TGFβ Modulation of Immunopathogenesis During Alphaviral Encephalomyelitis in IL-10 Deficient Mice

Immunology;IL-10;Immunopathogenesis;Virology;Alphavirus;TGF-beta;Encephalitis;Sindbis Virus;Flow Cytometry;Immunology

Martin, Nina MCalabresi, Peter A. ;

Johns Hopkins University

关键词: Immunology;    IL-10;    Immunopathogenesis;    Virology;    Alphavirus;    TGF-beta;    Encephalitis;    Sindbis Virus;    Flow Cytometry;    Immunology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/58689/MARTIN-DISSERTATION-2017.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Alphaviruses are an important cause of mosquito-borne outbreaks of arthritis, rash and encephalomyelitis. Sindbis virus (SINV) causes viral encephalitis in mice, with different SINV strains leading to varying degrees of morbidity and mortality. Previous studies in mice with a virulent strain (NSV) of SINV identified a role for Th17 cells and regulation by IL-10 in the pathogenesis of fatal encephalomyelitis (Kulcsar et al, Proc Natl Acad Sci USA 111:16053-16058, 2014). The current study considers the role of another regulatory cytokine, transforming growth factor beta (TGF). Comparisons of IL10KO and WT mice after infection with avirulent TE, intermediate virulent TE12, and virulent NSV show that NSV-infected IL-10KO mice have greater amounts of both TGFβ1 and TGFβ3 proteins, while TE and TE12-infected IL-10KO mice have greater induction of TGFβ1, but not TGFβ3 when compared to WT control mice. These findings support the hypothesis that TGFβ3, but not TGFβ1 is responsible for promotion of the differentiation of pathogenic TH17 cells. In addition, more severe disease and impaired virus clearance in IL-10KO mice compared to wild type mice were associated with more Th1 cells; fewer Th2 cells, innate lymphoid type 2 cells, regulatory cells and B cells and delayed production of antiviral antibody in the central nervous system without an effect on Th17 cells. Therefore, IL-10 deficiency led to more severe disease, for example, in TE12-infected mice by increasing Th1 cells and by hampering development of the local B cell responses necessary for rapid production of antiviral antibody and virus clearance from the CNS. In addition, the shift from Th17 to Th1 responses with decreased virus virulence indicates that the effects of IL-10 deficiency on immunopathologic responses in the CNS during alphavirus infection are influenced by virus strain.