A TLR7 antagonist restricts interferon-dependent and -independent immunopathology in a mouse model of severe influenza

Rappe, JCF; Finsterbusch, K; Crotta, S; Mack, M; Priestnall, SL; Wack, A

Abstract

Cytokine-mediated immune-cell recruitment and inflammation contribute to protection in respiratory virus infection. However, uncontrolled inflammation and the "cytokine storm" are hallmarks of immunopathology in severe infection. Cytokine storm is a broad term for a phenomenon with diverse characteristics and drivers, depending on host genetics, age, and other factors. Taking advantage of the differential use of virus-sensing systems by different cell types, we test the hypothesis that specifically blocking TLR7-dependent, immune cell-produced cytokines reduces influenza-related immunopathology. In a mouse model of severe influenza characterized by a type I interferon (IFN-I)-driven cytokine storm, TLR7 antagonist treatment leaves epithelial antiviral responses unaltered but acts through pDCs and monocytes to reduce IFN-I and other cytokines in the lung, thus ameliorating inflammation and severity. Moreover, even in the absence of IFN-I signaling, TLR7 antagonism reduces inflammation and mortality driven by monocyte-produced chemoattractants and neutrophil recruitment into the infected lung. Hence, TLR7 antagonism reduces diverse types of cytokine storm in severe influenza.

Citation

Rappe, J., Finsterbusch, K., Crotta, S., Mack, M., Priestnall, S., & Wack, A. (2021). A TLR7 antagonist restricts interferon-dependent and -independent immunopathology in a mouse model of severe influenza. Journal of Experimental Medicine, 218(11), https://doi.org/10.1084/jem.20201631

• Journal Article Type: Article
• Acceptance Date: Sep 1, 2021
• Publication Date: 2021
• Deposit Date: Dec 15, 2021
• Publicly Available Date: Dec 15, 2021
• Print ISSN: 0022-1007
• Publisher: Rockefeller University Press
• Peer Reviewed: Peer Reviewed
• Volume: 218
• Issue: 11
• DOI: https://doi.org/10.1084/jem.20201631
• Keywords: PLASMACYTOID DENDRITIC CELLS; DEMONSTRATES CLINICAL ACTIVITY; SINGLE-STRANDED RNA; I INTERFERON; LUNG INJURY; RECEPTOR 7; AIRWAY INFLAMMATION; MURINE MODEL; PHASE 2A; RECOGNITION
• Public URL: https://rvc-repository.worktribe.com/output/1553337