Definition and mapping of Cmv5 interval associated effects on the innate immune response to acute Murine Cytomegalovirus infection.

Abstract MHC-I molecule H-2D kconfers resistance to acute murine cytomegalovirus (MCMV) infection in both C57L and MA/My mice. M.H2 k/bmice are MA/My background aside from a C57L-derived region within the MHC (Cmv5), which diminishes this resistance. Thus M.H2 k/bmice lose more weight during infection and present with increased viral load. Additionally, M.H2 k/bmice have fewer, more activated NK cells and significant spleen histopathology measured by decreased white pulp area, loss of marginal zone definition, and increasing red pulp acellularity. To better understand how the Cmv5interval regulates the response to MCMV, we generated several Cmv5recombinant mouse strains and screened them in vivo, allowing us to narrow the phenotype-associated interval as much as 14 times from the original size of 23.08 Mb. In addition, we sought to further characterize the Cmv5-associated phenotypes in their temporal appearance and potential direct relation to viral load. To this end, we found that many Cmv5phenotypes could not be fully mirrored in the MA/My mice with increased viral dose, and that marginal zone disruption was one of the first Cmv5phenotypes to appear, being reliably quantified as early as 2 days post infection (dpi) in the M.H2 k/bmice. This suggests that splenic tissue disruption, occurring prior to increase in weight loss or NK cell activation, may be a primary target of the Cmv5genetic interval and its impact on the response to MCMV. In conclusion, we verified and defined the Cmv5-associated susceptibility to MCMV infection, generated and tested several Cmv5recombinant strains resulting in a substantially reduced interval size, and determined that the full Cmv5phenotype is unlikely to be a direct result of increased viral load. NIH NIAID R01AI50072, Department of Medicine/Nephrology, Center for Immunity Inflammation and Regenerative Medicine, Beirne B Carter Center for Immunology Research.