| Project Detail |
Background and rationale: B cell responses can significantly contribute to immune control of persistent viral infections such as HIV/AIDS and hepatitis C, and they represent the correlate of vaccine protection against hepatitis B virus persistence, diseases that altogether affect ~400 million people worldwide. Persistent infection results in “T cell exhaustion” but the effects on antiviral B cell responses and these cells’ suppression by viral persistence remain ill-defined. Important knowledge gaps comprise i) the impact of chronic infection on affinity-based clonal selection of B cells and ii) the transcriptional regulation and subset differentiation of memory B cells under conditions of long-term antigen overload.Working hypothesis: We hypothesize that I) chronic viral infection interferes with affinity maturation of antiviral B cells. The failure to efficiently mature B cell responses may be reflected in a transcriptional program accompanied by non-canonical positioning in lymphoid organs. Biased terminal differentiation and excessive AID-mediated hypermutation may also contribute. II) Memory B cells (MBCs) in chronic viral infection exhibit an atypical T-bet-dependent (atMBC) phenotype. atMBC exhibit low proliferative activity but retain differentiation potential. Accordingly, they represent a resting memory subset that is required to sustain antibody responses over time, at least in part through extrafollicular plasma cell differentiation.Experimental model and methods: B cell responses to chronic viral infection will be studied in the prototypic lymphocytic choriomeningitis virus (LCMV) model in mice. LCMV-specific B cell receptor (BCR) transgenic mice will serve as B cell donors for adoptive transfer studies. Recipients will be infected with reverse-engineered LCM viruses that differ in binding to these cells’ BCR. GC fate mapping reporter and transcription factor knock-out alleles will be combined with BCR repertoire analysis, single cell RNA sequencing and multiparameter immunohistochemistry to decipher B cell clonal dominance patterns and differentiation subset relationships in the chronic infection context.Specific aims: To further our understanding of B cell responses to chronic viral infection we aim to:1.Investigate limitations of B cell affinity maturation in chronic viral infection.2.Decipher the origin and differentiation potential of MBCs in chronic viral infection.Expected results and significance: These studies in a relevant small animal model promise to characterize new mechanisms of B cell subversion in chronic viral infection and to identify the B cell subsets that sustain antibody responses in this context. In conjunction, these insights should provide a conceptual basis to counter the subversion of humoral immune defense and restore immune control in chronic microbial diseases, a major challenge of contemporary biomedicine. |
