PMID- 34047696 OWN - NLM STAT- MEDLINE DCOM- 20211019 LR - 20240226 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 10 DP - 2021 May 28 TI - A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection. LID - 10.7554/eLife.65762 [doi] LID - e65762 AB - 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 IFNalpha/beta receptor 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 interferon (IFN) signaling is a driver of pathogenic neutrophil responses and identifies IL-18 as a novel component of disease during genital HSV-2 infection. CI - (c) 2021, Lebratti et al. FAU - Lebratti, Tania AU - Lebratti T AD - Department of Medicine/Division of Infectious Diseases, Washington University School of Medicine, St Louis, United States. FAU - Lim, Ying Shiang AU - Lim YS AD - Department of Medicine/Division of Infectious Diseases, Washington University School of Medicine, St Louis, United States. FAU - Cofie, Adjoa AU - Cofie A AD - Department of Medicine/Division of Infectious Diseases, Washington University School of Medicine, St Louis, United States. FAU - Andhey, Prabhakar AU - Andhey P AD - Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States. FAU - Jiang, Xiaoping AU - Jiang X AD - Department of Medicine/Division of Infectious Diseases, Washington University School of Medicine, St Louis, United States. FAU - Scott, Jason AU - Scott J AD - Department of Medicine/Division of Infectious Diseases, Washington University School of Medicine, St Louis, United States. FAU - Fabbrizi, Maria Rita AU - Fabbrizi MR AUID- ORCID: 0000-0002-5156-1575 AD - Department of Medicine/Division of Infectious Diseases, Washington University School of Medicine, St Louis, United States. FAU - Ozanturk, Ayse Naz AU - Ozanturk AN AUID- ORCID: 0000-0002-0187-3642 AD - Department of Medicine/Division of Infectious Diseases, Washington University School of Medicine, St Louis, United States. FAU - Pham, Christine AU - Pham C AD - Department of Medicine/Division of Rheumatology, Washington University School of Medicine, St Louis, United States. FAU - Clemens, Regina AU - Clemens R AD - Department of Pediatrics/Division of Critical Care Medicine, Washington University School of Medicine, St Louis, United States. FAU - Artyomov, Maxim AU - Artyomov M AD - Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States. FAU - Dinauer, Mary AU - Dinauer M AD - Department of Pediatrics/Hematology and Oncology, Washington University School of Medicine, St Louis, United States. FAU - Shin, Haina AU - Shin H AUID- ORCID: 0000-0002-1014-1451 AD - Department of Medicine/Division of Infectious Diseases, Washington University School of Medicine, St Louis, United States. LA - eng SI - GEO/GSE161336 GR - R01 AI134962/AI/NIAID NIH HHS/United States GR - R21 AI150418/AI/NIAID NIH HHS/United States GR - T32 AI007163/AI/NIAID NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210528 PL - England TA - Elife JT - eLife JID - 101579614 RN - 0 (Antibodies) RN - 0 (Ifnar1 protein, mouse) RN - 0 (Interferon Type I) RN - 0 (Interleukin-18) RN - 156986-95-7 (Receptor, Interferon alpha-beta) SB - IM MH - Animals MH - Antibodies/pharmacology MH - Chlorocebus aethiops MH - Disease Models, Animal MH - Female MH - Herpes Genitalis/immunology/metabolism/prevention & control/*virology MH - Herpesvirus 1, Human/immunology/pathogenicity MH - Herpesvirus 2, Human/immunology/*pathogenicity MH - Host-Pathogen Interactions MH - *Immunity, Mucosal/drug effects MH - Interferon Type I/*metabolism MH - Interleukin-18/*metabolism MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Mucous Membrane/drug effects/innervation/metabolism/*virology MH - *Neutrophil Activation/drug effects MH - Neutrophils/drug effects/immunology/metabolism/*virology MH - Receptor, Interferon alpha-beta/antagonists & inhibitors/metabolism MH - Signal Transduction MH - Vagina/drug effects/immunology/metabolism/*virology MH - Vero Cells MH - Mice PMC - PMC8163503 OAB - Herpes simplex virus (HSV) is a human pathogen that causes genital herpes, an incurable disease that results in recurrent sores and inflammation. Infection with HSV induces a strong antiviral immune response, which results in large numbers of immune cells arriving at these lesions. But while some of these cells help to control viral replication, others might contribute to the inflammation that drives the disease. One of the first immune cells to respond to infection are neutrophils. Although neutrophils are generally protective, especially against bacteria and fungi, they have also been implicated in tissue damage and severe inflammation during viral infections. But what determines whether a neutrophil will help to fight off an infection or increase disease severity is still an open question. To investigate this, Lebratti, Lim et al. studied mice that had been infected with the genital herpes virus HSV-2, which is known to cause significant amounts of inflammation in mice. The experiments revealed that a signaling molecule called type I interferon, which is thought to be antiviral, causes neutrophils at the site of the infection to produce proteins, such as IL-18, which trigger an inflammatory reaction. Lebratti, Lim et al. found that type I interferon and IL-18 had shifting roles during the course of infection. In the early stages, both molecules had a protective effect, confirming results from previous studies. However, as the infection progressed, sustained levels of type I interferon signaling in neutrophils led to excess amounts of IL-18. Lebratti, Lim et al. discovered that blocking interferon signaling or decreasing the levels of IL-18 later during infection unexpectedly reduced the severity of the disease and resulted in less genital tissue damage. Further experiments also showed that mice infected with another genital herpes virus called HSV-1 did not experience sustained levels of type I interferon. This may explain why this virus causes less severe disease in mice. Understanding how the immune system reacts to viruses could reveal new targets for treatments of genital herpes. At the moment, there is little information about IL-18 production during genital herpes in humans. So, the next step is to see whether neutrophils behave in the same way and whether IL-18 can be detected during human disease. It is possible that the same immune components could promote disease in other infections too. If so, this work may help uncover new drug targets for other viral diseases. OABL- eng OTO - NOTNLM OT - genital herpes OT - immunology OT - immunopathology OT - infectious disease OT - inflammation OT - interferon OT - microbiology OT - mouse OT - neutrophils OT - virus COIS- TL, YL, AC, PA, XJ, JS, MF, AO, CP, RC, MA, MD, HS No competing interests declared EDAT- 2021/05/29 06:00 MHDA- 2021/10/21 06:00 PMCR- 2021/05/28 CRDT- 2021/05/28 12:12 PHST- 2020/12/15 00:00 [received] PHST- 2021/04/21 00:00 [accepted] PHST- 2021/05/28 12:12 [entrez] PHST- 2021/05/29 06:00 [pubmed] PHST- 2021/10/21 06:00 [medline] PHST- 2021/05/28 00:00 [pmc-release] AID - 65762 [pii] AID - 10.7554/eLife.65762 [doi] PST - epublish SO - Elife. 2021 May 28;10:e65762. doi: 10.7554/eLife.65762.