Human cytomegalovirus pathogenesis and persistence.
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Human cytomegalovirus (HCMV), a betaherpesvirus, is endemic throughout the world with seropositivity reaching 50 to 80% in the United States. Although HCMV infection is generally asymptomatic in immunocompetent individuals, HCMV is a primary viral candidate in the etiology of several diseases, including atherosclerosis and glioblastoma multiforme. In immunocompromised individuals, such as neonates, AID patients, and transplant recipients, HCMV infection can lead to multiorgan failure resulting in significant morbidity and mortality. The myriad of organ diseases associated with HCMV infection is a direct pathological consequence of the systemic viral spread to and infection of multiple organ sites that occurs during either asymptomatic or symptomatic infections, which is necessary for the establishment of viral persistence within the infected host.
Currently, there are 3 main projects within the laboratory.
1) HCMV regulation of monocyte-to-macrophage differentiation.
HCMV infection is characterized by a monocyte-associated viremia prior to the onset of viral pathogenesis, suggesting that HCMV may utilize these blood sentinels as vehicles to mediate hematogenous dissemination of the virus to several organ sites. In support, monocytes are the primary cell type infected in the blood during acute HCMV infection and are the predominant infiltrating cell type found in infected organs. However, despite monocytes being "in the right place, at the right time", these cells have a short lifespan of approximately 2 days and are not permissive for viral replication. We have recently shown that, in order to overcome this biological quandary, HCMV infection stimulates the differentiation of short-lived, viral replication non-permissive monocytes into long-lived, viral replication permissive macrophages. Currently, our laboratory focuses on the role of cellular signaling pathways, cellular miRNAs, and viral miRNAs in regulating the monocyte survival and differentiation machinery following HCMV infection.
2) Novel anti-HCMV inhibitors.
HCMV is considered the most significant infectious cause of post-transplant illness and death. Antiviral prophylaxis is given during high-risk transplants [(i.e. HCMV-seropositive donors (D+) to seronegative recipients (R-)] to suppress virus replication. However, current prophylaxis has simply delayed the kinetics of HCMV disease until after the antiviral regimen is completed. We believe this kinetic shift in HCMV pathogenesis is due to the inability of antiviral drugs to eliminate infiltrating infected inflammatory monocytes, which are not permissive for virus replication and the principle cell type found in infected organs of transplant patients. Thus, we advocate that suppression of HCMV replication with current prophylactic antiviral drugs must be in combination with novel drugs that can specifically kill infected monocytes. We have identified several cellular proteins, which HCMV specifically induces in order to promote the survival of infected monocytes. We are currently testing the antiviral activity of novel small-molecule inhibitors that target these HCMV-induced survival proteins.
3) Disease burden of congenital HCMV infection on Kenyan children.
HCMV is the most common cause of congenital infection in developed countries, including the United States, estimated to occur in 1-2% of all live births. Clinically, both symptomatic and asymptomatic infected neonates are at risk of death or developing permanent neurological sequelae, including cognitive, hearing, and vision impairment. Indeed, HCMV causes more cases of congenital disease than the combination of the 29 currently screened conditions in the United States. However, despite the known medical burden of congenital HCMV infection in developed countries, estimates on rates and disease outcomes in developing countries are limited. The paradigm that maternal immunity to HCMV prior to conception limits in utero transmission and/or prevents sequelae has resulted in a neglect of congenital HCMV infection in developing nations, where HCMV seroprevalence is believed to be >95%. However, we have new data indicating that developing countries may in fact be the largest contributors to the global disease burden of congenital HCMV infection. In collaboration with Dr. Rosemary Rochford, we are currently following an infant-mother cohort in Kenya in order to understand the societal impact and the pathogenesis of congenital HCMV infection.