A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection

Abstract

Pulmonary tissue damage resulting from influenza virus infection is caused by both the cytolytic activity of the virus and the host immune response. Immune-mediated injury results from T cellmediated destruction of virus-infected cells and by release of cytokines and chemokines that attract polymorphonuclear leukocytes (PML) and macrophages to the infected site. The cytokines/ chemokines potentiate dendritic cell (DC) activation and T cell expansion, which further enhances local damage. Here we report that immune modulation by local administration to the respiratory tract of sphingosine analog AAL-R significantly dampens the release of cytokines and chemokines while maintaining protective neutralizing antibody and cytotoxic T cell responses. As a result there was a marked reduction of infiltrating PML and macrophages into the lung and resultant pulmonary tissue injury. DC maturation was suppressed, which limited proliferation of specific antiviral T cells in the lung and draining lymph nodes. Further, AAL-R was effective in controlling CD8 ؉ T cell accumulation in the lungs even when given 4 days after initiation of influenza virus infection. These data indicate that sphingosine analogs display useful potential for controlling the immunopathology caused by influenza virus.immunopathology ͉ dendritic cells ͉ cytokine storm ͉ T cells T he antiviral host response evolved to limit the spread of infection at the cost of causing tissue injury. There is a balance between the protective and injurious responses that leads either to the purging of infectious virus and host recovery or to severe disease and even death. Thus, strategies to balance the antiviral immune response in favor of host outcome need to be developed.T cell response elicited early in the course of infection recognizes, attacks and lyses virus-infected cells to eliminate potential factories of progeny viruses (1-5). The protective influenza antibody response is elicited later and plays a role in controlling re-infection (6, 7). The innate and adaptive immune systems release wide varieties of cytokines and chemokines that activate and attract inflammatory cells to the site of infection (2,8,9). However, these molecules can also cause the host harm by a phenomenon known as cytokine storm. Cytokine storm has been convincingly documented both in experimental animals infected with the 1918/1919 and H5N1 influenza viruses (2, 10-13) as well as in humans (14-18) succumbing to H5N1 infection. Although antiviral drugs can be used to treat the virus, a strategy to balance the resultant cytokine release and lung injury while maintaining benefits of the antiviral protective immune response is needed (19). Influenza virus replication is most often limited primarily to the respiratory tract but the systemic signs and symptoms of disease, e.g., fever, muscle pain and shakes, intestinal tract involvement, are related to cytokine effects (20, 21).We reported that intratracheal (i.t.) delivery of the sphingosine analog AAL-R or its phosphate ester inhibited virus-specifi...

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.…”

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.…”

Inhibiting influenza's immunopathology

“…1 Thus, the Scripps team wrote in the Proceedings of the National Academy of Sciences that "although antiviral drugs can be used to treat the virus, a strategy to balance the resultant cytokine release and lung injury while maintaining benefits of the antiviral protective immune response is needed." 2 In a mouse model of H1N1 influenza virus infection, a single dose of (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol (AAL-R) into the lungs at the time of infection decreased the release of cytokines and chemokines from dying, virusinfected cells compared with what was seen in controls. Importantly, influenza-neutralizing antibody titers and the overall cytotoxic T cell response were maintained with use of the sphingosine 1-phosphate receptor (S1PR)-binding sphingosine analog.…”