A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection
ABSTRACT Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/βreceptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I IFN signaling is a driver of pathogenic neutrophil responses, and identifies IL-18 as a novel component of disease during genital HSV-2 infection..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 16. Okt. Zur Gesamtaufnahme - year:2023 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lebratti, Tania J. [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
10.1101/2020.12.20.423690 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI019590466 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI019590466 | ||
| 003 | DE-627 | ||
| 005 | 20231205150424.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 201229s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2020.12.20.423690 |2 doi | |
| 035 | |a (DE-627)XBI019590466 | ||
| 035 | |a (biorXiv)10.1101/2020.12.20.423690 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lebratti, Tania J. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a ABSTRACT Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/βreceptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I IFN signaling is a driver of pathogenic neutrophil responses, and identifies IL-18 as a novel component of disease during genital HSV-2 infection. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Lim, Ying Shiang |4 aut | |
| 700 | 1 | |a Cofie, Adjoa |4 aut | |
| 700 | 1 | |a Andey, Prabhakar S. |4 aut | |
| 700 | 1 | |a Jiang, Xiaoping |4 aut | |
| 700 | 1 | |a Scott, Jason M. |4 aut | |
| 700 | 1 | |a Fabbrizi, Maria Rita |4 aut | |
| 700 | 1 | |a Ozanturk, Ayse N. |0 (orcid)0000-0002-0187-3642 |4 aut | |
| 700 | 1 | |a Pham, Christine T.N. |4 aut | |
| 700 | 1 | |a Clemens, Regina A. |4 aut | |
| 700 | 1 | |a Artyomov, Maxim |4 aut | |
| 700 | 1 | |a Dinauer, Mary C. |4 aut | |
| 700 | 1 | |a Shin, Haina |0 (orcid)0000-0002-1014-1451 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2023) vom: 16. Okt. |
| 773 | 1 | 8 | |g year:2023 |g day:16 |g month:10 |
| 856 | 4 | 0 | |u https://doi.org/10.7554/elife.65762 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2020.12.20.423690 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 16 |c 10 | ||