Retroviral evasion of immune response

点击翻译按钮获取中文摘要

Most viral pathogens launch acute infections, whereby the virus replicates rapidly and disseminates to another organism prior to immune clearance or death of the host. In contrast, some viruses are able to establish persistent infections through adoption of complex relationships with their hosts and manipulation of a wide array of cellular mechanisms for their own advantage. Even though persistent viruses have evolved distinct mechanisms to enable long-term survival in the host, they all share a common trait-the ability to evade the immune system. We found that mice that ingest mouse mammary tumor virus (MMTV), a retrovirus transmitted though the milk, cannot be stimulated to respond to viral antigens throughout their lifetime. This phenotype is highly reminiscent of a phenomenon termed 'oral tolerance', in which ingested antigens render the host unresponsive to a systemic challenge. Our previous data demonstrated that MMTV uses signaling through the innate immune Toll-like receptor (TLR) 4 to evade the adaptive anti-viral response of the host. Newly generated preliminary data suggest that MMTV interaction with TLR4 triggers production of the cytokines interleukin 10 (IL-10) and IL-6, which are both required for blockage of the anti-viral response. In the course of these studies, we discovered that MMTV does not signal directly through TLR4 but uses bacterially produced lipopolysaccharide (LPS), a well-characterized TLR4 ligand, to trigger the signaling, and that LPS- free MMTV stocks failed to induce IL-10 production. Most excitingly, germ-free (GF) mice infected with MMTV by intaperitoneal injection were unable to transmit infectious virus to their offspring. These results provide the rationale for the hypothesis that, as an oral pathogen, MMTV requires commensal microbiota to induce tolerance via subverting innate immune signaling, and thus to counteract anti-viral immune responses. Clearly, similar mechanisms might operate upon infection with viruses of different families or other pathogens that spread via the gastrointestinal route, making this application broadly significant. We propose to further investigate the role of innate immune and adaptive responses in retrovirus transmission. The overall objective of this proposal is to identify the precise mechanism by which retroviruses induce immune tolerance to enable their persistence and to determine the innate immune pathway(s) involved in sensing retroviruses.