DESCRIPTION (provided by applicant): MHC class I Dk mediates genetic resistance to murine cytomegalovirus (MCMV). The resistance effect requires a specific subset of NK cells marked by an inhibitory NK receptor, Ly49G2, that protects against viral spread. Preliminary data in the proposal has revealed a major genetic modifier, provisionally designated Cmv5, of Dk- dependent virus resistance. Cmv5 was genetically mapped nearby, but distal to the MHC. Preliminary results show that it also regulates protection of secondary lymphoid organ structure (SLO) and expansion of NK cells in spleen soon after MCMV infection. It is not known how Cmv5 spleen resilience to infection is regulated, how distinct alleles differently affect histopathological outcomes or if the genetic effect manifests through hematopoietic cells, non-hematopoietic cells or both. The peak genetic map position for Cmv5 coincides with the Trem/Trem-like gene cluster that encodes molecules known for regulating inflammation. Cmv5 is predicted to intensify virus clearance by protecting spleen SLO structure and by expanding competent NK cells to mediate specific virus clearance. A long-term goal is to identify Cmv5 and investigate how naturally selected alleles alter its basic biological functions and further shape immune responsiveness, inflammation and disease outcomes. A genetic basis for protection of SLO structure and regulation of necrosis and NK cell accumulation after virus infection is unknown. Cmv5-disparate mice will be used to explore the genetic relationship between lymphoid structure, NK cell accumulation and innate viral immunity. Cmv5 regulation of the biology of repair/regeneration in response to virus infection will be studied. Inasmuch as Trems are implicated by positional genetic mapping data, exome sequence analysis and for their proclivity to regulate inflammation, a possible role for Trem/Trem-like molecules in virus-induced inflammation and viral clearance will also be investigated. Two specific aims are proposed to address the long-term goal. Aim 1 investigates the cellular basis of Cmv5 locus dependent protection of secondary lymphoid organ (SLO) structure and NK cell accrual in spleen after MCMV infection. Cmv5 is predicted to protect stromal cells in the red and white pulp regions of the spleen. Aim1 therefore investigates the relationship between stromal cells and cytokines released by them, and their capability to support and/or regenerate SLO structure that may be further required to regulate leukocyte recruitment and retention. Aim 2 performs precision Cmv5 mapping and analysis of TREM expression, function and support of SLO structure after MCMV infection. A 16- Mb interval on mouse chr-17 is predicted to span the Cmv5 locus that regulates SLO structure, tissue necrosis and expansion of NK cells in spleen after virus infection. Inasmuch as the locus spans the Trem/Trem-like gene cluster that encodes myeloid-derived proteins needed to regulate inflammation, a further prediction is that one or more Trem / Trem-like proteins regulates SLO structure/function, NK cells expansion and enhancement of viral immunity.

PUBLIC HEALTH RELEVANCE: One quarter of the human population worldwide is expected to perish due to infectious diseases and new threats continue to emerge or re-emerge (e.g. SARS, Ebola, Chikungunya). The genetics of resistance to viral infection in mammalian hosts has been studied for more than 80 years, though its basis, in many cases, is still poorly defined. This proposal investigates the genetic basis of resistance to virus infection using a powerful new genetic model to explore the effect of inherited genes on immune system structure and function, inflammation, and acquisition of killer immune lymphocytes that help to eliminate viral infection.