In conclusion, the present study substantiates differential host temperature as a critical barrier for infection by avian influenza viruses. Since the ciliated airway epithelium of the proximal airways is a major portal for influenza virus infection and spread, accessible by multiple inoculation routes (e.g., ocular, nasopharyngeal or aerosol), the inability of avian influenza viruses to establish infection and spread in these regions would be predicted to reduce the frequency of successful zoonotic transmission. Furthermore, the ability of human influenza viruses to generate high viral titers in the human proximal airways is likely a factor in effective human-to-human transmission and the induction of airway epithelial cell cytotoxicity as shown in this study may increase particulate matter perhaps associated with virus that facilitates inoculation of new hosts. Rapid induction of cytotopathic effects by human, but not avian, influenza virus infection at the temperature of the human proximal airways may also contribute to the onset of other host defenses such as sneezing and coughing that facilitate clearance of particulate matter/virus from the airways and potentially promote transmission between human hosts.