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(Unpublished)
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.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| 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: |
11 May 2022 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38773 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}