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J Exp Med
. 2021 Nov 1;218(11):e20201631.
doi: 10.1084/jem.20201631. Epub 2021 Sep 2.
A TLR7 antagonist restricts interferon-dependent and -independent immunopathology in a mouse model of severe influenza
Julie C F Rappe # 1 , Katja Finsterbusch # 1 , Stefania Crotta 1 , Matthias Mack 2 , Simon L Priestnall 3 4 , Andreas Wack 1
Affiliations
- PMID: 34473195
- DOI: 10.1084/jem.20201631
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.