Regulation of myeloid cells and inflammation marks increased susceptibility in a genetic model of acute viral infection-induced tissue damage

Newswise — M.H2^k/b mice are identical to MA/My parent strain aside from a C57L-derived region within the MHC, which causes these mice to develop significant splenic tissue damage during acute murine cytomegalovirus (MCMV) infection. To understand how MCMV infection leads to the induction of tissue damage, we probed immunological differences between the M.H2^k/b and MA/My mice over time. Using tissue imagin8 and flow cytometry, we observed increased infiltration of neutrophils to the marginal zones of the M.H2^k/b mice aligning with the appearance of necrosis at 2 days post infection (dpi). While TUNEL staining identified increased cell death within these clusters, apoptosis was reduced, suggesting an inflammatory death pathway in the M.H2^k/b neutrophils. In line with this hypothesis, multiplex ELISA identified increased IL-6 and TGF in the spleens of M.H2^k/b mice at this time. Intriguingly, depletion of neutrophils prior to infection did not alleviate M.H2^k/b histopathology or inflammation. Seeing the differential regulation of neutrophils, we assessed the state of other myeloid populations in the spleen during acute MCMV infection. We observed significant loss of marginal zone and red pulp macrophages (MZMs, RPMs) beginning at 2dpi and worsening over time in the M.H2^k/b mice. Further exploration into how the loss of these populations may contribute to tissue damage identified buildup of toxic lipid peroxidation byproduct 4HNE early in the MZMs and progressing through the RPMs alongside the development of histopathology. In conclusion, we have identified increased inflammation, oxidative stress, and macrophage loss in M.H2^k/b spleens during acute MCMV infection that tracks with localization and temporal appearance of histopathology.