Latent Murine Cytomegalovirus Infection: Impact on Breast Cancer Metastasis and Tissue Cytokine Profiles in Males and Females

Human cytomegalovirus (HCMV) infects 40-100% of adults worldwide depending on the country. After initial infection, HCMV enters a lifelong period of latency, which can be punctuated by reactivation. HCMV seropositivity is associated with worse outcomes in diseases including cardiovascular disorders, immunosenscence in aging, and worse outcomes and metastasis in several cancers, including breast cancer. Our group has previously shown that Canadian women with breast cancer who are HCMV seropositive are 5.6 times more likely to develop stage IV metastasis. We also found that mice with a latent murine cytomegalovirus (mCMV) infection and breast cancer had increased lung metastasis compared to uninfected mice. The possible mechanisms through which a latent HCMV or mCMV infection may impact breast cancer metastasis or other pathologies are unknown. Recent studies have shown long-term changes to the cytokine and immune cell profiles in the salivary glands and adipose tissue of male mice with a latent mCMV infection. Additionally, there are sex differences in the immune response to infection and diseases including cancer; however, the impact of sex on the immune changes during HCMV or mCMV infection is largely unstudied. I hypothesized that there would be chronic long-lasting changes to cytokine profiles in organ microenvironments of mice with latent mCMV infections that will be sex-dependent. In tumors and lungs, these changes will be prometastatic including increased EMT, lung fibrosis, immunosuppression, and increased vascular permeability. Two markers for EMT, E-cadherin (p=0.54) and vimentin (p=0.23) were not different in breast tumors from MMTV-PyVT mice with latent mCMV infections compared to uninfected controls when measured by immunofluorescence. Contrary to the progression of EMT, vimentin measured by western blot was lower (p=0.023) in the breast tumors from the latent mCMV-infected mice; however, vimentin levels in these tumors were positively associated with the size of lung metastases. To determine whether a condition such as infection before cancer development could impact breast cancer metastasis I examined the lungs of mice with latent mCMV infections without cancer. The lungs are a metastatic target for breast cancer, and I measured several pro-metastatic changes that can occur including fibrosis, immunosuppression, and vascular permeability in female BALB/c mice with latent mCMV infections in the absence of breast tumors There was no evidence of lung fibrosis in the BALB/c model or in latent mCMV-infected MMTV-PyVT mice, which develop spontaneous breast tumors (p=0.52). In BALB/c mice with latent infections, without tumors, 10 cytokines were increased significantly in the lungs including pro-metastatic, immunosuppressive IL-4 (p=0.009), and IL-10 (0.004). Several cytokines were altered in the plasma and each organ except the spleen, indicating immune profile alterations in multiple female mouse organs due to latent infection in the absence of tumors. There was also an increase in soluble VE-cadherin in the lungs of mice with latent mCMV infection (p=0.02), indicating a possible increase in vascular permeability. To study the interaction of sex and latent mCMV infection on changes in immune profiles, latent infections with mCMV were established in male and female mice and 32 cytokines in the plasma, lungs, hearts, kidneys, livers, and spleens were measured by array. 20/32 cytokines in the plasma, 17/32 in the lungs, 25/32 in the hearts, 31/32 in the kidneys, 24/32 in the livers, and 23/32 in the spleen were significantly altered in a sex- and/or infection-dependent manner. This demonstrates that the complex interplay between mCMV infection and sex can also differ by tissue. The strongest patterns in terms of sex and infection across several organs were seen for some chemokines including eotaxin (CCL11), LIX (CXCL5), and MIG (CXCL9). These novel findings indicate a possible role for chronic long-term effects of mCMV infection in increasing or suppressing immune cell migration into tissues. Overall, this project provides new information on the chronic long-term changes to host tissue microenvironments that occur in mice with latent mCMV infection, even though it appears to be asymptomatic. This work provides new foundational research into how cytokine/chemokine profiles and vascular permeability are altered in mice with latent mCMV infection and how sex may impact response to this infection. From this work, new mechanisms through which latent mCMV and HCMV affect diseases like breast cancer and cardiovascular disease can be tested and then targeted to improve outcomes and survival.

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