Human pandemic H1N1 (2009) influenza virus rapidly infected millions worldwide and caused significant morbidity and mortality that was associated with cytokine storm and virus-induced cytopathology. Antiviral drugs are the primary therapy to treat disease, although there are limitations to their effective use: 1) administration must be early for optimal efficacy; 2) selective pressure is exerted on the virus resulting in the generation of viral progeny that are resistant to treatment; 3) treatment does not directly inhibit immune-mediated tissue damage, a significant component of disease. Here we show in a mouse model of infection with pathogenic pandemic H1N1 (2009) influenza virus that an immunomodulatory drug, AAL-R, provides significantly greater protection than that occurring with the antiviral drug, oseltamivir. Combined administration of both AAL-R and oseltamivir enhances survival over that from either drug alone protecting 94% of infected mice from a lethal inoculation of virus. Mechanistically, AAL-R significantly downregulates host cellular as well as cytokine responses thereby limiting pulmonary damage ultimately enhancing survival without interfering with host control of pandemic H1N1 (2009) influenza virus replication. Suppressing cytokine storm using sphingosine analogs may prove to be a useful therapy against influenza virus as well as other respiratory diseases where immune-mediated tissue injury is a significant component of disease.
- Copyright © 2011 by The American Association of Immunologists, Inc.