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“As an immunologist, my hope is that something I am working on is going to make a difference to human health.”
Chris Benedict, Ph.D.
Associate Professor
Center for Infectious Disease; Division of Immune Regulation

cell-bullet1.jpg 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.

Chris Benedict, Ph.D.Dr. Benedict is an Associate Professor 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 Associate Professor in 2005.

research focus

cell-bullet2.jpg 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 influenza virus, adenovirus and several members of the herpesvirus family, most notably cytomegalovirus (CMV). Our lab focuses heavily on finding new ways to combat CMV, which is the No. 1 infectious cause of birth defects in the U.S. today. CMV causes severe disease if immunity is naïve or compromised (e.g. infection of babies in the womb and transplant patients), and vaccine development is a high priority. Although primary CMV infection is largely benign if immunity is intact, lifelong latency and sporadic reactivation are likely cofactors in auto-inflammatory disorders (e.g. vascular disease and immune senescence). One of our recent discoveries could aid efforts to in the development of a CMV vaccine. For more information on this discovery and CMV, click here.

In addition to this latest CMV work, we have delved into many aspects of this virus’ ability to avoid detection by the immune system. This includes uncovering a link between lymphotoxins (LT) and the regulation of type I interferons (IFN-I) during CMV infection. Mice deficient in LT signaling pathways show increased susceptibility to infection with mouse CMV (MCMV), and cannot mount the initial IFN-I response to infection. Triggering signaling by the LTß-receptor at the earliest times of CMV infection can restore IFN-I production and prolong mouse survival, highlighting this pathway as critical for innate defense to this virus. Our recent work has demonstrated that this LT-regulated pathway emanates from stromal cells located in the splenic marginal zone, and that these cells make copious amounts of IFN-I, similar in magnitude to that produced by plasmacytoid dendritic cells (pDC). In addition, it is the ‘stroma derived’ IFN-I that is critical for controlling replication of MCMV at the earliest times of infection, not that produced by pDC and other DC subsets. Signaling by LTß can also dramatically increase production of IFN-I in human CMV infected cells, indicating a conserved importance of this cytokine "axis" in the regulation of CMV pathogenesis.

A second connection between the TNF related cytokines and CMV is the ul144 orf encoded by virulent isolates of human CMV (HCMV). We originally identified UL144 as an orthologue of the herpesvirus entry mediator (HVEM), a member of the TNF receptor superfamily. When the B and T lymphocyte attenuator (BTLA) was identified as a ligand for HVEM, a negative cosignaling receptor of the Ig-family, we identified UL144 as a BTLA binding partner as well. Recently, we have shown that UL144 is expressed in myeloid cells latently infected with HCMV, strongly suggesting that this viral protein plays a key role in promoting persistence. Further studies regarding the functional consequences of the UL144-BTLA interaction, both during lytic and latent infection, are a topic of current interest for our 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 (TRAIL death receptors, DRs). We have shown previously that human adenovirus encodes 3 proteins in the E3 region of its genome (10.4K/14.5K/6.7K) that specifically downregulate the TRAIL DRs from surface of infected cells, desensitizing them to TRAIL-mediated killing. Recently, we have discovered that HCMV also inhibits expression of the TRAIL DRs, and uses the UL141 protein to accomplish this task. In turn, we have solved the three dimensional structure of the UL141/TRAIL-R2 complex by X-ray crystallography in collaboration with the group of Dr. Zajonc at LIAI. The role that TRAIL plays in host defense to viral infection, in particular that of adenovirus, influenza and CMV, is a topic of current interest in the lab.

CMV-specific CD8 T cells are protective in cellular immunotherapy of immunocompromised humans and mice, and their long-term maintenance is enhanced by CMV-specific CD4 T cells. Importantly, a robust HCMV-specific CD4 T cell response correlates with protection against congenital infection. In addition, CD4 T cells are absolutely required for controlling persistent MCMV replication in the salivary gland (SG), the major site of MCMV horizontal transmission, and CD8 T cells provide no control in this organ. We were the first to identify MCMV epitope-specific CD4T cells, and are interested in the potential to harness these cells for clinical gain. We have shown that cosignaling by the B7-CD28, PDL1-PD1, OX40-OX40L, 41BB-41BBL pathways regulates the development and function of MCMV-specific T cells. In turn, viral inhibition of B7-CD28 signaling is critical for the success of the virus to establish persistent infection and blunt the antiviral CD4 T cell response. Further deciphering the mechanism(s) by which the diverse CMV-specific CD4 T cell response is generated is critical, and will help elucidate how persistent infection is controlled and provide insight for vaccine development.

In total, the Benedict lab is interested in how the various TNF-family cytokines regulate antiviral defenses, and what viruses do to thwart those mechanisms in order to productively replicate.

selected publications

Lymphoid tissue stromal cells coordinate innate defense to cytomegalovirus. J. Virol. 2013.

The myeloid transcription factor GATA-2 regulates the viral UL144 gene during human cytomegalovirus latency in an isolate-specific manner. J. Virol. 2013. 

Human Cytomegalovirus UL141 targets the TRAIL death receptors to inhibit host innate defenses. Cell Host & Microbe 2013

Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov. 2013

TRAIL: not just for tumors anymore? J. Exp. Med. 2012.

Dissecting the requirements for maintenance of the CMV-specific memory T cell pool.
Viral Immunol. 2011

The Mouse Cytomegalovirus Glycoprotein m155 Inhibits CD40 Expression and Restricts CD4 T Cell Responses. J. Virol. 2011
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Differential B7-CD28 costimulatory requirements for stable and inflationary MCMV-specific memory CD8 T cell populations. J. Immunol. 2011

The specificity of innate immune responses is enforced by repression of interferon response elements by NF-κB p50. Sci. Signal. 2011
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B7-mediated costimulation of CD4 T cells constrains cytomegalovirus persistence.
J. Virol.
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Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells. P Natl Acad Sci USA. 2010
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Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells. 
Eur J Immunol. 2010
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Modulation of host innate and adaptive immune defenses by cytomegalovirus: timing is everything. J Intern Med. 2010
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CD4+ T cell help has an epitope-dependent impact on CD8+ T cell memory inflation during murine cytomegalovirus infection. J Immunol. 2009
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DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. EMBO Rep. 2009
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Cardif-mediated signaling controls the initial innate response to dengue virus in vivo.
J Virol. 2009
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A proviral role for CpG in cytomegalovirus infection.
J. Immunol. 2009
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Cutting Edge: The mechanism of invariant NKT cells response to viral danger signals.
J. Immunol.

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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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staff list
upcoming seminars
    "Zinc-induced Polymerization of Receptor at the Plasma Membrane: A New Form of Regulated Signal Transduction?"
    Wednesday 05/18/16: 12:00 PM
    "Exploring the Roles of Type-2 Cytokine-producing Mucosal Mast Cells in Allergic Disorder"
    Wednesday 06/01/16: 12:00 PM
  • Arthritis National Research Foundation Eng Tan Scholar, 2006
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