KSEF RDE: Role of the horse in interspecies transmission of influenza viruses

Type A influenza virus is an established pathogen of humans, swine, avians, and horses. The role of avian species as host reservoir for an extensive viral gene pool, and of swine as potential intermediate host for humanl avian virus reassortment, has been established over the. past 30 years and confirmed by the 2009 'swine flu' pandemic. Over this same period, however, the role of the horse has become less certain rather than more. Equine influenza viruses. though evolved from avian influenza viruses, were noUhought to naturally transmit to any other species. Since 2005, however, it has been shown that equine influenza viruses naturally infect canines, making influenza a newly emerging disease of dogs. Also, from the Middle Ages through the nineteenth century, equine influenza epizoot!cs and human influenza epidemics were repeatedly noted as coinciding with each other. This argues that the horse is not a dead end, isolated niche in influenza virus ecology but can play an important role in the introduction of new influenza viruses to other mammals and potentially to humans. I propose to study this from two directions. (1) What avian influenza A virus subtypes are infectious for horses? This will be done by initial in vitro screening using an equine respiratory epithelialceH system. We have preliminary data on hemagglutinin ('H') subtypes compatible with replication in equine cells, but nothing on the neuraminidase ('N') subtypes. Following in vitro screening, leading candidates will be studied in in vivo horse infection experiments. (2) What makes equine influenza viruses infectious for other mammals? This is a broad question, but I propose to start by examining a set of mutant equine influenza viruses we have previously published, bearing mutations affecting hemagglutinin receptor specificity, for their infectivity in swine respiratory epithelial cells in vitro and in swine in vivo.