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My laboratory is studying various molecular strategies that viruses
employ to modulate host immune defenses. We focus mainly on viral
targeting of signaling pathways initiated by cytokines of the tumor
necrosis factor (TNF) and interferon (IFN) families, which regulate
both cell death and multiple aspects of the host inflammatory response.
We utilize several different viral model systems both in tissue culture
and in vivo including several members of the herpesvirus family
(cytomegalovirus and herpes simplex virus), influenza virus and
adenovirus.
In the case of cytomegalovirus infection (CMV, a ß-herpesvirus), we have uncovered a link between lymphotoxins (LT·ß) and the regulation of type I interferons (IFN·ß). Mice deficient in LT·ß signaling pathways show increased susceptibility to infection with mouse CMV, and cannot mount an efficient, early IFNαß response. Triggering signaling by the LTß-receptor at the time of infection in LT·ß-/- mice can restore IFNαß production and prolong survival, suggesting an important effector role for LTß-receptor signaling in innate host defense to CMV. Importantly, signaling by LT·ß can also dramatically increase production of IFNß from human CMV infected cells, indicating a conserved importance of this cytokine "axis" in the regulation of CMV pathogenesis.
We are currently exploring the mechanisms and cell-types involved in the LT·ß-dependent regulation of the IFNaß response in various mouse and tissue culture models, and are exploring how these innate defense pathways might contribute to the development of adaptive immunity to CMV. Virtually all TNF-related cytokines activate nuclear factor-kappa B (NF-ÎB) dependent signaling pathways, and NF-ÎB is required for the transcription of IFNß. Consequently, we have been actively exploring the requirements and regulation of the "canonical" and "noncanonical" NF-ÎB pathway during CMV infection. Additionally, we are testing whether this cytokine system contributes to IFN·ß responses upon infection with influenza virus and members of the bunyaviridae (Rift Valley fever virus and La Crosse virus), biodefense category A-C pathogens.
A second connection between the TNF related cytokines and the ß-herpesviruses is the ul144 orf encoded by virulent isolates of human CMV. We originally identified UL144 as an orthologue of the herpesvirus entry mediator (HVEM), a member of the TNF receptor superfamily. Recently, with the identification of HVEM as a ligand for B and T lymphocyte attenuator (BTLA, a negative costimulatory molecule of the Ig-domain containing class of molecules) we have identified UL144 as a BTLA binding partner. Further studies regarding the functional consequences of the UL144-BTLA interaction, and addressing its importance in the context of human CMV infection using recombinant viral mutants lacking UL144 is a topic of current study in the lab.
TNF-related apoptosis inducing ligand (TRAIL) can bind to several receptors (TRAIL receptor- 1, 2 ,3 and 4), of which two (R1 and R2) encode a cytoplasmic "death domain" and can mediate apoptosis of transformed cells. We have shown that human adenovirus encodes 3 proteins in the E3 region of its genome (10.4K/14.5K/6.7K) that specifically downregulate the proapoptotic TRAIL receptors from the cell surface of infected cells, desensitizing them to TRAIL-mediated killing. The role that TRAIL plays in host defense to viral infection, and the strategies used by adenovirus (and potentially other viruses) to regulate TRAIL signaling is currently being pursued in the lab.