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Contributions of Innate and Adaptive Immunity in the Development of Herpes Stromal Keratitis After Corneal HSV-1 Infection

Carroll, Kate (2020) Contributions of Innate and Adaptive Immunity in the Development of Herpes Stromal Keratitis After Corneal HSV-1 Infection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Acute herpes simplex virus type 1 (HSV-1) infection is readily cleared by the host’s immune system; however, HSV-1 also establishes a lifelong latent infection within neurons. HSV-1 can remain latent indefinitely but can also reactivate and cause recurrent peripheral disease. The cornea is one potential site of HSV-1 infection and viral reactivation can lead to the development of herpes stromal keratitis (HSK). HSK is characterized by progressive corneal opacity, neovascularization, and hypoesthesia that can lead to blindness. Although most people contract HSV-1 by adulthood, only a fraction develop HSK, despite many showing evidence of viral shedding. This disparity raises the questions of what triggers HSK development in only some individuals and how we can prevent reactivation events that contribute to HSK development. It has previously been shown that HSV-1-specific CD8+ T cells are crucial in preventing reactivation in the neurons of the trigeminal ganglion (TG); however, a portion of these cells undergo functional impairment. To better understand how function is regulated in these cells, we assessed the expression of checkpoint molecules and unexpectedly found that T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), which has previously been associated with functional impairment, is found on highly functional cells within the TG. Tim-3 expression on CD8+ T cells was influenced by viral gene expression and marked cells that produced effector molecules during both acute and latent infection, suggesting that Tim-3 expression indicates recent stimulation, rather than exhaustion. These results suggest that T cell impairment in HSV-1 infection may be phenotypically distinct from exhaustion in chronic infections. To address what triggers HSK development, we utilized pathogenic and nonpathogenic strains of HSV-1 to assess the immune response during infection. We found that mice infected with the pathogenic strain had lower viral titers in the cornea but a more robust immune response, which included increased numbers of inflammatory innate immune cells and upregulation of proinflammatory mediators. This suggests that early interventions that blunt the innate response to HSV-1 may result in more favorable visual outcomes. Collectively, this work further defines HSV-1-specific CD8+ T cell impairment in the TG and identifies early innate responses as orchestrating HSK development.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Carroll, Katekac245@pitt.edukac2450000-0003-3867-2892
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorSt. Leger, AnthonyAnthony.stleger@pitt.edu
Committee MemberKinchington, Paulkinch@pitt.edu
Committee MemberD’Cruz, Louiseldcruz@pitt.edu
Committee MemberKane, Lawrencelkane@pitt.edu
Committee MemberWilliams, Johnjvw@pitt.edu
Date: 11 May 2020
Date Type: Publication
Defense Date: 22 January 2020
Approval Date: 11 May 2020
Submission Date: 23 April 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 182
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: HSV-1, CD8+ T cells, Tim-3, Herpes stromal keratitis
Date Deposited: 12 May 2020 00:22
Last Modified: 12 May 2020 00:22
URI: http://d-scholarship.pitt.edu/id/eprint/38773

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