UTMB Department of Pathology

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Innate Immune Responses and Viral Pathogenesis

My laboratory is investigating the molecular interaction of herpes simplex virus (HSV), Chlamydia trachomatis, Francisella tularensis and hepatitis C and B viruses (HCV, HBV) with the host. HSV is an extremely efficient pathogen infecting an estimated 80% of the human population. Chlamydia is one of the most common sexually transmitted infections (STI) associated with infertility and cervical cancers. Francisella is a potential bioweapon and one of the most infectious bacteria known. Finally, HCV and HBV are the most common causes of hepatocellular carcinoma and can lead to chronic life threatening infections. Current projects in my lab include, evaluation of innate immune response modifiers as preventatives against STI and Francisella, identification of novel antivirals potent against HCV as well as clinical studies of patients that are multiply infected with combinations of HIV, HCV and HBV. My lab also has ongoing studies of the effect of host factors, such as neurotrophins or neural cytoskeletal proteins, on the reactivation of latent HSV infections.

Innate immune responses can be ‘primed’ to generate a mucosal surface that is more resistant to infection. Recent work has identified a family of proteins, designated toll-like receptors (TLR), that recognize molecular patters associated with pathogens. TLR activation produces cytokines, chemokines and reactive oxygen species that limit the infectious capability of the pathogen. We have established that priming this response with synthetic TLR agonists produces a resistant genital surface that is protected against infection with HSV and Chlamydia in small animals models of genital infection and more recently in novel human genital epithelial cell cultures. The safety of these compounds also are under evaluation. We have extended this work to respiratory mucosal surfaces. Protection of the respiratory tract is of particular interest because many agents of biological warfare are likely to be delivered in aerosol form.

I have employed molecular biological approaches to study viral life cycles and pathogenesis. More recently we have applied these techniques for the identification of novel HCV antivirals. This work also has allowed us to begin to examine the development of drug resistance and its impact on viral fitness. In the context of co-infections with HIV and HBV these drug resistant HCV strains are of particular importance. Our molecular assays can provide an indication of viral fitness in the context of these drug resistance mutations. For HSV, we have constructed a panel of recombinant HSV strains that carry alterations in key viral proteins and are testing them in animal models. By incorporating reporter genes into HSV (see below) we have been able to detect infected cells as well as subcellular locations of viral proteins.

In addition to these basic science projects, my lab also is active in clinical research studies. Utilizing the Sealy Center for Vaccine Developments diagnostic PCR Core facility, we have established a number of quantitative real time PCR assays for analyses of human samples. These same assays are also utilized for our preclinical studies in cultured cells and in animal models.