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Dr. Sarawar received her Ph.D from the Department of Biochemistry and Molecular Biology at the University of Manchester, England, where she also did her postdoctoral training in the Departments of Pathology and Immunology. She held positions at St Jude Children’s Research Hospital and the La Jolla Institute of Allergy and Immunology between 1992 and 2003 and was recruited to the Torrey Pines Institute for Molecular Studies in October 2003.

Research in this laboratory is focused on understanding the role of cytokines and costimulatory molecules in viral immunity and pathogenesis. We also have a long-term interest in studying the impact of viral infections on other disease states such as asthma, bacterial infections and autoimmunity.

The role of cytokines and costimulatory molecule in the long-term control of a persistent viral infection.

Some viruses are able to persist in a latent form, after an initial replicative phase. The immune system generally maintains control of latent viruses throughout the lifetime of an immunocompetent host. However, failure to control latent herpesviruses (including gammaherpesviruses) presents a particular problem in immunocompromised individuals, such as AIDS patients, who lack effective CD4 T cell function. This leads to a variety of serious and potentially life-threatening conditions, including several types of cancer. CD4 T cells play a pivotal role in the immune response to viral infection, providing help for CD8 T cells and B cells in addition to functioning as effector cells in viral clearance. In these studies, we plan to identify the key components of CD4 T cell help and the requirements for effective CD8 T cell function in the long-term control of a persistent viral infection. Using a CD4 T cell deficient mouse model of opportunistic infection, we have shown that agonistic antibodies to CD40 can substitute for CD4 T cell function in preventing reactivation of a latent gammaherpesvirus, by a CD8 T cell dependent mechanism. CD40-/- mice also show viral reactivation in the lungs. These data suggest that the interaction between CD40 and CD40L is a key costimulatory event during the development of the CD8 T cell response. We are currently dissecting the pathway by which CD40 activation leads to effective CD8 T cell function. Such studies will provide insight into the long-term control of persistent viral infections and may eventually lead to the development of novel approaches to treat or prevent viral infections in immunocompromised patients.

We are also using the gammaherpesvirus model to study early events in T cell activation leading to primary clearance of replicating virus. Although long-term control of latent gammaherpesvirus infection in this model is CD4 T cell dependent, primary clearance of replicating virus by CD8 T cells is CD4-T cell independent. We are currently comparing the costimulatory requirements for acute and long-term control of the virus. We have shown that interactions between OX40-OX40L, CD28-B7 and CD40-CD40L are not essential for the activation of T cells, which mediate primary viral clearance. Interestingly the signaling pathway leading to T cell activation in this viral infection does appears to be dependent on protein kinase C theta, which was previously thought to be an absolute requirement for T cell activation.

Chemokines and leukocyte trafficking during viral infection

The objective of this study is to explore the regulation of leukocyte trafficking to the lung during viral respiratory disease and why this process becomes deregulated in asthmatic patients, who often suffer severe asthma exacerbations following respiratory viral infections. We are particularly interested in the role of chemokines in this process. Within the scope of this project, we are also investigating the role of viral chemokine receptor homologues that are encoded by gamma-2-herpesviruses and have been implicated in viral persistence and tumorigenesis. We have conducted a detailed assessment of the chemokines produced during primary infections with gammaherpesvirus and influenza virus and are currently investigating the in vivo significance of the chemokines detected, using chemokine or chemokine receptor deficient mice. Armed with this knowledge, we plan to further extend these studies to investigate the role of cytokines and chemokines in the deregulated leukocyte trafficking that occurs during viral infection of individuals with pre-existing allergic inflammation.

The MHV-68 genome encodes a membrane-bound CXCR2 chemokine receptor homologue, which is conserved in other members of the gamma-2-herpesvirus family, including the Kaposi’s sarcoma associated herpesvirus. As a group, the herpesviruses have evolved numerous immune evasion strategies, to either evade or to usurp components of the immune system, enabling the viruses to spread and establish latent infections. It has been suggested that viral chemokine receptor homologues may assist in dissemination of virus or in sequestering chemokines, locally. In an ongoing collaboration with Dr. Heiko Adler, we have used MHV-68 mutants lacking the CXCR2 homologue to examine the role of this chemokine receptor in viral replication and reactivation from latency. Our in vitro experiments show that CXC chemokines increase the replication of wildtype but not mutant viruses via a pertussis toxin-insensitive, MEK and PI3 kinase-dependent pathway. The mutant viruses also showed a striking impairment in reactivation from latently-infected cells in vitro. Utilizing a viral CXCR2 homologue to enhance replication and reactivation from latency represents a novel mechanism by which gammaherpesviruses can subvert the immune system. Our future studies will be directed at dissecting the signaling pathways by which the viral chemokine receptors mediate these effects and further examining the pathogenesis of the mutant viruses in vivo. Studies on these mutant viruses will increase our understanding of the pathogenic mechanisms of gammaherpesviruses.

Gammaherpesvirus and Systemic Lupus Erythematosus (SLE)

SLE is an autoimmune disease, which is characterized by inflammation and the production of autoantibodies to a wide spectrum of nuclear, cytoplasmic and cell surface antigens. Glomerulonephritis, atherosclerosis and thrombosis are the more serious manifestations of this disease. Studies on the etiology of SLE indicate that both genetic and environmental factors influence disease penetrance. In this study, we will investigate the strong correlation that has been reported between gammaherpesvirus infection and systemic lupus erythematosus (SLE). Dr. Ward Wakeland an colleagues have generated C57/BL6 congenic mouse strains carrying one or more of 3 lupus susceptibility loci, designated Sle 1, 2, and 3. It has been shown that the presence of at least 2 loci is necessary for high disease penetrance. We will determine whether gammaherpesvirus infection can trigger disease in mice congenic for a single locus. We will utilize the mouse gammaherpesvirus which does not induce overt autoimmune disease in C57BL/6 mice, but like the closely-related human gammaherpesvirus Epstein Barr virus, is able to induce non-specific B cell activation. Therefore, infection of the congenic mice with mouse gammaherpesvirus (MHV-68) provides a useful model in which to dissect mechanisms by which viruses can trigger autoimmune disease.