The Role of Endogenous Retroviruses in Shaping the Host Anti-Viral Immunity
Date of Award
Doctor of Philosophy (PhD)
One unique feature of retroviruses among other virus genre is their capability of reverse-transcribing their genetic material and integrating into the host genome. In the short term at the scale of the host life span, integrated proviruses became a genetic reservoir for chronic viral infection. In the long term at the scale of species evolution, proviruses integrated into the germ cells accumulate and comprise a substantial portion of the host genome, and became endogenous retroviruses (ERVs). Up to 10% of the vertebrate genome are remnants of such ancient genetic invaders. It is well established that the host immune system co-evolved with pathogens, driven by the selective pressure during the constant arm-race between pathogens and the host. The consequences of chronic retroviral infection on the host immune landscape are well exemplified by human immunodeficiency virus (HIV). ERVs, as the endogenized counterpart of myriad retroviruses coexist with the host during long-term evolution, has instead established a symbiotic role in which the host co-op ERV sequences for cell function. Such relationship is ensured by multi-layer control of ERV expression and suppression of ERV emergence. Although multiple cell-intrinsic machineries are utilized to suppress ERV transcription, ERVs with intact coding potential were found to reactivate in immunodeficient mice, suggesting an indispensable role of the host immune system in the blockade of ERV reactivation. While previous studies have indicated that B cells are indispensable for preventing ERV reactivation, it is not yet clear which B cell population mediates the blockade of ERV emergence to prevent subsequent damage to the host. In this thesis, we employed direct labeling of B cells reactive with emerged ERV particles to characterize the B cell population and clonal repertoire responsible for recognition of ERV, and to study the mechanism by which B cells provide protection against ERV emergence. We found that ERV-reactive B cells are enriched in innate-like B-1 cell compartment that predominantly reside in peritoneal and pleural cavities. We identified ERV-reactive antibodies in the sera of unimmunized mice. B cell receptor repertoire profiling of ERV-reactive B-1 cells revealed increased usage of Igh VH genes that give rise to glycan-specific antibodies targeting terminal N-acetylglucosamine (GlcNAc) moieties exhibited by ERV viral glycoproteins, which further engage complement pathway to protect the host from ERV emergence. The same antibodies also recognize glycoproteins of other enveloped viruses, but not self-proteins, which is dependent on terminal GlcNAc recognition. Phenotypically, ERV-reactive B-1 cells exhibited gene expression feature enabling self-renewal and cell survival at steady state. Upon direct innate sensor stimulation or unrelated exogenous viral challenge, ERV-reactive antibodies were upregulated. Interestingly, recent findings have suggested cross-reactivity of certain natural antibodies to both commensal microbiota and ERV. It has been demonstrated that microbiome colonization drive expansion of these cross-reactive clones, while “self-antigens” of unknown sources are involved given the presence of these clones in germ-free mice. We further discussed a model in which ERV may play a role in the development of pre-immune repertoire. In conclusion, these results collectively reveal an innate antiviral mechanism by germline encoded antibodies with broad reactivity to ERV and exogenous enveloped viruses, whose absence leads to the emergence of infectious ERVs. Future work will be focusing on understanding the biosynthetic pathway leading to exposure of terminal GlcNAc on viral glycoproteins and investigating the broad-spectrum antiviral potential of natural antibodies targeting conserved glycans.
Yang, Yexin, "The Role of Endogenous Retroviruses in Shaping the Host Anti-Viral Immunity" (2022). Yale Graduate School of Arts and Sciences Dissertations. 540.