Title: Professor and Chief, Division of Infectious Diseases and Global Medicine
Research Interests: Human immunodeficiency virus (HIV), Hepatitis C virus (HCV)
C. Difficile Microbiome and Molecular Biology of Viruses
Our laboratory has a longstanding interest in the pathogenesis of viruses that cause chronic human infections, in particular, human immunodeficiency virus (HIV) and Hepatitis C virus (HCV). We are also fascinated by how humans live in symbiosis with a diverse community of commensal organisms, and by how perturbation of this fine balance can lead to devastating infections. Building on our expertise in infectious diseases and genomics, our laboratory is interested in understand the role of indigenous microbial communities in human infections. Thus, our current research falls within the general themes of host-pathogen interactions, and is divided into two major areas: (1) studies of microbiome in Clostridioides difficile infection, and (2) methods development for accurate and sensitive detection of drug resistance in HIV and HCV. Our studies include investigations of gut microbiota in Clostridioides difficile infection using germ-free and gnotobiotic mouse models and in human subjects, subgingival microbiome in periodontal disease, lung microbiome in cystic fibrosis, and HIV and HCV drug resistance in experimental systems and human subjects. We use a variety of techniques ranging from next-generation sequencing, bioinformatics and traditional methods of molecular biology and microbiology.
Molecular Studies of HCV Pathogenesis and Drug Resistance
Hepatitis C virus infects over 170 million individuals worldwide. Therapy using pegylated-interferon and ribavirin is curative in only up to 50% of individuals with genotype 1 virus infection, but treatment outcome has substantially improved with newer small molecular inhibitors that specifically target HCV-encoded protein. However, resistance to these new drugs is an important consideration in HCV therapy. We are currently investigating the prevalence, frequency, and the dynamics of naturally occurring mutations associated with NS3 protease resistance, including those that circulate at very low frequencies. These studies will provide an important framework for analyzing the emergence and dynamics of resistance during viral breakthrough or relapse after therapy with new therapeutic agents. Our long-term goal is to determine the most effective therapeutic strategies for the treatment of chronic HCV infection using the new generation of small molecule inhibitors.
Ecology of Indigenous Microbial Communities
Some 100 trillion microorganisms inhabit and colonize our human body. These commensal organisms, collectively known as human microbiota, serve a wide range of functions increasingly recognized as mutualistic and indispensable for the health of the host, including proper digestion, metabolism, and, importantly, colonization resistance against pathogens. Alterations of human microbiota have been linked to asthma, allergic diseases, immune system development, and inflammatory bowel diseases. Our research focuses on understanding the ecology and variations of indigenous microbial communities in relation to infectious diseases. For example, in one recent study, we identified several essential butyrate and short-chain fatty acid producing bacteria that were markedly depleted in Clostridium difficile infection (CDI), a health care associated infection that is responsible for 3 million cases of diarrhea in the US annually. Our results implicate butyric acid-producing anaerobic bacteria in C. difficile pathogenesis and suggest a potential role in colonization resistance against C. difficile. The discovery of potential protective organisms in the gut will greatly increase the understanding of C. difficile pathogenesis, and may lead to the development of novel approaches for the prevention and treatment of CDI based on probiotics.
