Immunity to cytomegalovirus in mucosal tissues
Cytomegalovirus (CMV) causes a common congenital infection, leading to hearing loss, vision impairment and cognitive/motor deficits in 0.1 - 0.2% of all newborns in the US. These devastating outcomes most often occur when the virus infects a pregnant woman who was previously CMV naive. Thus, it is critical to develop vaccines to prevent CMV infection. Protection against CMV will depend on stopping the virus at the site of entry or preventing infection of the fetus by stopping the virus as it disseminates through the body. To accomplish this, we need an understanding of: i) immunity at the natural site of viral infection, ii) how protective responses can be targeted to this tissue, iii) how CMV spreads within its host and iv) how the immune system can interrupt viral transit. For decades it was assumed that natural CMV infection occurred through the gastrointestinal tract after oral ingestion of CMV shed in breast milk, saliva, and urine. However, compelling recent evidence implicates the nasal mucosa as the site of natural infection, even for virus ingested in fluids such as breast milk. Most immunological studies of the nasal mucosa have focused on allergy and chronic TH2 cytokine-mediated inflammation, with little known about viral defense mechanisms at this important barrier tissue. Our preliminary data show that murine (M)CMV primes relatively weak T cell responses that fail to control viral replication in the nasal mucosa after intranasal (i.n.) infection.
Nevertheless, our data suggest that T cells can restrain viral spread from this tissue and that viral immune evasion may be essential for dissemination from the nasal mucosa to other tissues in the body. We found that tissue-resident memory T cells (TRM) can be parked in the nasal mucosa efficiently, but that CD4+ T cell help will be essential for developing protective CD8+ T cells after infection or vaccination through the nasal mucosa. With these tools, we investigate the development of protective immunity in the nasal mucosa (the site of entry) and the salivary gland (the site of shedding) after MCMV infection or vaccination, and the mechanisms limiting viral control in these tissues.
The use of cytomegalovirus to modify the tumor environment
Despite substantial effort, vaccines that elicit effective anti-tumor immunity are rare. Cytomegalovirus (CMV) is a herpesvirus that causes minimal or no disease in immune competent hosts, but still stimulates the largest known T cell populations in the circulation of adults. Recent work has shown that CMV-based vaccine vectors stimulate incredibly strong immune responses. Thus, CMV-based vaccines for humans are currently in development. However, while substantial pre-clinical data demonstrates the efficacy of CMV-based vaccines for infectious diseases including HIV, very little is known about how effective CMV-based vaccines will be for tumors. We have been exploring the efficacy of CMV-based vaccines in mouse models of melanoma and squamous cell carcinoma using the natural mouse CMV (MCMV). Unexpectedly, we found that direct intratumoral infection by MCMV had a profound influence on the tumor environment and promoted T cell-mediated destruction of tumors, without the use of foreign antigens in the tumor, adoptive T cell therapy to enhance T cell numbers, or checkpoint blockers to alleviate immune suppression. Remarkably however, blocking the immune checkpoint PD-1 robustly synergized with MCMV infection to destroy well-established melanomas. This effect was largely, but not completely dependent on CD8+ T cells in the mouse. Our data suggest that MCMV alters the tumor environment through infection of tumor associated macrophages and recruitment of new macrophages into the tumor. With this system, we investigate how MCMV and its human counterpart (HCMV) modulate macrophages and how this infection impacts the tumor environment to facilitate T cell-mediated immune destruction.