Fibroblastic cells are a site of mouse cytomegalovirusin vivolytic replication and latent persistence oppositely regulated byStat1

Abstract

Latent cytomegalovirus (CMV) infections affect most of the human population, yet our understanding of the cell types that carry latent CMV in vivo remains limited. Here, using the mouse model of latent CMV infection, we comprehensively assessed the prevalence of latent mouse CMV (MCMV) genomes in highly purified populations of fibroblasts, endothelial cells and tissue-resident macrophages across multiple organs upon two distinct infection routes. We describe organ-specific and infection route-specific patterns of viral genome distribution in tissue-resident cells. Strikingly, PDGFRα+ fibroblasts contained the highest MCMV genome load in most organs and conditions analysed. Lytic gene expression was almost completely silenced with only few stochastic transcripts, but the virus ex vivo reactivation from PDGFRα+ fibroblasts was consistent and reproducible, arguing that this cell type supports latent infection. Importantly, the same PDGFRα+ fibroblasts supported also the productive MCMV infection in vivo. In sum, these results reveal a role for non-hematopoietic fibroblastic cells as a common site of both lytic MCMV replication and latency in vivo.

Rethinking human cytomegalovirus latency reservoir

“…A recent study further confirmed the wide distribution of MCMV genomes in different cell types, in the latent stage, but in most organs, fibroblasts contained the highest load of MCMV genomes. Ex vivo culturing of these cells led to virus reactivation, suggesting these cells indeed support MCMV latent infection in vivo 52 . In the lung, unlike other tissues, the highest load of MCMV genomes—during latency in vivo —was found in endothelial cells, 52,53 consistent with interstitial lung disease being a common manifestation of CMV infection following transplantations 54 .…”

“…Ex vivo culturing of these cells led to virus reactivation, suggesting these cells indeed support MCMV latent infection in vivo. 52 In the lung, unlike other tissues, the highest load of MCMV genomes-during latency in vivo-was found in endothelial cells, 52,53 consistent with interstitial lung disease being a common manifestation of CMV infection following transplantations. 54 Thus, during MCMV latent infection, the virus can be carried by different cells that differ between different organs.…”