Abstract
Herpesviruses are characterized by their ability to establish lifelong latent infection. The gammaherpesvirus subfamily is distinguished by lymphotropism, establishing and maintaining latent infection predominantly in B lymphocytes. Consequently, gammaherpesvirus pathogenesis is closely linked to normal B cell physiology. Murine gammaherpesvirus 68 (MHV68) pathogenesis in laboratory mice has been extensively studied as a model system to gain insights into the nature of gammaherpesvirus infection in B cells and their associated lymphoid compartments. In addition to B cells, MHV68 infection of macrophages contributes significantly to the frequency of viral genome-positive cells in the peritoneal cavity throughout latency. The omentum, a sheet of richly-vascularized adipose tissue, resides in the peritoneal cavity and contains clusters of immune cell aggregates termed milky spots. Although the value of the omentum in surgical wound-healing has long been appreciated, the unique properties of this tissue and its contribution to both innate and adaptive immunity have only recently been recognized. To determine whether the omentum plays a role in gammaherpesvirus pathogenesis we examined this site during early MHV68 infection and long-term latency. Following intraperitoneal infection, immune aggregates within the omentum expanded in size and number and contained virus-infected cells. Notably, a germinal-center B cell population appeared in the omentum of infected animals with earlier kinetics and greater magnitude than that observed in the spleen. Furthermore, the omentum harbored a stable frequency of viral genome-positive cells through early and into long-term latency, while removal of the omentum prior to infection resulted in a slight decrease in the establishment of splenic latency following intraperitoneal infection. These data provide the first evidence that the omentum is a site of chronic MHV68 infection that may contribute to the maintenance of chronic infection.
Highlights
Gammaherpesviruses are ubiquitous pathogens, with many viruses identified and exhibiting tropism across a variety of different species, including elephants, rodents, non-human primates, and humans
Increased follicle size or frequency was not observed in the spleen by day 5, suggesting that peritoneal Murine gammaherpesvirus 68 (MHV68) infection induces a immunological response in the omentum which results in sustained expansion of germinal center-like lymphoid aggregates with distinct kinetics from that observed in the spleen
We demonstrate a marked immunological response to MHV68 infection in the omentum by this route, including growth and expansion of immune aggregates and a germinal center population that occurs prior to a similar response in the spleen
Summary
Gammaherpesviruses are ubiquitous pathogens, with many viruses identified and exhibiting tropism across a variety of different species, including elephants, rodents, non-human primates, and humans. Epstein-Barr virus (EBV) is the most common gammaherpesvirus with as many as 95% of humans tested exhibiting seropositivity. Kaposi’s Sarcoma-associated herpesvirus (KSHV) is another less common but relatively widespread human gammaherpesvirus. Like EBV, KSHV is usually of limited pathogenecity in healthy, immunocompetent individuals. When the immune system is compromised, the presumably innocuous hostpathogen balance is disrupted and gammaherpesvirus-associated pathogeneses arise. The most common of these are lymphoproliferative diseases such as PTLD, often presenting in solid-organ transplant patients on intensive immunosuppression regimens, and PEL and Kaposi’s sarcoma, seen most often in AIDS patients with profoundly compromised immune systems
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