Herpes simplex virus type 1 (HSV-1) is one of the most common neurotropic pathogens in humans with a seroprevalence rate increasing up to 60-80% by the 5th decade of life. Clinical diseases associated with HSV-1 include herpetic stromal keratits, the leading cause of infectious corneal blindness in the industrialized world, and frank sporadic encephalitis, a rare but debilitating disease that can result in death. Resistance to infection includes the innate immune system. Central to the innate immune response to virus infection is the type I interferon (IFN) pathway which upon activation by a variety of means including pattern recognition receptors results in the expression of potent anti-viral pathways that block virus replication at the transcriptional and translational levels. Recently, we have begun to explore the relationship between virus infection in the nervous system (peripheral and central) and the role of the type I IFN system in local host resistance and the ensuing adaptive immune response to the insult. Mice deficient in a functional type I IFN pathway (i.e., absence of the alpha chain of the type I IFN receptor, CD118-/-) are found to be highly sensitive to HSV-1 succumbing to infection within 6 days associated with an elevation in virus titer in the peripheral and central nervous systems. Moreover, there is a massive loss of cells residing in the draining lymph node associated with an increase in T cell apoptosis and necrosis. There are also notable changes in recruitment of leukocytes residing in the nervous system post infection of CD118-/- mice. Changes in leukocyte recruitment to the nervous system are reflected by specific changes in select chemokines including CXCL1, CXCL10 and CCL2 in the infected tissue. However, the contribution of resident cells (including astrocytes and microglia) versus infiltrating leukocyte populations within the nervous system or the organized lymphoid tissue (i.e., draining lymph node) in the context of a functional type I IFN pathway in response to infection and the ensuing adaptive immune response and neuropathology is unexplored. We propose to employ mice deficient in select genes as well as mouse chimeras to address this question. Preliminary, unpublished data suggest the resident cells residing in the brain stem with an intact type I IFN system are critical to control viral infection whereas in the peripheral nervous system (i.e., trigeminal ganglion) or cornea, both resident and bone marrow-derived cells with a functional type I IFN pathway are required to maximize resistance to infection. We propose two specific aims within this competitive renewal.
The first aim will test the hypothesis microglia with a functional type I IFN receptor maintain resistance to HSV-1 following ocular infection.
The second aim will test the hypothesis that both leukocytes and resident cells within the TG, cornea, and draining lymph node with a functional type I IFN receptor are required to maximize resistance to HSV-1 infection. It is anticipated the outcome of this project will identify key central components of innate and adaptive immunity within the CNS and peripheral tissues (including sensory ganglia and cornea) that are critical for viral surveillance unique to each tissue. In so doing, a focus on the development of vaccines that utilize (via expansion or activation) such components will provide superior efficacy compared to current strategies that utilize viral encoded proteins that typically generate an immune response incorporating only antibody production or T effector cells. Alternatively, mediators of neuropathogenesis can be targeted to alleviate collateral damage and thus, preservation of neurons in patients that suffer from acute or recurrent HSV-1 CNS or peripheral nerve infection.

Public Health Relevance

Herpes simplex virus type 1 (HSV-1) is a human pathogen that can lead to sporadic encephalitis or other neuropathological conditions in patients that suffer reactivation episodes. The role of the principal innate immune response associated with the control of viral replication and spread, the type I interferons (IFNs), as it relates to the reduction of CNS inflammation and development of the adaptive immune response within the nervous system will be investigated using whole animal, cellular, and molecular techniques. It is anticipated the outcome of the study will identify novel mediators of inflammation responsible for tissue destruction and neuropathology but irrelevant in the control of virus infection. Consequently, by targeting the inflammatory mediators, it may be possible to contain the severity of neuroinflammation without compromising the host ability to control virus replication and spread.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-C (02))
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Challberg, Mark D
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University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
United States
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Menendez, Chandra M; Carr, Daniel J J (2017) Herpes simplex virus-1 infects the olfactory bulb shortly following ocular infection and exhibits a long-term inflammatory profile in the form of effector and HSV-1-specific T cells. J Neuroinflammation 14:124
Menendez, Chandra M; Carr, Daniel J J (2017) Defining nervous system susceptibility during acute and latent herpes simplex virus-1 infection. J Neuroimmunol 308:43-49
Zander, Ryan A; Guthmiller, Jenna J; Graham, Amy C et al. (2016) Type I Interferons Induce T Regulatory 1 Responses and Restrict Humoral Immunity during Experimental Malaria. PLoS Pathog 12:e1005945
Royer, Derek J; Conrady, Christopher D; Carr, Daniel J J (2016) Herpesvirus-Associated Lymphadenitis Distorts Fibroblastic Reticular Cell Microarchitecture and Attenuates CD8 T Cell Responses to Neurotropic Infection in Mice Lacking the STING-IFN?/? Defense Pathways. J Immunol 197:2338-52
Menendez, Chandra M; Jinkins, Jeremy K; Carr, Daniel J J (2016) Resident T Cells Are Unable To Control Herpes Simplex Virus-1 Activity in the Brain Ependymal Region during Latency. J Immunol 197:1262-75
Royer, D J; Carr, D J J (2016) A STING-dependent innate-sensing pathway mediates resistance to corneal HSV-1 infection via upregulation of the antiviral effector tetherin. Mucosal Immunol 9:1065-75
Kroll, Chandra M; Zheng, Min; Carr, Daniel J J (2014) Enhanced resistance of CXCR3 deficient mice to ocular HSV-1 infection is due to control of replication in the brain ependyma. J Neuroimmunol 276:219-23
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Bryant-Hudson, Katie; Conrady, Christopher D; Carr, Daniel J J (2013) Type I interferon and lymphangiogenesis in the HSV-1 infected cornea - are they beneficial to the host? Prog Retin Eye Res 36:281-91

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