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

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-1phosphate-1 receptor (S1P1R) signaling pro...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-03, Vol.111 (10), p.3799-3804
Main Authors: Teijaro, John R., Walsh, Kevin B., Rice, Stephanie, Rosen, Hugh, Oldstone, Michael B. A.
Format: Article
Language:English
Subjects:
Agonists
Animals
Biological Sciences
Bone Marrow Transplantation
Chemokines
Cytokines
Cytokines - immunology
Dogs
Flow Cytometry
Immunity, Innate - immunology
Infections
Influenza
Influenza virus
Lungs
Madin Darby Canine Kidney Cells
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Morbidity
Mortality
Myeloid Differentiation Factor 88
Neutrophils
Orthomyxoviridae
Orthomyxoviridae Infections - immunology
Orthomyxoviridae Infections - physiopathology
Receptors, Lysosphingolipid - metabolism
Signal amplification
Signal transduction
Signal Transduction - immunology
T cell receptors
Vehicles
Viruses
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Summary: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-1phosphate-1 receptor (S1P1R) 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 S1P1R agonist treatment suppresses global cytokine amplification. Importantly, S1P1R 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. S1P1R signaling suppression of cytokine amplification was independent of multiple innate signaling adaptor pathways for myeloid differentiation primary response gene 88 (MyD88) and IFN-δ 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1400593111