UNIVERSITY OF CHICAGO, THE
Innate immunity Toll-like receptors (TLR) have a crucial role in the detection of microbial infection. Specificity for conserved pathogen-associated molecular patterns (PAMPs) allows TLR proteins to detect the presence of pathogens and to induce the activation of innate and subsequently, adaptive anti-microbial immune responses. Viruses, like bacteria and fungi, encounter innate and adaptive immune systems, and thus, have evolved to evade both the innate and adaptive immune responses. Some viruses even take advantage of fundamental properties of the immune system, and subvert them for their own benefit. 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 make the host unresponsive to a systemic challenge. Our previous data demonstrated that MMTV used signaling through the innate Toll-like receptor 4 (TLR4) to evade the adaptive anti-viral response of the host. Newly generated preliminary data suggest that MMTV interaction with TLR4 triggers production of cytokines IL-b and IL-6, which are both required for the blockage of the anti-viral response. In the course of these studies, we discovered that MMTV does not directly signal through TLR4 but uses bacterially produced Iipopolysaccharide, a well-characterized TLR4 ligand, to trigger the signaling, and the LPS-free MMTV stock failed to induce IL-IC production. Most excitingly, germ free mice infected with MMTV by an intaperitoneal injection were unable to transmit infectious virus to their offspring. These results provide the rationale for a hypothesis that as an oral pathogen, MMTV requires commensal microbiota to induce tolerance and thus, counteract anti-viral immune responses. We believe that 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. The overall objective of this proposal is to identify the precise mechanism by which retroviruses induce immune tolerance to enable their persistence (Specific Aim I) and to determine an innate immune pathway(s) that are involved in sensing retroviruses (Specific Aim 2).