Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection

Abstract

During pathogenic influenza virus infection, robust cytokine production (cytokine storm), excessive inflammatory infiltrates, and virus-induced tissue destruction all contribute to morbidity and mortality. Earlier we reported that modulation of sphingosine-1-phosphate-1 receptor (S1P 1 R) signaling provided a chemically tractable approach for the effective blunting of cytokine storm, leading to the improvement of clinical and survival outcomes. Here, we show that S1P 1 R agonist treatment suppresses global cytokine amplification. Importantly, S1P 1 R agonist treatment was able to blunt cytokine/chemokine production and innate immune cell recruitment in the lung independently of endosomal and cytosolic innate sensing pathways. S1P 1 R signaling suppression of cytokine amplification was independent of multiple innate signaling adaptor pathways for myeloid differentiation primary response gene 88 (MyD88) and IFN-β promoter stimulator-1 signaling, indicating a common pathway inhibition of cytokine storm. We identify the MyD88 adaptor molecule as responsible for the majority of cytokine amplification observed following influenza virus challenge.pathology | pulmonary O verabundant innate immune responses correlate with increased morbidity and mortality during multiple pathogenic respiratory viral infections (1-5). When studying human pandemic H1N1/2009 influenza virus in mice and ferrets, we found direct evidence that cytokine storm was chemically tractable using a sphingosine-1-phosphate receptor-1 (S1P 1 R) selective agonists. S1P 1 R agonist therapy suppressed innate immune cell recruitment, cytokine-chemokine production, and improved survival without altering viral clearance, indicating that cytokine storm was causative to disease pathogenesis and that S1P therapy could suppress detrimental innate immune responses without hindering virus control (6, 7). The identification that S1P 1 R agonists suppress detrimental innate immune responses without hindering virus control indicates that S1P 1 R probes may serve as both viable drug leads to curb influenza virus morbidity and mortality, and as research tools to identify additional cellular signaling pathways that can be targeted to improve clinical outcomes during respiratory viral infection.To generate a molecular understanding how S1P 1 R agonist therapy effectively blunts pathological innate inflammatory responses, we systematically assessed the role various innate signaling pathways play in S1P 1 R-mediated suppression of inflammation following influenza virus infection. Using an S1P 1 R selective agonist synergistically with genetic and biochemical tools, we reveal that S1P 1 R signaling effectively suppressed global cytokine amplification at a point that converged downstream of multiple innate signaling pathways. We reveal that S1P 1 R signaling can suppress innate cellular recruitment and cytokine amplification downstream of both endosome and cytosolic innate sensing pathways. Moreover, we identify myeloid differentiation primary response gene 88 (MyD88) as the ...

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

“…S1PR1 expression in pDCs and its functional coupling to turnover of IFNAR1 and STAT1 down-modulation may reflect an evolutionary pathway suited to therapeutic exploitation. We have shown that S1PR1 agonism protects from influenza and mouse pulmonary virus immunopathology while allowing full development of sterilizing immunity, neutralizing Abs, and quantitatively normal immunological memory (10,(20)(21)(22)(23). Thus, blunting, but not abolishing, IFN-I amplification by the S1P/S1PR1 signaling axis allows host defense from pathogens.…”

“…Moreover, IFN-α signaling promotes autoimmune (1), viral (2)(3)(4)(5), and bacterial disease pathogenesis (6). Suppression of IFN-α signaling has demonstrated efficacy in multiple autoimmune mouse models (7)(8)(9) and during influenza viral infection (4,10); however, the mechanism by which sphingosine 1-phosphate receptor 1 (S1PR1) signaling prevents IFN-α amplification during these disease states is currently unknown.…”

“…S1PR1 agonist therapy suppressed innate immune cell recruitment and cytokine-chemokine production and improved survival without postponing viral clearance, indicating that cytokine storm was causative of disease pathogenesis and that S1P agonist therapy could suppress detrimental innate immune responses without hindering virus control (10,11). The identification that S1PR1 agonists suppress detrimental innate immune responses indicates that S1PR1 probes may serve as viable drug leads to curb resulting immune pathology during both infectious and autoimmune disease states.…”

Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

“…S1P 1 activation blunted the inflammatory signaling cascade downstream of several innate sensing pathways, including those derived from myeloid differentiation primary response gene 88 (MYD88) and IFN-β promoter stimulator-1 signaling (MAVS, also known as IPS1). The results suggest that short-term use of S1P 1 agonists may be therapeutic in suppressing the pathogenic cytokine storm in influenza and possibly in other acute respiratory diseases (93). However, the ability of these agents to induce lymphopenia and potentially suppress adaptive immune responses could outweigh the beneficial antiinflammatory effects in the vasculature.…”

Hydrogen Medicine Therapy: An Effective and Promising Novel Treatment for Multiple Organ Dysfunction Syndrome (MODS) Induced by Influenza and Other Viral Infections Diseases?

“…Viruses that cause influenza, Ebola, Severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome (MERS) are emerging as infectious pathogens in this century that are extremely difficult to control effectively, triggering MODS [18][19][20][21]. The trends, spread, scope, and development speed of these emerging infectious diseases cannot be estimated, as their routes of transmission and patterns of spread are extensive and different.…”