After peripheral infection, Herpes Simplex Virus (HSV) spreads rapidly to the PNS and CNS via intra- axonal transport in sensory neurons. An appropriately controlled immune response to the virus determines the outcome of CMS infection. While resistant mouse strains control the virus and survive, susceptible strains suffer severe CNS inflammation and develop HSV encephalitis (HSVE) resulting in high mortality. The cells and signaling molecules involved in these beneficial or detrimental immune responses in the CNS remain poorly defined. We present evidence for immune cell mediated CNS pathology originating with bone marrow of susceptible mice for which integral components are macrophages, T lymphocytes, cytokines (IFN-y, TNF) and chemokines (MIG, IP10) involved in recruitment of Thl-like lymphocytes. Susceptible mice show stronger Th1-like immune responses, greater CNS inflammation and higher mortality than resistant mice. We hypothesize that an exaggerated inflammatory response to HSV infection in the CNS is pathological, and that such a response distinguishes susceptible from resistant mouse strains. We will explore the contribution of immune cell mediated pathology to the overall'complex of responses during HSV encephalitis that also includes direct viral cytopathology. Thus, this proposal focuses on immune responses in the CNS of susceptible mice, contrasted with resistant mice as appropriate. The hypothesis for this proposal is that macrophages and effector T-cells are major contributors to HSVE development and that macrophages in addition regulate the response of effector T-cells.
The Specific Aims of this proposal are therefore: 1) to characterize activation of macrophages that infiltrate the CNS and determine by adoptive transfer their contribution to HSVE and 2) to determine the role of T cell recruitment and activation and identify by adoptive transfer a specific subset involved in HSVE, and examine the influence of macrophages on this process. Thorough definition of the responses that control an immune cell-mediated pathological response within the CNS has implications beyond HSV infection. CNS pathology for other encephalitic viruses and that occurring in Multiple Sclerosis, Alzheimer's Disease, and HIV/AIDS has been linked to inappropriate immune responses. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense Study Section (IHD)
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Johnson, David R
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City of Hope/Beckman Research Institute
United States
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Ramakrishna, Chandran; Openshaw, Harry; Cantin, Edouard M (2013) The case for immunomodulatory approaches in treating HSV encephalitis. Future Virol 8:259-272
Lundberg, Patric; Ramakrishna, Chandran; Brown, Jeffrey et al. (2008) The immune response to herpes simplex virus type 1 infection in susceptible mice is a major cause of central nervous system pathology resulting in fatal encephalitis. J Virol 82:7078-88