Biomedical Sciences ETDs

Publication Date



Highly pathogenic avian influenza (HPAI), subtype H5N1, has continued to infect humans every year since its initial outbreak in 1997. The overall mortality is approximately 60% and while the emergence of this avian influenza virus has yet to reach the Western Hemisphere, its high lethality and pandemic potential warrant attention from the research community to better understand HPAI disease. Neuroinvasiveness of H5N1 virus is poorly understood and using two HPAI strains of varying lethality in the ferret model provide a basis for comparing differences in neuropathogenesis and its contribution to lethality. The studies described herein used two methods of HPAI exposure in ferrets to elucidate the neuropathogenesis of the virus and its correlation between neurological signs of infection and lesions within the central nervous system (CNS). Following both methods of exposure to low doses of a lethal strain of H5N1, we observed 100% lethality in conjunction with the neurological signs of infection that correlated with lesions within the CNS. Furthermore, we showed that an H5N1 strain that does not cause neurological signs does not replicate in the brain and has attenuated lethality. We concluded that CNS involvement leads to a poor outcome following H5N1 infection. The increased understanding of the temporal-spatial kinetics of neuroinvasion and the correlation of neuroanatomical locations of lesions with the neurological signs observed during these studies could be useful for identifying routes of neuroinvasion and identifying targets for therapeutics to block CNS entry of HPAI. Finally, understanding the neurological sequelae of HPAI infection could aid clinicians in a more rapid diagnosis of influenza infection when patients present with atypical symptoms.


highly pathogenic avian influenza, H5N1, ferrets, neurovirulence, pathogenesis, aerosol model

Document Type




Degree Name

Biomedical Sciences

Level of Degree


Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Hjelle, Brian

Second Committee Member

Ozbun, Michelle

Third Committee Member

Chackerian, Bryce

Fourth Committee Member

Davis, Larry

Fifth Committee Member

Harrod, Kevin