As an immunologist, my hope is that something I am working on is going to make a difference to human health. That’s what interests me – the possibility to combat human disease.”  - Chris Benedict, Ph.D.

Dr. Benedict is an assistant member in the division of molecular immunology. Dr. Benedict's research is focused on the role that signaling by TNF-related cytokines play in antiviral defense, and what viruses do in turn to counteract these cytokines.

Dr. Benedict received his B.S. in chemistry from the University of Minnesota in 1992, and his Ph.D. in 1997 from the University of Southern California in the department of biochemistry and molecular biology. Dr. Benedict did his postdoctoral training at LIAI from 1998-2001, was a research scientist from 2001-2005 and was appointed to the faculty as an Assistant Member in 2005.

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.

A proviral role for CpG in cytomegalovirus infection. J. Immunol. 2009

Cutting Edge: The mechanism of invariant NKT cells response to viral danger signals. J. Immunol. 2008

Cutting Edge:  Murine cytomegalovirus induces a polyfunctional CD4 T cell response. J. Immunol. 2008
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Dendritic cell programming by cytomegalovirus stunts naïve T cell responses via the PD-L1/PD-1 pathway. J. Immunol. 2008
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Lymphotoxin-mediated crosstalk between B-cells and stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe. 2008
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Specific remodeling of splenic architecture by cytomegalovirus. PLoS Pathogen. 2006
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RIGing a virus trap. Nature Med. 2005
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Poxviruses aren’t stuPYD. Immunity. 2005
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Human NK cells inhibit cytomegalovirus replication through a noncytolytic mechanism involving lymphotoxin-dependent induction of IFN-b.  J. of Immunol. 2005
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Evolutionary Divergent Herpesviruses Modulate T cell activation by Targeting the Herpesvirus Entry Mediator (HVEM) Cosignaling Pathway.  Proc. Natl. Acad. Sci. 2005
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A lymphotoxin-interferonb axis essential for lymphocyte survival revealed during cytomegalovirus infection. J. Immunol. 2005
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Neutrality of the canonical NFkB-dependent pathway for human and murine cytomegalovirus transcription and replication in vitro. J. Virol. 2004
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Viruses and the TNF-related cytokines, an evolving battle. Cytokine Growth Factor Rev. 2003
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To kill or be killed: viral evasion of cell death. Nature Immunol. 2002
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Three adenovirus E3 proteins cooperate to evade apoptosis by tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and –2. J. of Biol. Chem. 2001
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Lymphotoxins and cytomegalovirus cooperatively induce interferon-b, establishing host-virus détente. Immunity. 2001
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Cutting Edge:  A Novel Viral TNF Receptor Superfamily Member in Virulent Strains of Human Cytomegalovirus. J. Immunol. 1999
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