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

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.

Identification of Neutrophil-Related Factor LCN2 for Predicting Severity of Patients With Influenza A Virus and SARS-CoV-2 Infection

“…Increasing evidence indicates that excessive immune response leads to immune-mediated damage and affects disease process and prognosis ( Guo et al, 2021 ; Karki et al, 2021 ; Rappe et al, 2021 ). This emphasizes the importance of host factors in predicting clinical progression and prognosis in patients with viral infectious diseases.…”

“…Interaction between hosts and the virus determines prognosis of the disease ( Ito et al, 2011 ; Mahler et al, 2021 ). Although an effective immune response is indispensible for eliminating virus, exaggerated response characterized by the so-called “cytokine storm” can trigger severe immune pathological damage ( Karki et al, 2021 ; Rappe et al, 2021 ). Changes in the expression levels of host factors and abnormal immunity, such as cytokine storm ( Liu et al, 2016 ; Guo and Thomas, 2017 ), lymphopenia ( Cheng et al, 2019 ; Zhang et al, 2020b ), and T cell exhaustion ( Valero-Pacheco et al, 2013 ; Diao et al, 2020 ), during virus infection have been reported.…”

Toll-like receptor-agonist-based therapies for respiratory viral diseases: thinking outside the cell

“…TLR7 agonist treatment is also not well suited for treatment of acute, severe respiratory viral lung disease with potential contribution to acute virus-induced immunopathology exemplified by a study that reported blockade of TLR7 reduced mortality in a mouse model of severe influenza. Rather than reducing the innate immune response in AECs, the TLR7 antagonist reduced excessive type I IFN and inflammatory cytokine/chemokine production by pDC and monocytes and this reduced mortality [101]. This also highlights the safety concerns related to bystander immune cell activation by topical (e.g.…”

Insights into pandemic respiratory viruses: manipulation of the antiviral interferon response by SARS-CoV-2 and influenza A virus

“…Genetic studies revealed that inborn deficiency in TLR3 and TLR7 signaling underlies defective type I IFN production and severe disease in a group of COVID-19 patients 25 , 26 . TLR7-mediated type I IFN responses in plasmacytoid dendritic cells reportedly play a critical role in protection against severe COVID-19 [27] , while uncontrolled TLR7 activation can lead to CSS in severe influenza [28] . cGAS activation following mitochondrial DNA release during SARS-CoV-2 infection was shown to elicit aberrant IFN production, which causes IFN-mediated immunopathology in severe COVID-19 [29] .…”