NK cell-derived extracellular granzyme B drives epithelial ulceration during HSV-2 genital infection
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
Genital herpes is characterized by recurrent episodes of epithelial blistering. The mechanisms causing this pathology are ill defined. Using a mouse model of vaginal herpes simplex virus 2 (HSV-2) infection, we show that interleukin-18 (IL-18) acts upon natural killer (NK) cells to promote accumulation of the serine protease granzyme B in the vagina, coinciding with vaginal epithelial ulceration. Genetic loss of granzyme B or therapeutic inhibition by a specific protease inhibitor reduces disease and restores epithelial integrity without altering viral control. Distinct effects of granzyme B and perforin deficiency on pathology indicates that granzyme B acts independent of its classic cytotoxic role. IL-18 and granzyme B are markedly elevated in human herpetic ulcers compared with non-herpetic ulcers, suggesting engagement of these pathways in HSV-infected patients. Our study reveals a role for granzyme B in destructing mucosal epithelium during HSV-2 infection, identifying a therapeutic target to augment treatment of genital herpes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:42 |
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| Enthalten in: |
Cell reports - 42(2023), 4 vom: 25. Apr., Seite 112410 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lim, Ying Shiang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.10.2023 Date Revised 10.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2023.112410 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM355754339 |
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| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Genital herpes is characterized by recurrent episodes of epithelial blistering. The mechanisms causing this pathology are ill defined. Using a mouse model of vaginal herpes simplex virus 2 (HSV-2) infection, we show that interleukin-18 (IL-18) acts upon natural killer (NK) cells to promote accumulation of the serine protease granzyme B in the vagina, coinciding with vaginal epithelial ulceration. Genetic loss of granzyme B or therapeutic inhibition by a specific protease inhibitor reduces disease and restores epithelial integrity without altering viral control. Distinct effects of granzyme B and perforin deficiency on pathology indicates that granzyme B acts independent of its classic cytotoxic role. IL-18 and granzyme B are markedly elevated in human herpetic ulcers compared with non-herpetic ulcers, suggesting engagement of these pathways in HSV-infected patients. Our study reveals a role for granzyme B in destructing mucosal epithelium during HSV-2 infection, identifying a therapeutic target to augment treatment of genital herpes | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 4 | |a CP: Immunology | |
| 650 | 4 | |a Immunology and Inflammation | |
| 650 | 4 | |a genital herpes | |
| 650 | 4 | |a immunopathology | |
| 650 | 4 | |a viral infection | |
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| 700 | 1 | |a Jiang, Xiaoping |e verfasserin |4 aut | |
| 700 | 1 | |a Scott, Jason M |e verfasserin |4 aut | |
| 700 | 1 | |a Cofie, Adjoa |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Sandeep |e verfasserin |4 aut | |
| 700 | 1 | |a Kennedy, Dania |e verfasserin |4 aut | |
| 700 | 1 | |a Granville, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Shin, Haina |e verfasserin |4 aut | |
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