- A.B., Harvard University, 1982
- M.D., Columbia University, 1986
- Internal Medicine Residency, Columbia-Presbyterian Medical Center, New York, NY, 1986-89
- Infectious Disease Fellowship, Beth-Israel Hospital, Brigham & Women's Hospital, and Dana-Farber Cancer Institute, Boston, MA, 1989-92
- National Board of Medical Examiners, 1987
- Diplomate, American Board of Internal Medicine, 1989
- Diplomate, American Board of Internal Medicine (Infectious Diseases), 1992, 2002
Honors and Awards:
- Leukemia & Lymphoma Society of America, Translational Research Award
- Physician Scientist Award
- Michael Aranow Award, College of Physicians and Surgeons
- Cum Laude, Biology, Harvard University, Cambridge, MA
My research interests are in the mechanisms that viruses employ to evade innate immunity, including cell-mediated death pathways that ordinarily regulate viral replication. Specifically, my laboratory is studying:
- the function of novel viral bcl-2s in the EBV and poxvirus life-cycles,
- TNF family members’ effects upon viral replication, and
- mechanisms of viral evasion of the innate immune response.
Poxvirus Inhibitin of Innate Immune Signaling
Toll like receptors (TLRs) are receptors for molecular patterns of microbial pathogens. TLRs signal to transcription factors such as NF-kB & IRF3, inducing antiviral cytokines and interferons.
N1L is a vaccinia virus gene responsible for a 10,000 fold increase in virulence (Kotwal, 1989), inhibition of NF-kB and IRF3 signaling (DiPerna, 2004), and encodes an anti-apoptotic bcl-2 (Aoyagi, 2007).
All of the characterized A52R family of genes inhibit NF-kB signaling (see Figure below). A52R affects p38 kinase activity, all the rest also inhibit IRF3 signaling and one (N1L) encodes a vbcl-2.
Despite this apparent redundancy, deletion of A52R, A46R, or N1L significantly attenuates infection. Our lab is attempting to understand the other mechanisms whereby members of this growing family of poxvirus genes function to modulate innate and adaptive immune responses.
In collaboration with the laboratories of other UMass faculty (Dr. Neal Silverman and Katherine Fitzgerald) we are attempting to define other mechanisms whereby N1L modulates innate immune responses. Dr. Fitzgerald’s laboratory is investigating the effects of RIG-I on viral replication. Two RNA-helicase and CARD-domain containing proteins, RIG-I and Mda5, are believed to recognize viral dsRNA in the cytoplasm. RIG-I and Mda5 are likely to play critical roles in the recognition of and response to many viral pathogens. RIG-I signals to MAVS/VISA/Cardif and then downstream to TBK-1.
TLR3-mediated signal transduction relies entirely on the TIR-adaptor protein TRIF. Macrophages lacking the TRIF gene replicate vaccinia virus to 20-fold higher titers. This result highlights the importance of signaling downstream of TRIF for the protection against poxvirus infection. N1L inhibits TLR3-mediated signaling and N1L-mutant vaccinia virus has 104-fold decreased virulence in vivo, and 10-fold reduced replication both ex vivo and in a mouse model of vaccinia virus infection. The effect of N1L on poxvirus virulence in vivo may be even greater than the effect of losing TLR3 signaling on replication because N1L may inhibit both TLR3 and RIG-I mediated activation of NF-kB and IRF3.