A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection
Tania Lebratti, Ying Shiang Lim, Adjoa Cofie, Prabhakar S. Andhey, Xiaoping Jiang, Jason M. Scott, Maria Rita Fabbrizi, Ayşe Naz Ozantürk, Christine T. N. Pham, Regina A. Clemens, Maxim N. Artyomov, Mary C. Dinauer, Haina Shin
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/β 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.