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.
Highlights
The first line of defense against respiratory viral infection is the anatomic barrier of lung epithelial cells and resident innate immune cells
Comparing bone marrow–derived plasmacytoid dendritic cells (pDCs) from WT and TLR7 KO mice stimulated with influenza virus (Fig. 1 D), we confirmed the strict dependence of pDCs on TLR7 for IFN-I production, consistent with previously published results (Diebold et al, 2004; Lund et al, 2004)
We conclude that in influenza responses not dominated by IFN-I, high neutrophil numbers contribute to immunopathology, and we find that immunoregulatory sequence 661 (IRS661) treatment reduces the monocyte-dependent infiltration of neutrophils into the lung
Summary
The first line of defense against respiratory viral infection is the anatomic barrier of lung epithelial cells and resident innate immune cells These cells sense virus-associated molecular patterns by different pattern recognition receptors that cause the induction of both intracellular antiviral defenses and inflammatory mediators such as cytokines and chemokines. These recruit and activate effector cells, contributing to the eventual elimination of the invading pathogen (Iwasaki et al, 2017). It is clinically relevant to identify different types of CS and understand how they are regulated
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