A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection

Lebratti, T.; Lim, Y. S.; Cofie, A.; Andhey, P.; Jiang, X.; Scott, J.; Fabbrizi, M. R.; Ozantürk, A. N.; Pham, C.; Clemens, R.; Artyomov, M.; Dinauer, M.; Shin, H.

doi:10.1101/2020.12.20.423690

bioRxiv · 10.1101/2020.12.20.423690

A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection

Lebratti, T.·Lim, Y. S.·Cofie, A.·Andhey, P.·Jiang, X.·Scott, J.·Fabbrizi, M. R.·Ozantürk, A. N.·Pham, C.·Clemens, R.·Artyomov, M.·Dinauer, M.·Shin, H.

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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 IFN/{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 IFN signaling is a driver of pathogenic neutrophil responses, and identifies IL-18 as a novel component of disease during genital HSV-2 infection.

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Lebratti, T., Lim, Y. S., Cofie, A., Andhey, P., Jiang, X., Scott, J., Fabbrizi, M. R., Ozantürk, A. N., Pham, C., Clemens, R., Artyomov, M., Dinauer, M., Shin, H.. 2020-12-23. A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection. https://doi.org/10.1101/2020.12.20.423690

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