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Stress Compromises HSV-1-Specific Immunity in Latently Infected Sensory Ganglia

Freeman, Michael L (2007) Stress Compromises HSV-1-Specific Immunity in Latently Infected Sensory Ganglia. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Recurrent HSV-1 ocular disease results from reactivation of latent virus in trigeminal ganglia (TG), often following immunosuppression or exposure to a variety of psychological or physical stressors. HSV-specific CD8+ T cells can block HSV-1 reactivation from latency in ex vivo TG cultures in part through production of IFN-&#947. Here we establish that either CD8+ T cell depletion or exposure to restraint stress permits HSV-1 to transiently escape from latency in vivo. Restraint stress caused a glucocorticoid-associated reduction of TG-resident HSV-specific CD8+ T cells, and a functional compromise of those cells that survive, at least partly mediated by catecholamines. Together, these effects of stress resulted in an approximate 65% reduction of cells capable of producing IFN-&#947, and impairment in the ability of those cells to release lytic granules, in response to reactivating virus. We also establish that restraint stress during the primary infection results in a 54% reduction of virus-specific IL-7R&#945+ memory precursor cells in the TG at the peak of expansion. When mice stressed early were stressed again during latency, their T cell response may be further compromised. Our findings demonstrate persistent in vivo regulation of latent HSV-1 by CD8+ T cells, and strongly support the concept that stress induces HSV-1 reactivation from latency at least in part by compromising CD8+ T cell surveillance of latently infected neurons.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Freeman, Michael Lmlf18@pitt.eduMLF18
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHendricks, Roberthendricksrr@upmc.eduRLH13
Committee MemberRabin, Brucerabinbs@upmc.eduBSR
Committee MemberFlynn, JoAnnejoanne@pitt.eduJOANNE
Committee MemberPiganelli, Jonjdp51@pitt.eduJDP51
Committee MemberKinchington, Paulkinchingtonp@upmc.eduKINCH
Date: 7 December 2007
Date Type: Completion
Defense Date: 26 September 2007
Approval Date: 7 December 2007
Submission Date: 7 December 2007
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: herpes simplex virus; immunology; stress
Other ID:, etd-12072007-123821
Date Deposited: 10 Nov 2011 20:08
Last Modified: 19 Dec 2016 14:38


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