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.
Highlights
Neutrophils are a critical component of the innate immune system
In order to focus on genital inflammation, mice were monitored for 1 week after infection, as progression of disease within the second week of our infection model is largely indicative of viral dissemination into the central nervous system
Differences in genital inflammation and mucosal damage were largely independent of changes in viral control in the absence of neutrophils, as viral shedding into the vaginal lumen (Figure 1D) and viral control in the tissue parenchyma (Figure 1E) were similar between the two groups
Summary
Neutrophils are a critical component of the innate immune system. In humans, they are the most abundant leukocytes in circulation and are often among the first wave of immune cells responding to pathogen invasion. The role of neutrophils during viral infection is less clear (Galani and Andreakos, 2015). While neutrophils have been reported to neutralize several viruses and display protective qualities in vivo (Akk et al, 2016; Jenne et al, 2013; Saitoh et al, 2012; Tate et al, 2009; Tate et al, 2011), they have been associated with
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