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Memory B cell immunity in chronic viral infection

Final Report Summary - IMMUNIBY (Memory B cell immunity in chronic viral infection)

The ability to form memory represents a hallmark of our body’s adaptive immune system, which is composed of B and T cells. While antiviral memory T cells have been investigated in great detail over the past decades, memory B cell immunity to persistent viral diseases represents a still understudied domain. Main aims of this project were to further our understanding how protective memory B cells are formed in persistent viral infections, how they can protect against viral persistence and how persistent microbes may subvert such B cell responses. Viral vaccines commonly protect by neutralizing antibodies (nAbs), but the induction thereof represents a challenging task when it comes to persistent viral diseases such as HIV or hepatitis C.
Here we used the murine infection model of lymphocytic choriomengitis virus (LCMV) to compare B cell responses during acute and chronic infection. Specific antiviral antibodies are required to control chronic LCMV infection. But they only arise after several weeks of protracted infection, thus with kinetics reminiscent of those observed in the aformentioned human diseases. By using reverse genetic techniques we found that specific sugars, a so-called glycan shield, on the envelope protein of LCMV prevent efficient antibody binding, thus explaining delayed nAb formation.
To investigate why such antibodies arose only in persistent but not in acute infection, we used gene-targeted “reporter” mice, in which B cells participating in germinal center reactions (a kind of “school” for B cells), can be irreversibly marked. We found that in persistent infection, B cells were recruited to the germinal center response for considerably longer periods of time than in acute infection, resulting in substantially higher numbers of specific cells. Also plasma cells, the factories of antibodies, were produced continuously in chronically but not acutely infected animals. The longer and more robust evolution of the B cell response provides a mechanistic explanation for the emergence of nAbs in chronic but not acute LCMV infection, and should help devising vaccination strategies whereby to mimic chronic infection for potent nAb induction.
Viral immune subversion represents a hallmark of persistent infection. In the context of this project we discovered that the early type I interferon (IFN-I) response to viral infection caused a quasi-complete deletion (“decimation”) of virus-specific B cells. Memory B cells as well as naïve antiviral B cells underwent rapid end-differentiation and apoptosis. This process was due to inflammation, and was triggered by type I interferon (IFN-I). When we blocked this pathway in mice, we rescued secondary germinal center formation, memory B cell formation and long-lived plasma cell generation. This “decimation” of the antiviral B cell repertoire was driven by IFN-I effects on several cell types including myeloid cells, dendritic cells and T cells but not in the antiviral B cells themselves. These observations established IFN-I-driven B cell repertoire decimation as a mechanistic link between virus-induced inflammation and humoral immune subversion. Accordingly, they provide a mechanistic basis to rationally address humoral immune subversion in persistent microbial infection.
Taken together, the scientific advancement resulting from this ERC grant should help in refining vaccination strategies to induce neutralizing antibody and memory B cell immunity against persistent microbial diseases of global health impact.