Single-cell transcriptome profiling and the use of AID deficient mice reveal that B cell activation combined with antibody class switch recombination and somatic hypermutation do not benefit the control of experimental trypanosomosis
| Autor: | Magdalena Radwanska, Stefan Magez, Hang Thi Thu Nguyen, Robin B. Guevarra |
|---|---|
| Přispěvatelé: | Department of Bio-engineering Sciences, Cellular and Molecular Immunology |
| Rok vydání: | 2021 |
| Předmět: |
B Cells
Physiology Quantitative Parasitology AUTOIMMUNITY Antibodies Protozoan Parasitemia Lymphocyte Activation Biochemistry Mice White Blood Cells Medical Conditions Spectrum Analysis Techniques Animal Cells Immune Physiology Medicine and Health Sciences Biology (General) Enzyme-Linked Immunoassays AFRICAN TRYPANOSOMES Cytidine Deaminase/physiology Mice Knockout Protozoans B-Lymphocytes Immune System Proteins biology Eukaryota B-Lymphocytes/immunology Flow Cytometry ACQUIRED-IMMUNITY Immunoglobulin Isotypes medicine.anatomical_structure Memory B Cells/immunology Spectrophotometry Female Cytophotometry Antibody Single-Cell Analysis Cellular Types Research Article EXPRESSION Trypanosomiasis/genetics Trypanosoma QH301-705.5 Immune Cells Immunology Somatic hypermutation Spleen Research and Analysis Methods Microbiology SYSTEMIC Antibodies Immune system Memory B Cells Trypanosomiasis Virology VARIANT SURFACE GLYCOPROTEIN Cytidine Deaminase Genetics medicine C-MYC Parasitic Diseases Animals Antibody-Producing Cells Immunoassays Molecular Biology B cell Blood Cells Antibodies Protozoan/immunology Single-Cell Analysis/methods Organisms NECROSIS-FACTOR-ALPHA Biology and Life Sciences Proteins Cell Biology Trypanosoma evansi RC581-607 medicine.disease biology.organism_classification Molecular biology Immunoglobulin Class Switching Parasitic Protozoans EVANSI INFECTION Mice Inbred C57BL Immunoglobulin class switching GERMINAL-CENTERS Mutation biology.protein Immunoglobulin Isotypes/immunology Trypanosoma/genetics Immunologic Techniques MARGINAL ZONE Parasitology Immunologic diseases. Allergy Transcriptome |
| Zdroj: | PLoS Pathogens PLOS PATHOGENS PLoS Pathogens, Vol 17, Iss 11, p e1010026 (2021) |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Salivarian trypanosomes are extracellular protozoan parasites causing infections in a wide range of mammalian hosts, with Trypanosoma evansi having the widest geographic distribution, reaching territories far outside Africa and occasionally even Europe. Besides causing the animal diseases, T. evansi can cause atypical Human Trypanosomosis. The success of this parasite is attributed to its capacity to evade and disable the mammalian defense response. To unravel the latter, we applied here for the first time a scRNA-seq analysis on splenocytes from trypanosome infected mice, at two time points during infection, i.e. just after control of the first parasitemia peak (day 14) and a late chronic time point during infection (day 42). This analysis was combined with flow cytometry and ELISA, revealing that T. evansi induces prompt activation of splenic IgM+CD1d+ Marginal Zone and IgMIntIgD+ Follicular B cells, coinciding with an increase in plasma IgG2c Ab levels. Despite the absence of follicles, a rapid accumulation of Aicda+ GC-like B cells followed first parasitemia peak clearance, accompanied by the occurrence of Xbp1+ expressing CD138+ plasma B cells and Tbx21+ atypical CD11c+ memory B cells. Ablation of immature CD93+ bone marrow and Vpreb3+Ly6d+Ighm+ expressing transitional spleen B cells prevented mature peripheral B cell replenishment. Interestingly, AID-/- mice that lack the capacity to mount anti-parasite IgG responses, exhibited a superior defense level against T. evansi infections. Here, elevated natural IgMs were able to exert in vivo and in vitro trypanocidal activity. Hence, we conclude that in immune competent mice, trypanosomosis associated B cell activation and switched IgG production is rapidly induced by T. evansi, facilitating an escape from the detrimental natural IgM killing activity, and resulting in increased host susceptibility. This unique role of IgM and its anti-trypanosome activity are discussed in the context of the dilemma this causes for the future development of anti-trypanosome vaccines. Author summary Trypanosoma evansi parasites can infect mammals, occasionally also humans, by evading the humoral immune response. In this study, cellular and transcriptomic profiling reveals that T. evansi induces rapid activation of mature splenic B cells, followed by differentiation into Aicda+ GC-like B cells, Tbx21+ atypical memory B cells and Sdc1+Xbp1+ plasma B cells. The process triggers early-stage Ighg2c expression in Follicular B cells. Simultaneous ablation of the bone marrow early B cell lineage prevents B cell replenishment, causing loss of the host’s parasitemia control capacity. Surprisingly, AID-/- mice lacking anti-parasite IgGs, exhibit a superior defense level against T. evansi infections, with elevated natural IgMs being able to exert trypanocidal activity. Hence, we conclude that in immune competent mice, trypanosomosis associated B cell Aicda activation and IgG2c production is rapidly induced by T. evansi in order to evade natural IgM mediated killing, resulting in increased host susceptibility. |
| Databáze: | OpenAIRE |
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