Glycan-Specific Natural Antibodies Mediate Blockade of Endogenous Retrovirus Emergence and Recognize a Broad-spectrum of Exogenous Viruses

Endogenous retroviruses (ERV), comprising a substantial portion of the vertebrate genome, are remnants of ancient genetic invaders. ERV with near-intact coding potential reactivate in B cell-deficient mice. Here, we employed an antigen-baiting strategy to enrich B cells reactive to ERV surface antigens. We identified ERV-reactive B-1 cells expressing germline-encoded natural IgM antibodies in naïve mice, the level of which further increases upon innate immune sensor stimulation. B cell receptor repertoire profiling of ERV-reactive B-1 cells revealed increased usage of Igh VH gene that gives rise to glycan-specific antibodies targeting terminal N-acetylglucosamine moieties on ERV glycoproteins, which further engage the complement pathway to protect the host from ERV emergence. These same antibodies also recognize glycoproteins of other enveloped viruses, but not self-proteins. These results reveal an innate antiviral mechanism of germline-encoded antibodies with broad reactivity to enveloped viruses, whose absence leads to the emergence of infectious ERV. We developed a FACS based approach to enrich ERV specific B cells. PE labeled murine leukemia viruses (MLV) were used to probe ERV-reactive B cells and PE-Alexa Fluor 647 labeled virus-like particle (VLP) devoid of surface viral antigens were used to block non-specific interactions. ERV-reactive B-1 cells from the peritoneal cavities of naive C57BL/6 mice were sorted and the BCR repertoire was profiled by Chromium Single-cell Immune Profiling (10X Genomics). Total B-1 cells from the peritoneal cavities of naive C57BL/6 (age and gender matched) were sorted for the control repertoire prior to ERV-baited enrichment.