Murine norovirus abrogates Chlamydia pneumoniae accelerated atherosclerosis in ApoE-/- mice
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Chlamydia pneumoniae (Cpn), a common respiratory pathogen of humans, has a strong seroepidemiologic association with cardiovascular disease as well as the ability to accelerate atherosclerosis in hyperlipidemic animal models. Our laboratory recently demonstrated that murine norovirus (MNV), a highly prevalent infection of laboratory mice, can variably alter atherosclerosis in hyperlipidemic Ldlr-/- and ApoE-/- mice. Given that MNV has a tropism for macrophages and has been shown to exacerbate atherogenesis under particular conditions, we investigated whether concurrent MNV and Cpn infection could alter macrophage phenotypes in vitro and atherosclerosis in ApoE-/- mice. In the presence of oxidized low-density lipoprotein (oxLDL), co-infection of ApoE-/- bone marrow derived macrophages (BMDM) with MNV and Cpn resulted in increases in gene expression of IL-6, MCP-1, iNOS, and TNF-α as compared with Cpn mono-infected BMDM. Based on these findings, we hypothesized that concurrent MNV infection would exacerbate vascular inflammation and increase plaque lesion size in Cpn infected ApoE-/- mice. As demonstrated previously, Cpn infection alone resulted in significantly larger plaques (64% increase in mean size) as compared with uninfected mice. In mice co-infected with MNV and Cpn however, there was a 54% decrease in mean lesion size compared with Cpn mono-infected mice. Mechanisms by which MNV could elicit this unexpected abrogation in Cpn infected ApoE-/- mice were investigated. There were significant increases (P < 0.05) in the circulating Ly6Chi monocyte subset in co-infected mice in comparison to either MNV mono-infected or uninfected mice. Further, there were no differences in cytokines locally at the site of lesion development, or in peritoneal macrophages 1 week following infection in mono-infected or co-infected mice as compared to controls. MNV was not detected in the aortic tissue of MNV infected mice at 1 week or 8 weeks post-infection regardless of Cpn status. These data suggest that MNV infection can abrogate the effect of Cpn on the progression of atherosclerosis and that this effect is likely through viral modulation of systemic responses rather than viral induction of inflammatory cytokines directly at the site of plaque formation in the aorta. These findings, regarding a highly prevalent virus of laboratory mice, should be a consideration for studies utilizing the ApoE-/- mouse model.