Animal Model of Respiratory Syncytial Virus: CD8 ⁺ T Cells Cause a Cytokine Storm That Is Chemically Tractable by Sphingosine-1-Phosphate 1 Receptor Agonist Therapy

Abstract

The cytokine storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by cytokine and immune cell components. The cytokine storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a cytokine storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8؉ T cells infiltrated into the lung, initiating a cytokine storm by their production of gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited cytokine storm by blunting the PVM-specific CD8 ؉ T cell response, resulting in diminished pulmonary disease and enhanced survival. IMPORTANCEA dysregulated overly exuberant immune response, termed a "cytokine storm," accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the cytokine storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the cytokine storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-␥ and TNF-␣. Blockading these cytokines with neutralizing antibodies blunts the cytokine storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.

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.…”

Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection

“…We and others have explored inflammatory responses to and immunomodulatory control of respiratory virus infection using the pneumonia virus of mice (PVM) model of acute pneumovirus infection (Dyer et al , 2012; Bondue et al , 2011; Walsh et al , 2014; Scheer et al , 2014; Siegle et al , 2011). PVM is closely related to RSV; however, unlike RSV, PVM undergoes robust replication in vivo , most prominently in bronchial epithelial cells of inbred strains of mice.…”

Reduction in sphingosine kinase 1 influences the susceptibility to dengue virus infection by altering antiviral responses

“…The product of SK activity, S1P, can have intracellular signalling functions or be secreted from cells to act on cell surface S1P receptors (Leclercq & Pitson, 2006;Rosen et al, 2014;Spiegel & Milstien, 2011;Xia & Wadham, 2011). A number of studies have shown that modulating the S1P/receptor can reduce virus-induced disease and tissue injury associated with IAV (Marsolais et al, 2009;Walsh et al, 2011) and in an animal model of RSV infection (Walsh et al, 2014). Thus, studies of the SK-virus interaction are of significant interest to potential therapeutic interventions for viral diseases.…”