Host immunity and murine gammaherpesvirus 68 infection

Pratyusha Mandal, Purdue University

Abstract

Herpesviruses are large highly prevalent DNA viruses. They are some of the commonly occurring chronic infections of human beings. Herpesviruses infect hosts causing modest to inconsequential disease before establishing life-long latent infection in hosts. Although latent infection is largely restricted for expression of viral genes, herpesviruses often undergo reversion to lytic cycle with gene expression in a phase known as reactivation. High levels of herpesviruse reactivation and associated pathogenesis is observed in immunodeficient patients. In this body of work we have studied the infection of a gammaherpesvirus. Gammaherpesvirus latency and reactivation are primarily associated with several cancers in immunocompromised patients. Hence it is important to understand immune responses which control gammaherpesviruses reactivation and pathogenesis. Here we have used a murine gammaherpesvirus (murine gammaherpesvirus 68 or MHV68) to study roles of secreted glycoproteins called interferons in controlling infection. MHV68 is closely related to the human gammaherpesviruses which are hard to study owing to their species specificity. Usage of MHV68 helps us study a gammaherpesvirus interaction with vertebrate immune system in vivo. We identified that antiviral type I interferons (comprising of interferon alpha and beta) regulate MHV68 replication in vivo, in vitro and prevents latent virus from reactivation from peritoneal cells and splenocytes of mice by directly inhibiting MHV68 M2gene expression. Functional type I interferons induce signaling pathway which upregulate expression of several genes including transcription factors called interferon regulatory factors (IRF). We observed that type I interferon induced IRF2 directly binds a promoter region on M2gene which is a reactivation associated gene and represses M2 transcription and associated viral reactivation. A mutant virus which is unable to bind IRF2 in M2 promoter displayed increased replication, reactivation and M2 gene expression in vivo which results in increased host lethality in immunocompromised mice. Hence MHV68 cooperates with antiviral effects of the interferon system to facilitate maintenance of latency and minimize host lethality long term. We further identified that although type I interferons significantly control MHV68 infection in vitro and in vivo, none of the effects are mediated by crucial interferon stimulated genes PKR and RNAseL. These interferon stimulated genes are considered to be among the first line of defense against any viral replication. Our investigations revealed that like the other human herpesviruses including the gammaherpesviruses, MHV68 also inhibits PKR-mediated antiviral response. Hence we have shown here a complicated relationship between a murine gammaherpesvirus and host type I interferon system. During replication, MHV68 inhibits type I interferon mediated antiviral response by inhibiting PKR-response; but to facilitate establishment and maintenance of long-term latency MHV68 cooperates with different antiviral responses mediated by type I interferons. These data can be used as valuable model to further our knowledge about the human gammaherpesviruses and better understanding of therapeutic design for patients suffering from herpesvirus reactivation associated diseases. Lastly, gammaherpesviruses establish latency for the life of the host. We wanted to study the effects of latency on other host responses and chose to study development of non-viral tumors in MHV68 infected mice. We identified that MHV68 latent infection changes host response (sometimes to facilitate and sometimes to inhibit) against foreign tumors introduced in mice. Human beings are infected with several herpesviruses and other chronic infections. It is of crucial importance to understand if these change the host response to tumors. Our data sheds lights on some new concepts regarding the relationship between gammaherpesvirus latency and non-viral tumors.

Degree

Ph.D.

Advisors

Stauffacher, Purdue University.

Subject Area

Virology

COinS