Professor and Chair
Molecular Microbiology and Immunology
Keck School of Medicine
- cancer cell biology cell cycle,
- growth & proliferation cell death membranes & transport signal transduction cancer biology gene regulation & transcription microbial & invertebrate genetics immunology virology
Research Overview1. Host and Virus Standoff: Co-existence of viruses with their hosts requires a balance between host immune responses and their evasion by viruses. To deal with the sophisticated host immune system, viruses have evolved a myriad of immune evasion mechanisms to avoid elimination by the hosts immune response.
Herpesvirus: Host immune responses, including cytotoxic T lymphocytes and Natural killer cells, play essential roles in the elimination of virus-infected cells. Additionally, interferon and lymphotoxin and their receptor pathways are critical to the early viral infection, ultimately kick-starting the innate and adaptive immune responses of the host defense. Finally, the host carries various intracellular restriction mechanisms to thwart the spread of pathogens. Gifted with large genetic capacity, herpesviruses encode a wider array of viral immune modulators to avoid these host innate and adaptive immune responses. Understanding herpesvirus-mediated immune evasion tactics is the primary goal of this avenue.
Influenza virus: The second avenue of this section is focused primarily on interferon (IFN)-mediated anti-virus immunity. Upon viral infection, the major defense mounted by the host immune system is activation of the IFN-mediated anti-viral innate immune pathway. In order to complete their life cycle, viruses that are obligatory intracellular parasites must modulate host IFN-mediated immune response. We study how the host recognizes viral infection with a specific focus on the RIG-I, TRIMs and IRF genes, and how influenza virus escapes host IFN-mediated anti-viral response with a specific focus on the Influenza virus NS1 gene. Genetically altered mice are used to demonstrate the in vivo roles of host and viral IFN regulatory genes.
2. Virus-Induced Cancer: This section is focused on understanding the molecular mechanisms of lymphoproliferative diseases induced by the gamma-2 herpesviruses and on developing animal models for human diseases. The gamma 2 herpesviruses include murine herpesvirus 68 (MHV68), herpesvirus saimiri (HVS), and Kaposis sarcoma associated herpesvirus (KSHV). KSHV is consistently associated with Kaposis sarcoma, which is a multifocal vascular tumor of mixed cellular composition and is the most common tumor in patients with AIDS. Infection of New World primates with HVS results in rapidly progressing malignant T cell lymphomas. Finally, MHV68 provides a small animal model to study viral persistent infection. Biochemical and immunological analyses of individual viral genes in cell culture and experimental infection of mouse or primate with recombinant herpesviruses are used to define their roles in the onset of disease.
3. Programmed cell death (PCD): Apoptosis has been a primary PCD mechanism to respond viral infection by participating in its own death. Autophagy (Greek, "to eat oneself") is a new, emerging cellular pathway in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins, cytoplasmic organelles, and invading pathogens. Thus, apoptotic and autophagic PCDs are important innate safeguard mechanisms to protect the organism against harmful microbes and unwanted cancerous cells. Viruses, in turn, have evolved elaborate mechanisms to subvert apoptotic and autophagic processes. This avenue is to understand how host initiates apoptosis and autophagy responses upon viral infection and how virus escapes host intracellular PCD-mediated innate immune controls to establish persistent infection and pathogenesis.
4. Acute Lymphoblastic Leukemia (ALL) and Prostate Cancer: We utilize genetically engineered mouse models and chemical inhibitors to investigate the molecular details of ALL and prostate cancer and to develop therapeutic strategies against these cancers.