDS) hypothesis, this paper raises the question as to whether MGL-mediated interactions may be relevant in the development of maternal tolerance toward male gametes and the fetus.
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Affiliation(s)
- Justyna Szczykutowicz
- Department of Biochemistry and Immunochemistry, Division of Chemistry and Immunochemistry, Wroclaw Medical University, Sklodowskiej-Curie 48/50, 50-369 Wroclaw, Poland
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Al-kuraishy HM, Al-Gareeb AI, Alkazmi L, El-Bouseary MM, Hamad RS, Abdelhamid M, Batiha GES. The Potential Nexus between Helminths and SARS-CoV-2 Infection: A Literature Review. J Immunol Res 2023; 2023:5544819. [PMID: 37383608 PMCID: PMC10299886 DOI: 10.1155/2023/5544819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 04/05/2023] [Accepted: 05/25/2023] [Indexed: 06/30/2023] Open
Abstract
Chronic helminth infections (CHIs) can induce immunological tolerance through the upregulation of regulatory T cells. In coronavirus disease 2019 (COVID-19), abnormal adaptive immune response and exaggerated immune response may cause immune-mediated tissue damage. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and CHIs establish complicated immune interactions due to SARS-CoV-2-induced immunological stimulation and CHIs-induced immunological tolerance. However, COVID-19 severity in patients with CHIs is mild, as immune-suppressive anti-inflammatory cytokines counterbalance the risk of cytokine storm. Since CHIs have immunomodulatory effects, therefore, this narrative review aimed to clarify how CHIs modulate the immunoinflammatory response in SARS-CoV-2 infection. CHIs, through helminth-derived molecules, may suppress SARS-CoV-2 entry and associated hyperinflammation through attenuation of the inflammatory signaling pathway. In addition, CHIs may reduce the COVID-19 severity by reducing the SARS-CoV-2 entry points in the initial phase and immunomodulation in the late phase of the disease by suppressing the release of pro-inflammatory cytokines. In conclusion, CHIs may reduce the severity of SARS-CoV-2 infection by reducing hyperinflammation and exaggerated immune response. Thus, retrospective and prospective studies are recommended in this regard.
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Affiliation(s)
- Hayder M. Al-kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
| | - Luay Alkazmi
- Biology Department, Faculty of Applied Sciences, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Maisra M. El-Bouseary
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Rabab S. Hamad
- Biological Sciences Department, College of Science, King Faisal University, Al Ahsa 31982, Saudi Arabia
- Central Laboratory, Theodor Bilharz Research Institute, Giza 12411, Egypt
| | - Mahmoud Abdelhamid
- Department of Parasitology, Faculty of Veterinary Medicine, Aswan University, Aswan 81528, Egypt
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt
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Mariki A, Barzin Z, Fasihi Harandi M, Karbasi Ravari K, Davoodi M, Mousavi SM, Rezakhani S, Nazeri M, Shabani M. Antigen B modulates anti-inflammatory cytokines in the EAE model of multiple sclerosis. Brain Behav 2023; 13:e2874. [PMID: 36582052 PMCID: PMC9927863 DOI: 10.1002/brb3.2874] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/13/2021] [Accepted: 01/22/2022] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Multiple sclerosis (MS) is characterized by the destruction of the blood-brain barrier, loss of myelin sheath, and contribution of inflammatory interleukins such as TNF-alpha, interleukin-17, and interleukin-6. METHODS The current study investigated the effect of antigen B of hydatid cyst fluid on the reduction of anti-inflammatory cytokines and nerve conduction velocity in rats with experimental autoimmune encephalomyelitis (EAE)-induced MS. After isolation of antigen B from sterile cyst fluid, the rats were randomly divided into four groups: saline, EAE, EAE + teriflunomide (EAE + TF), and EAE + antigen B (EAE + AngB). The EAE model was induced using cow spinal cord homogenization, in combination with Freund's complete adjuvant. The serum concentration of cytokines including IL-1B and IL-17, IL-10, IL-6, and TNF-X was measured by the ELISA method, and real-time PCR was performed to study gene expression. Electrophysiological, behavioral, and neuropathological tests were also conducted. RESULTS Nerve conduction velocity and IL-10 concentration were increased in the antigen B group. The results of this study showed that antigen B reduced the inflammatory component of the EAE MS animal model by modulating the immune system compared to teriflunomide, which eventually led to a reduction in symptoms at the behavioral and electrophysiological level. CONCLUSIONS It seems that antigen B plays a critical role in regulating immunity and it can be used as a possible therapeutic agent to modulate the immune system in MS patients. It might be rational to consider hydatid cyst fluid antigen as a modifier in MS.
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Affiliation(s)
- Aliakbar Mariki
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Zahra Barzin
- Department of Parasitology and Mycology, School of Medicine, Jiroft University of Medical Science, Jiroft, Kerman, Iran
| | - Majid Fasihi Harandi
- Research Center for Hydatid Disease in Iran, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Mahboubeh Davoodi
- Student Research Committee, Yasuj University of Medical sciences, Yasuj, Iran
| | - Seyed Mohammad Mousavi
- Research Center for Hydatid Disease in Iran, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Soheila Rezakhani
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Masoud Nazeri
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran.,Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, University Hospital Erlangen, Krankenhausstraße, Germany
| | - Mohammad Shabani
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
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Costain AH, Phythian-Adams AT, Colombo SAP, Marley AK, Owusu C, Cook PC, Brown SL, Webb LM, Lundie RJ, Borger JG, Smits HH, Berriman M, MacDonald AS. Dynamics of Host Immune Response Development During Schistosoma mansoni Infection. Front Immunol 2022; 13:906338. [PMID: 35958580 PMCID: PMC9362740 DOI: 10.3389/fimmu.2022.906338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/23/2022] [Indexed: 12/27/2022] Open
Abstract
Schistosomiasis is a disease of global significance, with severity and pathology directly related to how the host responds to infection. The immunological narrative of schistosomiasis has been constructed through decades of study, with researchers often focussing on isolated time points, cell types and tissue sites of interest. However, the field currently lacks a comprehensive and up-to-date understanding of the immune trajectory of schistosomiasis over infection and across multiple tissue sites. We have defined schistosome-elicited immune responses at several distinct stages of the parasite lifecycle, in three tissue sites affected by infection: the liver, spleen, and mesenteric lymph nodes. Additionally, by performing RNA-seq on the livers of schistosome infected mice, we have generated novel transcriptomic insight into the development of schistosome-associated liver pathology and fibrosis across the breadth of infection. Through depletion of CD11c+ cells during peak stages of schistosome-driven inflammation, we have revealed a critical role for CD11c+ cells in the co-ordination and regulation of Th2 inflammation during infection. Our data provide an updated and high-resolution account of how host immune responses evolve over the course of murine schistosomiasis, underscoring the significance of CD11c+ cells in dictating host immunopathology against this important helminth infection.
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Affiliation(s)
- Alice H. Costain
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | | | - Stefano A. P. Colombo
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
| | - Angela K. Marley
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
| | - Christian Owusu
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Peter C. Cook
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
- Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom
| | - Sheila L. Brown
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
| | - Lauren M. Webb
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
- Department of Immunology, University of Washington, Seattle, WA, United States
| | | | | | - Hermelijn H. Smits
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Matthew Berriman
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
- Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow, United Kingdom
| | - Andrew S. MacDonald
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, United Kingdom
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Zawistowska-Deniziak A, Lambooij JM, Kalinowska A, Patente TA, Łapiński M, van der Zande HJP, Basałaj K, de Korne CM, Chayé MAM, Gasan TA, Norbury LJ, Giera M, Zaldumbide A, Smits HH, Guigas B. Fasciola hepatica Fatty Acid Binding Protein 1 Modulates T cell Polarization by Promoting Dendritic Cell Thrombospondin-1 Secretion Without Affecting Metabolic Homeostasis in Obese Mice. Front Immunol 2022; 13:884663. [PMID: 35720355 PMCID: PMC9204345 DOI: 10.3389/fimmu.2022.884663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/19/2022] [Indexed: 11/24/2022] Open
Abstract
Background The parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4+ T cell subsets. Methodology/Principal Findings The immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4+ T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis. Conclusions/Significance We show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.
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Affiliation(s)
- Anna Zawistowska-Deniziak
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
- Witold Stefański Institute of Parasitology, Polish Academy of Sciences, Warsaw, Poland
- Leiden University Center for Infectious Diseases (LU-CID), Leiden, Netherlands
| | - Joost M. Lambooij
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
- Leiden University Center for Infectious Diseases (LU-CID), Leiden, Netherlands
| | - Alicja Kalinowska
- Witold Stefański Institute of Parasitology, Polish Academy of Sciences, Warsaw, Poland
| | - Thiago A. Patente
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
- Leiden University Center for Infectious Diseases (LU-CID), Leiden, Netherlands
| | - Maciej Łapiński
- International Institute of Molecular and Cell Biology, Warsaw, Poland
| | - Hendrik J. P. van der Zande
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
- Leiden University Center for Infectious Diseases (LU-CID), Leiden, Netherlands
| | - Katarzyna Basałaj
- Witold Stefański Institute of Parasitology, Polish Academy of Sciences, Warsaw, Poland
| | - Clarize M. de Korne
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
- Leiden University Center for Infectious Diseases (LU-CID), Leiden, Netherlands
- Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
| | - Mathilde A. M. Chayé
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
- Leiden University Center for Infectious Diseases (LU-CID), Leiden, Netherlands
| | - Thomas A. Gasan
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
- Leiden University Center for Infectious Diseases (LU-CID), Leiden, Netherlands
| | - Luke J. Norbury
- Witold Stefański Institute of Parasitology, Polish Academy of Sciences, Warsaw, Poland
- School of Science, STEM College, Royal Melbourne Institute of Technology (RMIT) University, Bundoora, VIC, Australia
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
| | - Hermelijn H. Smits
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
- Leiden University Center for Infectious Diseases (LU-CID), Leiden, Netherlands
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
- Leiden University Center for Infectious Diseases (LU-CID), Leiden, Netherlands
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12
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Bunte MJM, Schots A, Kammenga JE, Wilbers RHP. Helminth Glycans at the Host-Parasite Interface and Their Potential for Developing Novel Therapeutics. Front Mol Biosci 2022; 8:807821. [PMID: 35083280 PMCID: PMC8784694 DOI: 10.3389/fmolb.2021.807821] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/20/2021] [Indexed: 12/26/2022] Open
Abstract
Helminths are parasitic worms that have successfully co-evolved with their host immune system to sustain long-term infections. Their successful parasitism is mainly facilitated by modulation of the host immune system via the release of excretory-secretory (ES) products covered with glycan motifs such as Lewis X, fucosylated LDN, phosphorylcholine and tyvelose. Evidence is accumulating that these glycans play key roles in different aspects of helminth infection including interactions with immune cells for recognition and evasion of host defences. Moreover, antigenic properties of glycans can be exploited for improving the efficacy of anti-helminthic vaccines. Here, we illustrate that glycans have the potential to open new avenues for the development of novel biopharmaceuticals and effective vaccines based on helminth glycoproteins.
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13
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Anderluh M, Berti F, Bzducha‐Wróbel A, Chiodo F, Colombo C, Compostella F, Durlik K, Ferhati X, Holmdahl R, Jovanovic D, Kaca W, Lay L, Marinovic‐Cincovic M, Marradi M, Ozil M, Polito L, Reina‐Martin JJ, Reis CA, Sackstein R, Silipo A, Švajger U, Vaněk O, Yamamoto F, Richichi B, van Vliet SJ. Emerging glyco-based strategies to steer immune responses. FEBS J 2021; 288:4746-4772. [PMID: 33752265 PMCID: PMC8453523 DOI: 10.1111/febs.15830] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/12/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023]
Abstract
Glycan structures are common posttranslational modifications of proteins, which serve multiple important structural roles (for instance in protein folding), but also are crucial participants in cell-cell communications and in the regulation of immune responses. Through the interaction with glycan-binding receptors, glycans are able to affect the activation status of antigen-presenting cells, leading either to induction of pro-inflammatory responses or to suppression of immunity and instigation of immune tolerance. This unique feature of glycans has attracted the interest and spurred collaborations of glyco-chemists and glyco-immunologists to develop glycan-based tools as potential therapeutic approaches in the fight against diseases such as cancer and autoimmune conditions. In this review, we highlight emerging advances in this field, and in particular, we discuss on how glycan-modified conjugates or glycoengineered cells can be employed as targeting devices to direct tumor antigens to lectin receptors on antigen-presenting cells, like dendritic cells. In addition, we address how glycan-based nanoparticles can act as delivery platforms to enhance immune responses. Finally, we discuss some of the latest developments in glycan-based therapies, including chimeric antigen receptor (CAR)-T cells to achieve targeting of tumor-associated glycan-specific epitopes, as well as the use of glycan moieties to suppress ongoing immune responses, especially in the context of autoimmunity.
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Affiliation(s)
- Marko Anderluh
- Chair of Pharmaceutical ChemistryFaculty of PharmacyUniversity of LjubljanaSlovenia
| | | | - Anna Bzducha‐Wróbel
- Department of Biotechnology and Food MicrobiologyWarsaw University of Life Sciences‐SGGWPoland
| | - Fabrizio Chiodo
- Department of Molecular Cell Biology and ImmunologyCancer Center AmsterdamAmsterdam Infection and Immunity InstituteAmsterdam UMCVrije Universiteit AmsterdamNetherlands
| | - Cinzia Colombo
- Department of Chemistry and CRC Materiali Polimerici (LaMPo)University of MilanItaly
| | - Federica Compostella
- Department of Medical Biotechnology and Translational MedicineUniversity of MilanItaly
| | - Katarzyna Durlik
- Department of Microbiology and ParasitologyJan Kochanowski UniversityKielcePoland
| | - Xhenti Ferhati
- Department of Chemistry ‘Ugo Schiff’University of FlorenceFlorenceItaly
| | - Rikard Holmdahl
- Division of Medical Inflammation ResearchDepartment of Medical Biochemistry and BiophysicsKarolinska InstituteStockholmSweden
| | - Dragana Jovanovic
- Vinča Institute of Nuclear Sciences ‐ National Institute of the Republic of SerbiaUniversity of BelgradeSerbia
| | - Wieslaw Kaca
- Department of Microbiology and ParasitologyJan Kochanowski UniversityKielcePoland
| | - Luigi Lay
- Department of Chemistry and CRC Materiali Polimerici (LaMPo)University of MilanItaly
| | - Milena Marinovic‐Cincovic
- Vinča Institute of Nuclear Sciences ‐ National Institute of the Republic of SerbiaUniversity of BelgradeSerbia
| | - Marco Marradi
- Department of Chemistry ‘Ugo Schiff’University of FlorenceFlorenceItaly
| | - Musa Ozil
- Department of ChemistryFaculty of Arts and SciencesRecep Tayyip Erdogan University RizeTurkey
| | | | | | - Celso A. Reis
- I3S – Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortugal
- IPATIMUP‐Institute of Molecular Pathology and ImmunologyInstituto de Ciências Biomédicas Abel SalazarUniversity of PortoPortugal
| | - Robert Sackstein
- Department of Translational Medicinethe Translational Glycobiology InstituteHerbert Wertheim College of MedicineFlorida International UniversityMiamiFLUSA
| | - Alba Silipo
- Department of Chemical SciencesUniversity of Naples Federico IIComplesso Universitario Monte Sant’AngeloNapoliItaly
| | - Urban Švajger
- Blood Transfusion Center of SloveniaLjubljanaSlovenia
| | - Ondřej Vaněk
- Department of BiochemistryFaculty of ScienceCharles UniversityPragueCzech Republic
| | - Fumiichiro Yamamoto
- Immunohematology & Glycobiology LaboratoryJosep Carreras Leukaemia Research InstituteBadalonaSpain
| | - Barbara Richichi
- Department of Chemistry ‘Ugo Schiff’University of FlorenceFlorenceItaly
| | - Sandra J. van Vliet
- Department of Molecular Cell Biology and ImmunologyCancer Center AmsterdamAmsterdam Infection and Immunity InstituteAmsterdam UMCVrije Universiteit AmsterdamNetherlands
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14
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Ducarmon QR, Hoogerwerf MA, Janse JJ, Geelen AR, Koopman JPR, Zwittink RD, Goeman JJ, Kuijper EJ, Roestenberg M. Dynamics of the bacterial gut microbiota during controlled human infection with Necator americanus larvae. Gut Microbes 2020; 12:1-15. [PMID: 33222610 PMCID: PMC7714523 DOI: 10.1080/19490976.2020.1840764] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Hookworms are soil-transmitted helminths that use immune-evasive strategies to persist in the human duodenum where they are responsible for anemia and protein loss. Given their location and immune regulatory effects, hookworms likely impact the bacterial microbiota. However, microbiota studies struggle to deconvolute the effect of hookworms from confounders such as coinfections and malnutrition. We thus used an experimental human hookworm infection model to explore temporal changes in the gut microbiota before and during hookworm infection. Volunteers were dermally exposed to cumulative dosages of 50, 100 or 150 L3 Necator americanus larvae. Fecal samples were collected for microbiota profiling through 16S rRNA gene amplicon sequencing at weeks zero, four, eight, fourteen and twenty. During the acute infection phase (trial week zero to eight) no changes in bacterial diversity were detected. During the established infection phase (trial week eight to twenty), bacterial richness (Chao1, p = .0174) increased significantly over all volunteers. No relation was found between larval dosage and diversity, stability or relative abundance of individual bacterial taxa. GI symptoms were associated with an unstable microbiota during the first eight weeks and rapid recovery at week twenty. Barnesiella, amongst other taxa, was more abundant in volunteers with more GI symptoms throughout the study. In conclusion, this study showed that clinical GI symptoms following N. americanus infection are associated with temporary microbiota instability and relative abundance of specific bacterial taxa. These results suggest a possible role of hookworm-induced enteritis on microbiota stability.
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Affiliation(s)
- Q. R. Ducarmon
- Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands,Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands,CONTACT Meta Roestenberg Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - M. A. Hoogerwerf
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - J. J. Janse
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - A. R. Geelen
- Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands,Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - J. P. R. Koopman
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - R. D. Zwittink
- Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands,Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - J. J. Goeman
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands
| | - E. J. Kuijper
- Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands,Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - M. Roestenberg
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands,Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
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15
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Wysmołek ME, Klockiewicz M, Sobczak-Filipiak M, Długosz E, Wiśniewski M. Case Studies of Severe Microfilaremia in Four Dogs Naturally Infected With Dirofilaria repens as the Primary Disease or a Disease Complicating Factor. Front Vet Sci 2020; 7:577466. [PMID: 33195580 PMCID: PMC7536554 DOI: 10.3389/fvets.2020.577466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 08/18/2020] [Indexed: 11/25/2022] Open
Abstract
Subcutaneous dirofilariosis in dogs, caused by Dirofilaria repens, is an underdiagnosed disease, now recognized for its zoonotic potential, and growing distribution and prevalence across Europe and Asia. Our understanding of the pathogenicity in human and canine host remains unclear, but case reports suggest that microfilariae (Mf) as well as adult D. repens may directly cause internal organs damage or may be a factor complicating the course of other ailments. The purpose of the study was to report high Mf in dogs and to discuss potential relevance with co-morbidity. Our data from a modified Knott's test performed on 62 infected dogs indicate that the median Mf count in D. repens infections is 675 Mf/ml and we consider microfilaremia above 10,000 Mf/ml as high intensity. This collection of case reports discusses 4 cases of high intensity D. repens microfilaremia in companion dogs; one presenting pathology from a very high intensity of adult D. repens with post-treatment complications, and 3 dogs in which high microfilaremia was detected incidentally during the management of other primary illnesses. To our knowledge this report describes the highest D. repens microfilaremia ever detected in a dog, at 178,000 Mf/ml. The issue of high microfilaremic infections in dogs is poorly studied and there is growing need to identify the presentation and understand the mechanisms of associated pathogenesis in the host-parasite relationship.
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Affiliation(s)
- Magdalena E Wysmołek
- Division of Parasitology and Parasitic Diseases, Department of Pre-Clinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Maciej Klockiewicz
- Division of Parasitology and Parasitic Diseases, Department of Pre-Clinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Małgorzata Sobczak-Filipiak
- Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Ewa Długosz
- Division of Parasitology and Parasitic Diseases, Department of Pre-Clinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Marcin Wiśniewski
- Division of Parasitology and Parasitic Diseases, Department of Pre-Clinical Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
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Abstract
The hygiene hypothesis posits that the decreased incidence of parasitic infection in developed countries may underlie an increased prevalence of allergic and autoimmune diseases in these countries. As unique inflammation modulator of intracellular parasitism, Trichinella spiralis, or its excretory-secretory (ES) product, shows improved responses to allergies, autoimmune diseases, inflammatory bowel disease, type 1 diabetes, rheumatic arthritis and autoimmune encephalomyelitis by exerting immunomodulatory effects on both innate and adaptive immune cells in animal models. Research has shown that T. spiralis differs from other helminths in manipulation of the host immune response not only by well-known characteristics of its life cycle, but also by its inflammation modulation pathway. How the parasite achieves inflammation modulation has not been fully elucidated yet. This review will generalize the mechanism and focuses on ES immunomodulatory molecules of T. spiralis that may be important for developing new therapeutics for inflammatory disorders.
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17
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Lamiable O, Mayer JU, Munoz-Erazo L, Ronchese F. Dendritic cells in Th2 immune responses and allergic sensitization. Immunol Cell Biol 2020; 98:807-818. [PMID: 32738152 DOI: 10.1111/imcb.12387] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/29/2020] [Accepted: 07/29/2020] [Indexed: 12/23/2022]
Abstract
Allergic responses are characterized by the activation of a specific subset of effector CD4+ T cells, the T-helper type 2 (Th2) cells, that respond to harmless environmental antigens causing inflammation and pathology. Th2 cells are also found in the context of parasite infections, where they can mediate parasite clearance and expulsion, and support tissue repair. The process that leads to the activation of Th2 cells in vivo is incompletely understood: while it has become clear that "conventional" dendritic cells are essential antigen-presenting cells for the initiation of Th2 immune responses, the molecules that are expressed by dendritic cells exposed to allergens, and the mediators that are produced as a consequence and signal to naïve CD4+ T cells to promote their development into effector Th2, remain to be defined. Here we summarize recent developments in the identification of the dendritic cell subsets involved in Th2 responses, review potential mechanisms proposed to explain the generation of these immune responses, and discuss the direct and indirect signals that condition dendritic cells to drive the development of Th2 responses during allergen or parasite exposure.
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Affiliation(s)
| | | | | | - Franca Ronchese
- Malaghan Institute of Medical Research, Wellington, New Zealand
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19
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Jin X, Bai X, Yang Y, Ding J, Shi H, Fu B, Boireau P, Liu M, Liu X. NLRP3 played a role in Trichinella spiralis-triggered Th2 and regulatory T cells response. Vet Res 2020; 51:107. [PMID: 32854770 PMCID: PMC7457311 DOI: 10.1186/s13567-020-00829-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 08/10/2020] [Indexed: 01/05/2023] Open
Abstract
Trichinella spiralis maintains chronic infections within its host. Muscle larvae excretory-secretory products (MLES) typically induce parasite-specific immune responses such as the Th2 response and regulatory T cells (Tregs) by modulating dendritic cell (DC) phenotype via the recognition of pattern recognition receptors (PRRs), such as Nod-like receptors (NLRs). We aimed to investigate the role of NLRP3 in T. spiralis-triggered immune response. We found that larvae burden was increased in NLRP3−/− mice compared to wild type (WT) mice. Administration of MLES induced higher levels of IL-4, IL-10, TGF-β and population of Tregs in WT mice than in NLRP3−/− mice. In vitro, we showed that increased expression of CD40 on the surface of MLES-treated DCs was inhibited after NLRP3 knockout. Increased production of IL-1β, IL-18, IL-10 and TGF-β, but not IL-12p70, was significantly diminished in the absence of NLRP3. Furthermore, our results demonstrated that MLES-treated DCs induced higher levels of IL-4, IL-10 and TGF-β and populations of Tregs in vitro. These inductions were abolished by NLRP3 deficiency in DCs, suggesting that NLRP3 in MLES-treated DCs plays a role in promoting the Th2 and Treg response. Taken together, we identified for the first time the involvement of NLRP3 in host defences against T. spiralis.
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Affiliation(s)
- Xuemin Jin
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Xue Bai
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Yong Yang
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Jing Ding
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Haining Shi
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA
| | - Baoquan Fu
- Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Pascal Boireau
- JRU BIPAR, ANSES, École Nationale Vétérinaire d'Alfort, INRA, Université Paris-Est, Animal Health Laboratory, Maisons-Alfort, France
| | - Mingyuan Liu
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China. .,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, People's Republic of China.
| | - Xiaolei Liu
- Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China.
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20
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Mei X, Shi W, Zhao W, Luo H, Zhang Y, Wang Y, Sheng Z, Wang D, Zhu XQ, Huang W. Fasciola gigantica excretory-secretory products (FgESPs) modulate the differentiation and immune functions of buffalo dendritic cells through a mechanism involving DNMT1 and TET1. Parasit Vectors 2020; 13:355. [PMID: 32680546 PMCID: PMC7368760 DOI: 10.1186/s13071-020-04220-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022] Open
Abstract
Background Fasciola gigantica infection threatens the health of both humans and animals in the world. The excretory/secretory products (ESPs) of this fluke has been reported to impair the activation and maturation of immune cells. We have previously shown the influence of F. gigantica ESPs (FgESPs) on the maturation of buffalo dendritic cells (DCs). However, the underlying mechanisms remain unclear. The objective of this study was to investigate the potency of FgESPs in shifting the differentiation and immune functions of buffalo DCs. Methods Buffalo DCs were incubated with FgESPs directly or further co-cultured with lymphocytes in vitro. qRT-PCR was employed to determine the gene expression profile of DCs or the mixed cells, and an ELISA was used to measure cytokine levels in the supernatants. Hoechst and Giemsa staining assays, transmission electron microscopy, caspase-3/7 activity test and histone methylation test were performed to determine DC phenotyping, apoptosis and methylation. To investigate the mechanism involved with DNA methylation, a Co-IP assay and immunofluorescent staining assay were performed to observe if there was any direct interaction between FgESPs and DNMT1/TET1 in buffalo DCs, while RNAi technology was employed to knockdown DNMT1 and TET1 in order to evaluate any different influence of FgESPs on DCs when these genes were absent. Results qRT-PCR and ELISA data together demonstrated the upregulation of DC2 and Th2/Treg markers in DCs alone and DCs with a mixed lymphocyte reaction (MLR), suggesting a bias of DC2 that potentially directed Th2 differentiation in vitro. DC apoptosis was also found and evidenced morphologically and biochemically, which might be a source of tolerogenic DCs that led to Treg differentiation. In addition, FgESPs induced methylation level changes of histones H3K4 and H3K9, which correlate with DNA methylation. Co-IP and immunofluorescent subcellular localization assays showed no direct interaction between the FgESPs and DNMT1/TET1 in buffalo DCs. The productions of IL-6 and IL-12 were found separately altered by the knockdown of DNMT1 and TET1 in DCs after FgESPs treatment. Conclusions FgESPs may induce the DC2 phenotype or the apoptosis of buffalo DCs to induce the downstream Th2/Treg response of T cells, possibly through a DNMT1- or TET1-dependent manner(s).![]()
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Affiliation(s)
- Xuefang Mei
- School of Animal Science and Technology, Guangxi University, Nanning, 530005, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Wei Shi
- School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Wenping Zhao
- School of Animal Science and Technology, Guangxi University, Nanning, 530005, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Honglin Luo
- Guangxi Key Laboratory for Aquatic Genetic Breeding and Healthy Aquaculture, Guangxi Institute of Fishery Sciences, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yaoyao Zhang
- School of Animal Science and Technology, Guangxi University, Nanning, 530005, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yurui Wang
- School of Animal Science and Technology, Guangxi University, Nanning, 530005, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Zhaoan Sheng
- School of Animal Science and Technology, Guangxi University, Nanning, 530005, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Dongying Wang
- School of Animal Science and Technology, Guangxi University, Nanning, 530005, Guangxi Zhuang Autonomous Region, People's Republic of China.
| | - Xing-Quan Zhu
- State Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Veterinary Parasitology of Gansu Province, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730046, Gansu, People's Republic of China. .,Jiangsu Co-innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University College of Veterinary Medicine, Yangzhou, 225009, Jiangsu, People's Republic of China.
| | - Weiyi Huang
- School of Animal Science and Technology, Guangxi University, Nanning, 530005, Guangxi Zhuang Autonomous Region, People's Republic of China.
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ASGR1 and Its Enigmatic Relative, CLEC10A. Int J Mol Sci 2020; 21:ijms21144818. [PMID: 32650396 PMCID: PMC7404283 DOI: 10.3390/ijms21144818] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/19/2022] Open
Abstract
The large family of C-type lectin (CLEC) receptors comprises carbohydrate-binding proteins that require Ca2+ to bind a ligand. The prototypic receptor is the asialoglycoprotein receptor-1 (ASGR1, CLEC4H1) that is expressed primarily by hepatocytes. The early work on ASGR1, which is highly specific for N-acetylgalactosamine (GalNAc), established the foundation for understanding the overall function of CLEC receptors. Cells of the immune system generally express more than one CLEC receptor that serve diverse functions such as pathogen-recognition, initiation of cellular signaling, cellular adhesion, glycoprotein turnover, inflammation and immune responses. The receptor CLEC10A (C-type lectin domain family 10 member A, CD301; also called the macrophage galactose-type lectin, MGL) contains a carbohydrate-recognition domain (CRD) that is homologous to the CRD of ASGR1, and thus, is also specific for GalNAc. CLEC10A is most highly expressed on immature DCs, monocyte-derived DCs, and alternatively activated macrophages (subtype M2a) as well as oocytes and progenitor cells at several stages of embryonic development. This receptor is involved in initiation of TH1, TH2, and TH17 immune responses and induction of tolerance in naïve T cells. Ligand-mediated endocytosis of CLEC receptors initiates a Ca2+ signal that interestingly has different outcomes depending on ligand properties, concentration, and frequency of administration. This review summarizes studies that have been carried out on these receptors.
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Hidalgo C, Stoore C, Hernández M, Paredes R. Fasciola hepatica coinfection modifies the morphological and immunological features of Echinococcus granulosus cysts in cattle. Vet Res 2020; 51:76. [PMID: 32503674 PMCID: PMC7275569 DOI: 10.1186/s13567-020-00799-5] [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: 02/10/2020] [Accepted: 05/11/2020] [Indexed: 12/17/2022] Open
Abstract
Polyparasitism occurs when animals harbour multiple parasites concomitantly. It is a common occurrence but is generally understudied in wild and domestic animals. Fasciola hepatica and Echinococcus granulosus, which are helminths of ungulates, frequently coinfect cattle. The effects of this particular type of polyparasitism are not well documented. The metacestode of Echinococcus granulosus is surrounded by the adventitial layer, which constitutes the host immune response to the parasite. This layer in cattle is produced by a granulomatous reaction and is involved in echinococcal cyst (EC) fertility. Due to the systemic immune-modulating abilities of Fasciola hepatica, coinfection possibly generates a favourable environment for EC growth. A total of 203 Echinococcus granulosus sensu stricto cysts were found in 82 cattle, of which 42 ECs were found in 31 animals coinfected with Fasciola hepatica. The overall infection intensity was 3 cysts per animal. Coinfection with Fasciola hepatica decreased the mean infection intensity to 1.4 cysts per animal. Regarding EC size, coinfection resulted in smaller ECs (15.91 vs 22.09 mm), especially for infertile lung cysts. The adventitial layer of ECs in coinfected animals lacked lymphoid follicles and palisading macrophages, which are generally hallmarks of the granulomatous immune response. The ECs in coinfected animals had organized laminated layers, whereas those in animals without coinfection did not. Although coinfection was not statistically associated with EC fertility, we did not find fertile cysts in the livers of coinfected animals. We concluded that coinfection with Fasciola hepatica and Echinococcus granulosus has a detrimental effect on ECs, particularly infertile cysts.
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Affiliation(s)
- Christian Hidalgo
- Laboratorio de Medicina Veterinaria, Escuela de Medicina Veterinaria, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile.,Instituto de Ciencias Agroalimentarias, Animales y Ambientales (ICA3), Universidad de O'Higgins, San Fernando, Chile
| | - Caroll Stoore
- Laboratorio de Medicina Veterinaria, Escuela de Medicina Veterinaria, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile
| | - Marcela Hernández
- Laboratorio de Biología Periodontal y Departamento de Patología y Medicina Oral, Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | - Rodolfo Paredes
- Laboratorio de Medicina Veterinaria, Escuela de Medicina Veterinaria, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile.
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Rodriguez C. The global helminth belt and Covid-19: the new eosinophilic link. ACTA ACUST UNITED AC 2020. [DOI: 10.32388/iwkqh9.2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Abdoli A, Ardakani HM. Helminth infections and immunosenescence: The friend of my enemy. Exp Gerontol 2020; 133:110852. [PMID: 32007545 DOI: 10.1016/j.exger.2020.110852] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 12/13/2019] [Accepted: 01/21/2020] [Indexed: 12/14/2022]
Abstract
Age-associated alterations of the immune system, which known as "immunosenescence", is characterized by a decline in innate and adaptive immunity, which leading to increased susceptibility to age-associated diseases, such as infectious diseases, rheumatic disease and malignancies. On the other hand, helminth infections are among the most prevalent infections in older individuals, especially in the nursing homes. Most of helminth infections have minor clinical symptoms and usually causing chronic infections without treatment. Nevertheless, chronic helminthiasis alters immune responses somewhat similar to the immunosenescence. Some similarities also exist between helminth infections and immunosenescence: 1) both of them led to declining the immune responses; 2) undernutrition is a consequence of immunosenescence and helminthiasis; 3) vaccine efficacy declines in aging and individuals with helminth infections; 4) increase incidence and prevalence of infectious diseases in the elder individuals and patients with helminth infections; and 5) both of them promote tumorigenesis. Hence, it is probable that helminth infections in the elderly population can intensify the immunosenescence outcomes due to the synergistic immunoregulatory effects of each of them. It would be suggested that, diagnosis, treatment and prevention of helminth infections should be more considered in older individuals. Also, it would be suggested that helminths or their antigens can be used for investigation of immunosenescence because both of them possess some similarities in immune alterations. Taken together, this review offers new insights into the immunology of aging and helminth infections.
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Affiliation(s)
- Amir Abdoli
- Department of Parasitology and Mycology, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran; Zoonoses Research Center, Jahrom University of Medical Sciences, Jahrom, Iran; Research Center for Noncommunicable Diseases, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.
| | - Hoda Mirzaian Ardakani
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Abdoli A, Mirzaian Ardakani H. Potential application of helminth therapy for resolution of neuroinflammation in neuropsychiatric disorders. Metab Brain Dis 2020; 35:95-110. [PMID: 31352539 DOI: 10.1007/s11011-019-00466-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 07/14/2019] [Indexed: 12/19/2022]
Abstract
Neuropsychiatric disorders (NPDs) are among the major debilitating disorders worldwide with multiple etiological factors. However, in recent years, psychoneuroimmunology uncovered the role of inflammatory condition and autoimmune disorders in the etiopathogenesis of different NPDs. Hence, resolution of inflammation is a new therapeutic target of NPDs. On the other hand, Helminth infections are among the most prevalent infectious diseases in underdeveloped countries, which usually caused chronic infections with minor clinical symptoms. Remarkably, helminths are among the master regulator of inflammatory reactions and epidemiological studies have shown an inverse association between prevalence of autoimmune disorders with these infections. As such, changes of intestinal microbiota are known to be associated with inflammatory conditions in various NPDs. Conversely, helminth colonization alters the intestinal microbiota composition that leads to suppression of intestinal inflammation. In animal models and human studies, helminths or their antigens have shown to be protected against severe autoimmune and allergic disorders, decline the intensity of inflammatory reactions and improved clinical symptoms of the patients. Therefore, "helminthic therapy" have been used for modulation of immune disturbances in different autoimmunity illnesses, such as Multiple Sclerosis (MS) and Inflammatory Bowel Disease (IBD). Here, it is proposed that "helminthic therapy" is able to ameliorate neuroinflammation of NPDs through immunomodulation of inflammatory reactions and alteration of microbiota composition. This review discusses the potential application of "helminthic therapy" for resolution of neuroinflammation in NPDs.
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Affiliation(s)
- Amir Abdoli
- Department of Parasitology and Mycology, School of Medicine, Jahrom University of Medical Sciences, POBox 74148-46199, Ostad Motahari Ave, Jahrom, Iran.
- Zoonoses Research Center, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.
- Research Center for Noncommunicable Diseases, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.
| | - Hoda Mirzaian Ardakani
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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26
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Engineering universal cells that evade immune detection. Nat Rev Immunol 2019; 19:723-733. [DOI: 10.1038/s41577-019-0200-1] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2019] [Indexed: 12/15/2022]
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Zamora V, Rodero M, Andreu-Ballester JC, Mendez S, Cuéllar C. Induction of tolerogenic properties by Anisakis larval antigens on murine dendritic cells. Parasite Immunol 2019; 41:e12616. [PMID: 30719721 DOI: 10.1111/pim.12616] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 01/24/2019] [Accepted: 01/29/2019] [Indexed: 12/17/2022]
Abstract
AIMS The objective of this work is to investigate whether Anisakis simplex larval antigens present immunomodulatory properties by the induction of tolerogenic dendritic cells (DCs) from two strains of mice (BALB/c and C57BL/6J). METHODS AND RESULTS We used mouse bone marrow-derived DCs. We determined their antigen-presenting ability by expression of membrane markers (MHC I and MHC II, CD80, CD86) and intracellular expression levels of IL-10 and IL-12 cytokines. We also analysed whether stimulation with A simplex larval antigens is enhanced by the co-administration of the TLR4 and TLR9 agonists [LPS E coli 026B6 and CpG (ODN1826), respectively]. Two differential types of responses were found in the two mouse strains studied: the BALB/c strain showed an acute and inflammatory response, whereas the C57BL/6J mice developed a more discrete and resistant response. This suggests the coexistence of two opposing responses generated by A simplex larval antigens and confirms that the host genetic basis plays a role in the development of a Th2 or Treg response. CONCLUSION The study of the mechanisms by which Anisakis manipulates the immune response through anti-inflammatory molecules is of interest not only for the direct application on the development of anthelmintic strategies, but also for the development of new anti-inflammatory products.
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Affiliation(s)
- Vega Zamora
- Facultad de Farmacia, Departamento de Microbiología y Parasitología, Universidad Complutense, Madrid, Spain
| | - Marta Rodero
- Facultad de Farmacia, Departamento de Microbiología y Parasitología, Universidad Complutense, Madrid, Spain
| | | | - Susana Mendez
- Microbiology Review Branch, DHHS/NIH/NIAID/DEA/SRP, Rockville, Maryland
| | - Carmen Cuéllar
- Facultad de Farmacia, Departamento de Microbiología y Parasitología, Universidad Complutense, Madrid, Spain
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28
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Arroyo-López C. Helminth therapy for autism under gut-brain axis- hypothesis. Med Hypotheses 2019; 125:110-118. [PMID: 30902137 DOI: 10.1016/j.mehy.2019.02.042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/18/2019] [Indexed: 12/20/2022]
Abstract
Autism is a neurodevelopmental disease included within Autism Syndrome Disorder (ASD) spectrum. ASD has been linked to a series of genes that play a role in immune response function and patients with autism, commonly suffer from immune-related comorbidities. Despite the complex pathophysiology of autism, Gut-brain axis is gaining strength in the understanding of several neurological disorders. In addition, recent publications have shown the correlation between immune dysfunctions, gut microbiota and brain with the behavioral alterations and comorbid symptoms found in autism. Gut-brain axis acts as the "second brain", in a communication network established between neural, endocrine and the immunological systems. On the other hand, Hygiene Hypothesis suggests that the increase in the incidence of autoimmune diseases in the modern world can be attributed to the decrease of exposure to infectious agents, as parasitic nematodes. Helminths induce modulatory and protective effects against several inflammatory disorders, maintaining gastrointestinal homeostasis and modulating brain functions. Helminthic therapy has been previously performed in diseases such as ulcerative colitis, Crohn's disease, diabetes, multiple sclerosis, asthma, rheumatoid arthritis, and food allergies. Considering gut-brain axis, Hygiene Hypothesis, and the modulatory effects of helminths I hypothesized that a treatment with Trichuris suis soluble products represents a feasible holistic treatment for autism, and the key for the development of novel treatments. Preclinical studies are required to test this hypothesis.
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Affiliation(s)
- Celia Arroyo-López
- Department of Pathology and Laboratory Medicine, UC Davis School of Medicine; Institute for Pediatric Regenerative Medicine and Shriners Hospitals for Children of Northern California, United States.
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29
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30
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Gong W, Huang F, Sun L, Yu A, Zhang X, Xu Y, Shen Y, Cao J. Toll-like receptor-2 regulates macrophage polarization induced by excretory-secretory antigens from Schistosoma japonicum eggs and promotes liver pathology in murine schistosomiasis. PLoS Negl Trop Dis 2018; 12:e0007000. [PMID: 30589840 PMCID: PMC6307705 DOI: 10.1371/journal.pntd.0007000] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 11/14/2018] [Indexed: 12/30/2022] Open
Abstract
Schistosomiasis is endemic to many regions of the world and affects approximately 200 million people. Conventional adaptive T cell responses are considered to be the primary contributors to the pathogenesis of Schistosoma japonicum infection, leading to liver granuloma and fibrosis. However, the functional polarization of macrophages and the associated underlying molecular mechanisms during the pathogenesis of schistosomiasis remains unknown. In the present study, we found that excretory-secretory (ES) antigens derived from S. japonicum eggs can activate macrophages, which exhibit an M2b polarization. Furthermore, ES antigen-induced M2b polarization was found to be dependent on enhanced NF-κB signaling mediated by the MyD88/MAPK pathway in a TLR2-dependent manner. In addition, the cytokine profile of the liver macrophages from wild-type-infected mice are quite distinct from those found in TLR2 knockout-infected mice by quantitative PCR analysis. More importantly, the size of granuloma and the severity of the fibrosis in the livers of TLR2-/- mice were significantly reduced compared to that in WT mice. Our findings reveal a novel role for M2b polarization in the pathogenesis of schistosome infection. Schistosomiasis is a global health concern that affects primarily tropical and subtropical areas. During a schistosome infection, the eggs are trapped in the host liver and products derived from eggs induce a polarized Th2 response, resulting in granuloma formation and eventually fibrosis. Thus, it is important to elucidate the mechanism of granuloma formation and fibrosis development. Here, we show that activated macrophages play a novel role in the promotion of hepatic granuloma formation and liver fibrosis in a Schistosoma japonicum-infected mouse model. In addition, M2b polarization induced by egg products was dependent on enhanced NF-κB signaling mediated by the MyD88/MAPK pathway in a TLR2-dependent manner. Our findings reveal a novel role and mechanism of M2b polarization in the liver pathogenesis in S. japonicum-infected mice.
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Affiliation(s)
- Wenci Gong
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, China; National Center for International Research on Tropical Diseases, China; WHO Collaborating Center for Tropical Diseases, Shanghai, China
| | - Fengjuan Huang
- Department of Immunology, Tongji University School of Medicine, Shanghai, China
| | - Lei Sun
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, China; National Center for International Research on Tropical Diseases, China; WHO Collaborating Center for Tropical Diseases, Shanghai, China
| | - Aiping Yu
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, China; National Center for International Research on Tropical Diseases, China; WHO Collaborating Center for Tropical Diseases, Shanghai, China
| | - Xiaofan Zhang
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, China; National Center for International Research on Tropical Diseases, China; WHO Collaborating Center for Tropical Diseases, Shanghai, China
| | - Yuxin Xu
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, China; National Center for International Research on Tropical Diseases, China; WHO Collaborating Center for Tropical Diseases, Shanghai, China
| | - Yujuan Shen
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, China; National Center for International Research on Tropical Diseases, China; WHO Collaborating Center for Tropical Diseases, Shanghai, China
| | - Jianping Cao
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention; Key Laboratory of Parasite and Vector Biology, Ministry of Health, China; National Center for International Research on Tropical Diseases, China; WHO Collaborating Center for Tropical Diseases, Shanghai, China
- * E-mail:
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31
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Smita S, Ahad A, Ghosh A, Biswas VK, Koga MM, Gupta B, Acha-Orbea H, Raghav SK. Importance of EMT Factor ZEB1 in cDC1 "MutuDC Line" Mediated Induction of Th1 Immune Response. Front Immunol 2018; 9:2604. [PMID: 30483264 PMCID: PMC6243008 DOI: 10.3389/fimmu.2018.02604] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/23/2018] [Indexed: 12/12/2022] Open
Abstract
The role of Epithelial to Mesenchymal Transition (EMT) factor Zeb1 is well defined in metastasis and cancer progression but it's importance in dendritic cells (DCs) is unexplored until now. For the first time we report here that Zeb1 controls immunogenic responses of CD8α+ conventional Type-I (cDC1) DCs. We found that ZEB1 expression increases significantly after TLR9 stimulation and its depletion impairs activation, co-stimulation and secretion of important cytokines like IL-6, IL-10 and IL-12 in cDC1 MutuDC line. We further confirmed our findings in primary cDC1 DCs derived from bone marrow. Co-culture of these Zeb1 knock down (KD) DCs with OT-II CD4+ T helper cells skewed their differentiation toward Th2 subtype. Moreover, adoptive transfer of activated Zeb1 KD DCs cleared intestinal worms in helminth infected mice by increasing Th2 responses in vivo. Integrative genomic analysis showed Zeb1 as an activator of immune response genes in cDC1 MutuDCs as compared to other pathway genes. In addition, differentially regulated genes in Zeb1 KD RNA-seq showed significant enrichment of Th2 activation pathways supporting our in vitro findings. Mechanistically, we showed that decreased IL-12 secreted by Zeb1 KD DCs is the plausible mechanism for increased Th2 differentiation. Collectively our data demonstrate that Zeb1 could be targeted in DCs to modulate T-cell mediated adaptive immune responses.
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Affiliation(s)
- Shuchi Smita
- Immuno-genomics and Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, India.,Manipal Academy of Higher Education, Manipal, India
| | - Abdul Ahad
- Immuno-genomics and Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, India.,Manipal Academy of Higher Education, Manipal, India
| | - Arup Ghosh
- Immuno-genomics and Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, India.,Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, India
| | - Viplov K Biswas
- Immuno-genomics and Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, India.,Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, India
| | - Marianna M Koga
- Department of Biochemistry CIIL, University of Lausanne (UNIL), Epalinges, Switzerland
| | - Bhawna Gupta
- Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, India
| | - Hans Acha-Orbea
- Department of Biochemistry CIIL, University of Lausanne (UNIL), Epalinges, Switzerland
| | - Sunil K Raghav
- Immuno-genomics and Systems Biology Laboratory, Institute of Life Sciences (ILS), Bhubaneswar, India.,Manipal Academy of Higher Education, Manipal, India.,Department of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Bhubaneswar, India
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32
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King IL, Li Y. Host-Parasite Interactions Promote Disease Tolerance to Intestinal Helminth Infection. Front Immunol 2018; 9:2128. [PMID: 30298071 PMCID: PMC6160735 DOI: 10.3389/fimmu.2018.02128] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 08/29/2018] [Indexed: 12/15/2022] Open
Abstract
Parasitic helminths are among the most pervasive pathogens of the animal kingdom. To complete their life cycle, these intestinal worms migrate through host tissues causing significant damage in their wake. As a result, infection can lead to malnutrition, anemia and increased susceptibility to co-infection. Despite repeated deworming treatment, individuals living in endemic regions remain highly susceptible to re-infection by helminths, but rarely succumb to excessive tissue damage. The chronicity of infection and inability to resist numerous species of parasitic helminths that have co-evolved with their hosts over millenia suggests that mammals have developed mechanisms to tolerate this infectious disease. Distinct from resistance where the goal is to destroy and eliminate the pathogen, disease tolerance is an active process whereby immune and structural cells restrict tissue damage to maintain host fitness without directly affecting pathogen burden. Although disease tolerance is evolutionary conserved and has been well-described in plant systems, only recently has this mode of host defense, in its strictest sense, begun to be explored in mammals. In this review, we will examine the inter- and intracellular networks that support disease tolerance during enteric stages of parasitic helminth infection and why this alternative host defense strategy may have evolved to endure the presence of non-replicating pathogens and maintain the essential functions of the intestine.
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Affiliation(s)
- Irah L King
- McGill University Health Centre, Montreal, QC, Canada.,Meakins-Christie Laboratories, Montreal, QC, Canada
| | - Yue Li
- McGill University Health Centre, Montreal, QC, Canada.,Meakins-Christie Laboratories, Montreal, QC, Canada
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33
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Obieglo K, Schuijs MJ, Ozir-Fazalalikhan A, Otto F, van Wijck Y, Boon L, Lambrecht BN, Taube C, Smits HH. Isolated Schistosoma mansoni eggs prevent allergic airway inflammation. Parasite Immunol 2018; 40:e12579. [PMID: 30107039 PMCID: PMC6175163 DOI: 10.1111/pim.12579] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 07/30/2018] [Indexed: 12/26/2022]
Abstract
Chronic helminth infection with Schistosoma (S.) mansoni protects against allergic airway inflammation (AAI) in mice and is associated with reduced Th2 responses to inhaled allergens in humans, despite the presence of schistosome‐specific Th2 immunity. Schistosome eggs strongly induce type 2 immunity and allow to study the dynamics of Th2 versus regulatory responses in the absence of worms. Treatment with isolated S. mansoni eggs by i.p. injection prior to induction of AAI to ovalbumin (OVA)/alum led to significantly reduced AAI as assessed by less BAL and lung eosinophilia, less cellular influx into lung tissue, less OVA‐specific Th2 cytokines in lungs and lung‐draining mediastinal lymph nodes and less circulating allergen‐specific IgG1 and IgE antibodies. While OVA‐specific Th2 responses were inhibited, treatment induced a strong systemic Th2 response to the eggs. The protective effect of S. mansoni eggs was unaltered in μMT mice lacking mature (B2) B cells and unaffected by Treg cell depletion using anti‐CD25 blocking antibodies during egg treatment and allergic sensitization. Notably, prophylactic egg treatment resulted in a reduced influx of pro‐inflammatory, monocyte‐derived dendritic cells into lung tissue of allergic mice following challenge. Altogether, S. mansoni eggs can protect against the development of AAI, despite strong egg‐specific Th2 responses.
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Affiliation(s)
- Katja Obieglo
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - Martijn J Schuijs
- Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Ghent, Belgium.,Department of Internal Medicine, Ghent University, Ghent, Belgium
| | | | - Frank Otto
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - Yolanda van Wijck
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Bart N Lambrecht
- Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center, Ghent, Belgium.,Department of Internal Medicine, Ghent University, Ghent, Belgium
| | - Christian Taube
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Hermelijn H Smits
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
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Salazar-Castañón VH, Juárez-Avelar I, Legorreta-Herrera M, Govezensky T, Rodriguez-Sosa M. Co-infection: the outcome of Plasmodium infection differs according to the time of pre-existing helminth infection. Parasitol Res 2018; 117:2767-2784. [PMID: 29938323 DOI: 10.1007/s00436-018-5965-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 06/07/2018] [Indexed: 01/28/2023]
Abstract
Although helminth-Plasmodium coinfections are common in tropical regions, the implications of this co-existence for the host immune response are poorly understood. In order to understand the effect of helminth infection at different times of coinfection on the immune response against Plasmodium infection, BALB/c mice were intraperitoneally infected with Taenia crassiceps (Tc). At 2 (Tc2) or 8 (Tc8) weeks post-infection, mice were intravenously infected with 1 × 103 Plasmodium yoelii (Py) 17XL-parasitized red blood cells. Py 17XL-single-infected mice developed cachexia, splenomegaly, and anemia, and died at 11 days post-infection. Importantly, Tc2 + Py-coinfected mice showed increased survival of 58% on day 11, but developed pathology (cachexia and splenomegaly) and succumbed on day 18 post-coinfection, this latter associated with high levels of IL-1β and IL-12, and reduced IFN-γ in serum compared with Py 17XL-single-infected mice. Interestingly, Tc8 + Py-coinfected mice showed increased survival up to 80% on day 11 and succumbed on day 30 post-coinfection. This increased survival rate conferred by chronic helminth infection was associated with a decreased pathology and mixed inflammatory-type 1/anti-inflammatory-type 2 immune profile as evidenced by the production of high levels of IL-12 and IL-10, and reduced TNF-α from macrophages, high levels of IL-4 and IL-10, and low levels of IFN-γ from spleen cells. Also high serum levels of IL-1β, TNF-α, IL-12, IL-4, and IL-10, but a significant reduction of IFN-γ were observed. Together, these data indicate that polarization of the cell-mediated response modulated by a pre-existing helminth infection differentially impacts on the host immune response to Py 17XL in a time-dependent manner.
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Affiliation(s)
- Víctor H Salazar-Castañón
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Avenida de los Barrios Número 1, Colonia Los Reyes Iztacala, C.P. 54090, Tlalnepantla, Estado de México, Mexico
| | - Imelda Juárez-Avelar
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Avenida de los Barrios Número 1, Colonia Los Reyes Iztacala, C.P. 54090, Tlalnepantla, Estado de México, Mexico
| | - Martha Legorreta-Herrera
- Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Batalla 5 de mayo s/n, Col. Ejército de Oriente, Iztapalapa, C.P. 09230, Ciudad de México, Mexico
| | - Tzipe Govezensky
- Departamento de Biología Molecular, Instituto de Investigaciones Biomédicas, Universidad Nacional Autònoma de México (UNAM), Ciudad de México, Mexico
| | - Miriam Rodriguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), Avenida de los Barrios Número 1, Colonia Los Reyes Iztacala, C.P. 54090, Tlalnepantla, Estado de México, Mexico.
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35
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Sefiddashti RR, Sharafi SM, Ebrahimi SA, Akhlaghi L, Moosavi A, Eskandarian A, Darani HY. A 53 KDa Glycan Antigen of Hydatid Cyst Wall May Involve in Evasion from Host Immune System. Adv Biomed Res 2018; 7:82. [PMID: 29930922 PMCID: PMC5991282 DOI: 10.4103/abr.abr_287_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background: Recent studies have shown that similar host glycan antigens are expressed by helminths such as Echinococcus granulosus hydatid cysts to evade from host immune system. In this work to investigate these antigens further, immunological cross-reactivity between human sera and hydatid cyst wall antigens has been investigated. Materials and Methods: Hydatid cyst wall antigens were used in enzyme-linked immunosorbent assay and Western immunoblotting and probed with pooled sera of hydatidosis patients and healthy controls. Sodium metaperiodate treatment was used to investigate glycan antigens. Results: A band with molecular weight about 53 KDa reacted with both hydatid patients' sera and also normal human sera. It has been shown that this band was a glycan antigen. Conclusions: A 53 KDa glycan antigen of hydatid cyst wall that reacted with all human sera may have an important role for evasion from host immune system.
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Affiliation(s)
- Raheleh Rafiei Sefiddashti
- Department of Medical Parasitology and Mycology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyedeh Maryam Sharafi
- Infectious Diseases and Tropical Medicine Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Soltan Ahmad Ebrahimi
- Department of Pharmacology, Faculty of Medicine, Razi Institute for Drug Research, Iran University of Medical Sciences, Tehran, Iran
| | - Lame Akhlaghi
- Department of Medical Parasitology and Mycology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Moosavi
- Department of of Medical Parasitology and Mycology, Iran University of Medical Sciences, Tehran, Iran
| | - Abasali Eskandarian
- Department of Parasitology and Mycology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Yousofi Darani
- Department of Parasitology and Mycology, Isfahan University of Medical Sciences, Isfahan, Iran
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36
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Motran CC, Silvane L, Chiapello LS, Theumer MG, Ambrosio LF, Volpini X, Celias DP, Cervi L. Helminth Infections: Recognition and Modulation of the Immune Response by Innate Immune Cells. Front Immunol 2018; 9:664. [PMID: 29670630 PMCID: PMC5893867 DOI: 10.3389/fimmu.2018.00664] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 03/19/2018] [Indexed: 01/06/2023] Open
Abstract
The survival of helminths in the host over long periods of time is the result of a process of adaptation or dynamic co-evolution between the host and the parasite. However, infection with helminth parasites causes damage to the host tissues producing the release of danger signals that induce the recruitment of various cells, including innate immune cells such as macrophages (Mo), dendritic cells (DCs), eosinophils, basophils, and mast cells. In this scenario, these cells are able to secrete soluble factors, which orchestrate immune effector mechanisms that depend on the different niches these parasites inhabit. Here, we focus on recent advances in the knowledge of excretory-secretory products (ESP), resulting from helminth recognition by DCs and Mo. Phagocytes and other cells types such as innate lymphocyte T cells 2 (ILC2), when activated by ESP, participate in an intricate cytokine network to generate innate and adaptive Th2 responses. In this review, we also discuss the mechanisms of innate immune cell-induced parasite killing and the tissue repair necessary to assure helminth survival over long periods of time.
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Affiliation(s)
- Claudia Cristina Motran
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Córdoba, Argentina
| | - Leonardo Silvane
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Córdoba, Argentina
| | - Laura Silvina Chiapello
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Córdoba, Argentina
| | - Martin Gustavo Theumer
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Córdoba, Argentina
| | - Laura Fernanda Ambrosio
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Córdoba, Argentina
| | - Ximena Volpini
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Córdoba, Argentina
| | - Daiana Pamela Celias
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Córdoba, Argentina
| | - Laura Cervi
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Córdoba, Argentina
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37
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Vendelova E, Ashour D, Blank P, Erhard F, Saliba AE, Kalinke U, Lutz MB. Tolerogenic Transcriptional Signatures of Steady-State and Pathogen-Induced Dendritic Cells. Front Immunol 2018. [PMID: 29541071 PMCID: PMC5835767 DOI: 10.3389/fimmu.2018.00333] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Dendritic cells (DCs) are key directors of tolerogenic and immunogenic immune responses. During the steady state, DCs maintain T cell tolerance to self-antigens by multiple mechanisms including inducing anergy, deletion, and Treg activity. All of these mechanisms help to prevent autoimmune diseases or other hyperreactivities. Different DC subsets contribute to pathogen recognition by expression of different subsets of pattern recognition receptors, including Toll-like receptors or C-type lectins. In addition to the triggering of immune responses in infected hosts, most pathogens have evolved mechanisms for evasion of targeted responses. One such strategy is characterized by adopting the host’s T cell tolerance mechanisms. Understanding these tolerogenic mechanisms is of utmost importance for therapeutic approaches to treat immune pathologies, tumors and infections. Transcriptional profiling has developed into a potent tool for DC subset identification. Here, we review and compile pathogen-induced tolerogenic transcriptional signatures from mRNA profiling data of currently available bacterial- or helminth-induced transcriptional signatures. We compare them with signatures of tolerogenic steady-state DC subtypes to identify common and divergent strategies of pathogen induced immune evasion. Candidate molecules are discussed in detail. Our analysis provides further insights into tolerogenic DC signatures and their exploitation by different pathogens.
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Affiliation(s)
- Emilia Vendelova
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Diyaaeldin Ashour
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Patrick Blank
- 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
| | - Florian Erhard
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, 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
| | - Manfred B Lutz
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
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38
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Ilic N, Gruden-Movsesijan A, Cvetkovic J, Tomic S, Vucevic DB, Aranzamendi C, Colic M, Pinelli E, Sofronic-Milosavljevic L. Trichinella spiralis Excretory-Secretory Products Induce Tolerogenic Properties in Human Dendritic Cells via Toll-Like Receptors 2 and 4. Front Immunol 2018; 9:11. [PMID: 29416536 PMCID: PMC5787699 DOI: 10.3389/fimmu.2018.00011] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 01/04/2018] [Indexed: 12/20/2022] Open
Abstract
Trichinella spiralis, as well as its muscle larvae excretory–secretory products (ES L1), given either alone or via dendritic cells (DCs), induce a tolerogenic immune microenvironment in inbred rodents and successfully ameliorate experimental autoimmune encephalomyelitis. ES L1 directs the immunological balance away from T helper (Th)1, toward Th2 and regulatory responses by modulating DCs phenotype. The ultimate goal of our work is to find out if it is possible to translate knowledge obtained in animal model to humans and to generate human tolerogenic DCs suitable for therapy of autoimmune diseases through stimulation with ES L1. Here, the impact of ES L1 on the activation of human monocyte-derived DCs is explored for the first time. Under the influence of ES L1, DCs acquired tolerogenic (semi-matured) phenotype, characterized by low expression of HLA-DR, CD83, and CD86 as well as moderate expression of CD40, along with the unchanged production of interleukin (IL)-12 and elevated production of IL-10 and transforming growth factor (TGF)-β, compared to controls. The interaction with DCs involved toll-like receptors (TLR) 2 and 4, and this interaction was mainly responsible for the phenotypic and functional properties of ES L1-treated DCs. Importantly, ES L1 potentiated Th2 polarizing capacity of DCs, and impaired their allo-stimulatory and Th1/Th17 polarizing properties. Moreover, ES L1-treated DCs promoted the expansion of IL-10- and TGF-β- producing CD4+CD25hiFoxp3hi T cells in indolamine 2, 3 dioxygenase (IDO)-1-dependent manner and increased the suppressive potential of the primed T cell population. ES L1-treated DCs retained the tolerogenic properties, even after the challenge with different pro-inflammatory stimuli, including those acting via TLR3 and, especially TLR4. These results suggest that the induction of tolerogenic properties of DCs through stimulation with ES L1 could represent an innovative approach for the preparation of tolerogenic DC for treatment of inflammatory and autoimmune disorders.
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Affiliation(s)
- Nataša Ilic
- Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia
| | | | - Jelena Cvetkovic
- Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia
| | - Sergej Tomic
- Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia
| | | | - Carmen Aranzamendi
- Groningen Biomolecular Science and Biotechnology Institute (GBB), University of Groningen, Groningen, Netherlands.,Centre for Infectious Disease Control Netherlands, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
| | - Miodrag Colic
- Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia.,Medical Faculty of the Military Medical Academy, University of Defence, Belgrade, Serbia
| | - Elena Pinelli
- Centre for Infectious Disease Control Netherlands, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands
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39
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Redpath SA, Heieis GA, Reynolds LA, Fonseca NM, Kim SSY, Perona-Wright G. Functional specialization of intestinal dendritic cell subsets during Th2 helminth infection in mice. Eur J Immunol 2017; 48:87-98. [PMID: 28960280 DOI: 10.1002/eji.201747073] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 08/08/2017] [Accepted: 09/20/2017] [Indexed: 12/18/2022]
Abstract
Dendritic cells (DCs) are essential in dictating the nature and effectiveness of immune responses. In the intestine DCs can be separated into discrete subsets, defined by expression of CD11b and CD103, each with different developmental requirements and distinct functional potential. Recent evidence has shown that different intestinal DC subsets are involved in the induction of T helper (Th)17 and regulatory T cell responses, but the cells that initiate Th2 immune responses are still incompletely understood. We show that in the Th2 response to an intestinal helminth in mice, only CD11b+ and not CD11b- DCs accumulate in the local lymph node, upregulate PDL2 and express markers of alternative activation. An enteric Th1 response instead activated both CD11b+ and CD11b- DCs without eliciting alternative activation in either population. Functionally, only CD11b+ DCs activated during helminth infection supported Th2 differentiation in naive CD4+ T cells. Together our data demonstrate that the ability to prime Th2 cells during intestinal helminth infection, is a selective and inducible characteristic of CD11b+ DCs.
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Affiliation(s)
- Stephen A Redpath
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Graham A Heieis
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.,Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Lisa A Reynolds
- Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada
| | - Nicolette M Fonseca
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Sandra S-Y Kim
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Georgia Perona-Wright
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.,Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
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40
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TLR Specific Immune Responses against Helminth Infections. J Parasitol Res 2017; 2017:6865789. [PMID: 29225962 PMCID: PMC5684585 DOI: 10.1155/2017/6865789] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 09/21/2017] [Accepted: 10/03/2017] [Indexed: 01/07/2023] Open
Abstract
Despite marked improvement in the quality of lives across the globe, more than 2 million individuals in socioeconomically disadvantaged environments remain infected by helminth (worm) parasites. Owing to the longevity of the worms and paucity of immunologic controls, these parasites survive for long periods within the bloodstream, lymphatics, and gastrointestinal tract resulting in pathologic conditions such as anemia, cirrhosis, and lymphatic filariasis. Despite infection, an asymptomatic state may be maintained by the host immunoregulatory environment, which involves multiple levels of regulatory cells and cytokines; a breakdown of this regulation is observed in pathological disease. The role of TLR expression and function in relation to intracellular parasites has been documented but limited studies are available for multicellular helminth parasites. In this review, we discuss the unique and shared host effector mechanisms elicited by systemic helminth parasites and their derived products, including the role of TLRs and sphingolipids. Understanding and exploiting the interactions between these parasites and the host regulatory network are likely to highlight new strategies to control both infectious and immunological diseases.
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41
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Grubor NM, Jovanova-Nesic KD, Shoenfeld Y. Liver cystic echinococcosis and human host immune and autoimmune follow-up: A review. World J Hepatol 2017; 9:1176-1189. [PMID: 29109850 PMCID: PMC5666304 DOI: 10.4254/wjh.v9.i30.1176] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 08/28/2017] [Accepted: 09/14/2017] [Indexed: 02/06/2023] Open
Abstract
Cystic echinococcosis (CE) is an infectious disease caused by the larvae of parasite Echinococcus granulosus (E. granulosus). To successfully establish an infection, parasite release some substances and molecules that can modulate host immune functions, stimulating a strong anti-inflammatory reaction to carry favor to host and to reserve self-survival in the host. The literature was reviewed using MEDLINE, and an open access search for immunology of hydatidosis was performed. Accumulating data from animal experiments and human studies provided us with exciting insights into the mechanisms involved that affect all parts of immunity. In this review we used the existing scientific data and discuss how these findings assisted with a better understanding of the immunology of E. granulosus infection in man. The aim of this study is to point the several facts that challenge immune and autoimmune responses to protect E. granulosus from elimination and to minimize host severe pathology. Understanding the immune mechanisms of E. granulosus infection in an intermediate human host will provide, we believe, a more useful treatment with immunomodulating molecules and possibly better protection from parasitic infections. Besides that, the diagnosis of CE has improved due to the application of a new molecular tool for parasite identification by using of new recombinant antigens and immunogenic peptides. More studies for the better understanding of the mechanisms of parasite immune evasion is necessary. It will enable a novel approach in protection, detection and improving of the host inflammatory responses. In contrast, according to the "hygiene hypothesis", clinical applications that decrease the incidence of infection in developed countries and recently in developing countries are at the origin of the increasing incidence of both allergic and autoimmune diseases. Thus, an understanding of the immune mechanisms of E. granulosus infection is extremely important.
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Affiliation(s)
- Nikica M Grubor
- Department of Hepatobiliary and Pancreatic Surgery, First Surgical University Hospital, Clinical Center of Serbia, School of Medicine University of Belgrade, 11000 Belgrade, Serbia
| | - Katica D Jovanova-Nesic
- Immunology Research Center, Institute of Virology, Vaccine and Sera-Torlak, 11221 Belgrade, Serbia
- European Center for Peace and Development, University for Peace in the United Nation established in Belgrade, 11000 Belgrade, Serbia.
| | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Aviv University, 5265601 Tel-Hashomer, Tel Aviv, Israel
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42
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Abstract
Many major tropical diseases are caused by long-lived helminth parasites that are able to survive by modulation of the host immune system, including the innate compartment of myeloid cells. In particular, dendritic cells and macrophages show markedly altered phenotypes during parasite infections. In addition, many specialized subsets such as eosinophils and basophils expand dramatically in response to these pathogens. The changes in phenotype and function, and their effects on both immunity to infection and reactivity to bystander antigens such as allergens, are discussed.
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43
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Abstract
MS incidence has significantly increased during the second half of the 20th century, generating considerable interest in analyzing the basis for this rise in the developed world. Particular emphasis is being placed on the role infections might play in exacerbating or preventing disease onset. Epidemiological data suggest that improvement in sanitation conditions and reduced exposure to infection might explain, at least in part, these changes. The hygiene hypothesis is not new and is currently used to explain the increasing incidence of allergies and other autoimmune diseases. Because helminths are powerful modulators of host immunity, some authors hypothesize that reduced parasite exposure due to improved hygiene conditions may favor MS development. We discuss epidemiological, experimental, clinical and molecular data supporting the protective role of helminthes against MS. Better understanding of host–parasite interactions caused by specific parasite molecules with immunomodulatory effects will help combat allergies and autoimmune disease without the price of untoward infection as a side-effect.
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44
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Schistosome-induced pulmonary B cells inhibit allergic airway inflammation and display a reduced Th2-driving function. Int J Parasitol 2017; 47:545-554. [PMID: 28385494 DOI: 10.1016/j.ijpara.2017.02.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 02/13/2017] [Accepted: 02/15/2017] [Indexed: 12/31/2022]
Abstract
Chronic schistosome infections protect against allergic airway inflammation (AAI) via the induction of IL-10-producing splenic regulatory B (Breg) cells. Previous experiments have demonstrated that schistosome-induced pulmonary B cells can also reduce AAI, but act independently of IL-10. We have now further characterized the phenotype and inhibitory activity of these protective pulmonary B cells. We excluded a role for regulatory T (Treg) cell induction as putative AAI-protective mechanisms. Schistosome-induced B cells showed increased CD86 expression and reduced cytokine expression in response to Toll-like receptor (TLR) ligands compared with control B cells. To investigate the consequences for T cell activation we cultured ovalbumin (OVA)-pulsed, schistosome-induced B cells with OVA-specific transgenic T cells and observed less Th2 cytokine expression and T cell proliferation compared with control conditions. This suppressive effect was preserved even under optimal T cell stimulation by anti-CD3/28. Blocking of the inhibitory cytokines IL-10 or TGF-β only marginally restored Th2 cytokine induction. These data suggest that schistosome-induced pulmonary B cells are impaired in their capacity to produce cytokines to TLR ligands and to induce Th2 cytokine responses independent of their antigen-presenting function. These findings underline the presence of distinct B cell subsets with different stimulatory or inhibitory properties even if induced by the same type of helminth.
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45
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Vendelova E, Hrčková G, Lutz MB, Brehm K, Nono JK. In vitro culture of Mesocestoides corti metacestodes and isolation of immunomodulatory excretory-secretory products. Parasite Immunol 2017; 38:403-13. [PMID: 27120409 DOI: 10.1111/pim.12327] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 04/22/2016] [Indexed: 12/25/2022]
Abstract
Cestode-mediated diseases hold the interesting feature of persisting metacestode larvae dwelling within the host tissues, in the midst of the immune response. Excretory-secretory (ES) products of the metacestode larval stage modulate the host immune response and modify the outcome of the disease. Therefore, isolation and analysis of axenic metacestode ES products are crucial to study their properties. Here, we report the development of a system for long-term in vitro cultivation of the metacestode of the parasitic cestode Mesocestoides corti (syn. Mesocestoides vogae). Although feeder cells and host serum supported the early growth of the parasite, long-term survival was not dependent on host serum or host-derived factors enabling the collection of parasite released products in serum-free medium. Functionally, these axenic ES products recapitulated M. corti tetrathyridia's ability to inhibit LPS-driven IL-12p70 secretion by dendritic cells. Thus, our new axenic culture system will simplify the identification and characterization of M. corti-derived immunomodulatory factors that will indirectly enable the identification and characterization of corresponding factors in the metacestode larvae of medically relevant cestodes such as Echinococcus multilocularis that are not yet amenable to serum-free cultivation.
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Affiliation(s)
- E Vendelova
- Institute of Parasitology of the Slovak Academy of Sciences, Košice, Slovak Republic
| | - G Hrčková
- Institute of Parasitology of the Slovak Academy of Sciences, Košice, Slovak Republic
| | - M B Lutz
- Institute of Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - K Brehm
- Institute for Hygiene and Microbiology, University of Würzburg, Würzburg, Germany
| | - J K Nono
- Division of Immunology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Institute of Medical Research and Medicinal Plant Studies (IMPM), Ministry of Scientific Research and Innovation, Yaoundé, Cameroon
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46
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Peón AN, Ledesma-Soto Y, Terrazas LI. Regulation of immunity by Taeniids: lessons from animal models and in vitro studies. Parasite Immunol 2016; 38:124-35. [PMID: 26457989 DOI: 10.1111/pim.12289] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 10/01/2015] [Indexed: 02/06/2023]
Abstract
Taeniidae is the largest family of the Cyclophyllidea order of parasites despite being composed of just two genera: Taenia spp and Echinococcus spp. These parasites are flatworms with a terrestrial life cycle, having an immature or larval stage called metacestode, which develops into the mature form within the intestine of the primary host after being consumed in raw or poorly cooked meat. Consumed eggs hatch into oncospheres, penetrate the intestinal walls and are transported via the bloodstream to later develop into metacestodes within the muscles and internal organs of secondary and sometimes primary hosts, thereby initiating the cycle again. Larval stages of both Taenia spp and Echinococcus spp are well known to produce tissue-dwelling, long-lasting infections; in this stage, these parasites can reach centimetres (macroparasites) and both genera may cause life-threatening diseases in humans. Establishing such long-term infections requires an exceptional ability to modulate host immunity for long periods of time. In this review, we analyse the immunoregulatory mechanisms induced by these tapeworms and their products, mainly discussing the importance of taeniid strategies to successfully colonize their hosts, such as antigen-presenting cell phenotype manipulation and the consequent induction of T-cell anergy, among others.
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Affiliation(s)
- A N Peón
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, México
| | - Y Ledesma-Soto
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, México
| | - L I Terrazas
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, México
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47
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Laan LC, Williams AR, Stavenhagen K, Giera M, Kooij G, Vlasakov I, Kalay H, Kringel H, Nejsum P, Thamsborg SM, Wuhrer M, Dijkstra CD, Cummings RD, van Die I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J 2016; 31:719-731. [PMID: 27806992 DOI: 10.1096/fj.201600841r] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 10/24/2016] [Indexed: 12/11/2022]
Abstract
Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into the mechanisms by which this worm suppresses inflammatory responses, an active component was purified from T. suis soluble products (TsSPs) that suppress---- TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs). Analysis by liquid chromatography tandem mass spectrometry identified this compound as prostaglandin (PG)E2. The purified compound showed similar properties compared with TsSPs and commercial PGE2 in modulating LPS-induced expression of many cytokines and chemokines and in modulating Rab7B and P2RX7 expression in human DCs. Furthermore, the TsSP-induced reduction of TNF secretion from DCs is reversed by receptor antagonists for EP2 and EP4, indicating PGE2 action. T. suis secretes extremely high amounts of PGE2 (45-90 ng/mg protein) within their excretory/secretory products but few related lipid mediators as established by metabololipidomic analysis. Culture of T. suis with several cyclooxygenase (COX) inhibitors that inhibit mammalian prostaglandin synthesis affected the worm's motility but did not inhibit PGE2 secretion, suggesting that the worms can synthesize PGE2 via a COX-independent pathway. We conclude that T. suis secretes PGE2 to suppress proinflammatory responses in human DCs, thereby modulating the host's immune response.-Laan, L. C., Williams, A. R., Stavenhagen, K., Giera, M., Kooij, G., Vlasakov, I., Kalay, H., Kringel, H., Nejsum, P., Thamsborg, S. M., Wuhrer, M., Dijkstra, C. D., Cummings, R. D., van Die, I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells.
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Affiliation(s)
- Lisa C Laan
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Andrew R Williams
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Kathrin Stavenhagen
- Division of BioAnalytical Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Gijs Kooij
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands.,Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; and
| | - Iliyan Vlasakov
- Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; and
| | - Hakan Kalay
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Helene Kringel
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Peter Nejsum
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Stig M Thamsborg
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Manfred Wuhrer
- Division of BioAnalytical Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Christine D Dijkstra
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Richard D Cummings
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School Center for Glycosciences, Boston, Massachusetts, USA
| | - Irma van Die
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands;
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48
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Vendelova E, Camargo de Lima J, Lorenzatto KR, Monteiro KM, Mueller T, Veepaschit J, Grimm C, Brehm K, Hrčková G, Lutz MB, Ferreira HB, Nono JK. Proteomic Analysis of Excretory-Secretory Products of Mesocestoides corti Metacestodes Reveals Potential Suppressors of Dendritic Cell Functions. PLoS Negl Trop Dis 2016; 10:e0005061. [PMID: 27736880 PMCID: PMC5063416 DOI: 10.1371/journal.pntd.0005061] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 09/21/2016] [Indexed: 02/07/2023] Open
Abstract
Accumulating evidences have assigned a central role to parasite-derived proteins in immunomodulation. Here, we report on the proteomic identification and characterization of immunomodulatory excretory-secretory (ES) products from the metacestode larva (tetrathyridium) of the tapeworm Mesocestoides corti (syn. M. vogae). We demonstrate that ES products but not larval homogenates inhibit the stimuli-driven release of the pro-inflammatory, Th1-inducing cytokine IL-12p70 by murine bone marrow-derived dendritic cells (BMDCs). Within the ES fraction, we biochemically narrowed down the immunosuppressive activity to glycoproteins since active components were lipid-free, but sensitive to heat- and carbohydrate-treatment. Finally, using bioassay-guided chromatographic analyses assisted by comparative proteomics of active and inactive fractions of the ES products, we defined a comprehensive list of candidate proteins released by M. corti tetrathyridia as potential suppressors of DC functions. Our study provides a comprehensive library of somatic and ES products and highlight some candidate parasite factors that might drive the subversion of DC functions to facilitate the persistence of M. corti tetrathyridia in their hosts. The metacestode larval stages of life-threatening tapeworms grow within the organs of its mammalian hosts, thus causing severe and long-lasting morbidity. Immunosuppression, which mainly depends on factors that are released or leaking from the parasite, plays an important role in both survival and proliferation of the larvae. These parasite-derived molecules are potential targets for developing new anti-parasitic drugs and/or improving the effectiveness of current therapies. Moreover, an optimized use of such factors could help to minimize pathologies resulting from uncontrolled immune responses, like allergies and autoimmune diseases. The authors herein demonstrate that larvae from a parasitic cestode release factors that sufficiently support the suppression of dendritic cells, a set of innate immune cells that recognizes and initiates host immune responses against invading pathogens. Employing modern analytic proteomic tools combined with immunological bioassays, several cestode-derived candidate immunomodulators were identified. This is the first bioassay-guided comprehensive library of candidate immunomodulators from a tissue-dwelling cestode larva. This work validates the unmet value of the Mesocestoides corti system in characterizing the mechanisms of host immunomodulation by metacestodes and reveals the largest database of candidate metacestode-derived immunomodulators until date.
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Affiliation(s)
- Emilia Vendelova
- Institute of Parasitology of the Slovak Academy of Sciences, Košice, Slovak Republic
| | - Jeferson Camargo de Lima
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Karina Rodrigues Lorenzatto
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Karina Mariante Monteiro
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- Departamento de Biologia Molecular e Biotecnologia, Instituto de Biociências, (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Thomas Mueller
- Lehrstuhl für Molekulare Pflanzenphysiologie und Biophysik, Julius-von-Sachs Institut der Universität Würzburg, Würzburg, Germany
| | | | - Clemens Grimm
- Lehrstuhl für Biochemie, Biozentrum der Universität Würzburg, Würzburg, Germany
| | - Klaus Brehm
- University of Würzburg, Institute for Hygiene and Microbiology, Würzburg, Germany
| | - Gabriela Hrčková
- Institute of Parasitology of the Slovak Academy of Sciences, Košice, Slovak Republic
| | - Manfred B. Lutz
- University of Würzburg, Institute of Virology and Immunobiology, Würzburg, Germany
| | - Henrique B. Ferreira
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- Departamento de Biologia Molecular e Biotecnologia, Instituto de Biociências, (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
- * E-mail: (JKN); (HBF)
| | - Justin Komguep Nono
- Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology, University of Cape Town, Cape Town, South Africa
- Institute of Medical Research and Medicinal Plant Studies (IMPM), Ministry of Scientific Research and Innovation, Yaoundé, Cameroon
- * E-mail: (JKN); (HBF)
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49
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Motran CC, Ambrosio LF, Volpini X, Celias DP, Cervi L. Dendritic cells and parasites: from recognition and activation to immune response instruction. Semin Immunopathol 2016; 39:199-213. [DOI: 10.1007/s00281-016-0588-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Accepted: 08/22/2016] [Indexed: 12/20/2022]
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50
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Mukai K, Tsai M, Starkl P, Marichal T, Galli SJ. IgE and mast cells in host defense against parasites and venoms. Semin Immunopathol 2016; 38:581-603. [PMID: 27225312 PMCID: PMC5010491 DOI: 10.1007/s00281-016-0565-1] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 04/26/2016] [Indexed: 12/12/2022]
Abstract
IgE-dependent mast cell activation is a major effector mechanism underlying the pathology associated with allergic disorders. The most dramatic of these IgE-associated disorders is the fatal anaphylaxis which can occur in some people who have developed IgE antibodies to otherwise innocuous antigens, such as those contained in certain foods and medicines. Why would such a highly "maladaptive" immune response develop in evolution and be retained to the present day? Host defense against parasites has long been considered the only beneficial function that might be conferred by IgE and mast cells. However, recent studies have provided evidence that, in addition to participating in host resistance to certain parasites, mast cells and IgE are critical components of innate (mast cells) and adaptive (mast cells and IgE) immune responses that can enhance host defense against the toxicity of certain arthropod and animal venoms, including enhancing the survival of mice injected with such venoms. Yet, in some people, developing IgE antibodies to insect or snake venoms puts them at risk for having a potentially fatal anaphylactic reaction upon subsequent exposure to such venoms. Delineating the mechanisms underlying beneficial versus detrimental innate and adaptive immune responses associated with mast cell activation and IgE is likely to enhance our ability to identify potential therapeutic targets in such settings, not only for reducing the pathology associated with allergic disorders but perhaps also for enhancing immune protection against pathogens and animal venoms.
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Affiliation(s)
- Kaori Mukai
- Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324, USA
- Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, California 94305-5324, USA
| | - Mindy Tsai
- Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324, USA
- Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, California 94305-5324, USA
| | - Philipp Starkl
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, and Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria
| | - Thomas Marichal
- Laboratory of Cellular and Molecular Immunology, GIGA-Research and Faculty of Veterinary Medicine, University of Liège, 4000 Liège, Belgium
| | - Stephen J. Galli
- Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324, USA
- Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, California 94305-5324, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305-5324, USA
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