Influenza, Secondary Bacterial Infection, and Interleukin-23.

The economy of the racing industry relies upon healthy horses. Equine influenza is one of the most prevalent infectious diseases of horses, and its outbreaks can sometimes have large impacts on both the racing and breeding segments of the industry. Although equine influenza virus infection itself is generally not fatal in otherwise healthy horses, complications involving secondary bacterial infections impede a horse's recovery and return to performance, and can even be life-threatening. Reducing the harm from secondary bacterial infections lessens the impact of influenza and improves the welfare of racehorses. Interleukin (IL)-23 together with IL-17 form a newly-recognized innate immune pathway that acts against bacterial pathogens. Inhibition of the IL-23/IL-17 axis is associated with increased susceptibility to bacterial infection. Our central hypothesis is that influenza infection increases host susceptibility to secondary bacterial infection by disrupting the IL-23/IL-17 axis of immunity. Sub-hypotheses are: (1) Inhibition of the IL-23/IL-17 axis is specifically associated with influenza virus NS 1 protein-mediated inhibition of the ER stress induced transcription factor CHOP. (2) Inhibition ofIL-23/IL-17 axis results in reduced clearance of secondary bacterial infections. Our Preliminary Studies provide strong evidence that influenza infection inhibits IL-23 production in cell culture, by a mechanism involving the influenza viral NS1 protein, and also involving inhibition ofthe cellular protein CHOP. Whether this happens not just in cell culture but also happens in the native immune cells of the respiratory tract of an animal, and by a similar mechanism, is the focus of our proposal. For this we will use wild-type and NSI-minus mutant strains of influenza. Building upon that, we also propose to test whether influenza increases bacterial levels in the lungs· when an animal is infected with both virus and bacteria (Streptococcus zooepidemicus), compared with just bacteria alone, and also determine whether treatment by supplementationofIL-23 reduces/overcomes the effect of influenza. Understanding and counteracting the interaction of influenza with the IL-23/IL-17 axis will make a valuable addition to treatment strategies for equine influenza.