Year of Publication

2013

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Molecular and Cellular Biochemistry

First Advisor

Dr. Rebecca E. Dutch

Abstract

Human metapneumovirus (HMPV) is a respiratory pathogen in Paramyxovirus family that demonstrates extremely high morbidity in the population, with most individuals having been infected by the age of five. Despite the prevalence of this negative-sense RNA virus in the population for decades, it was only identified in 2001. As such, there is currently no specific treatment for HMPV and the potentially severe consequences of infection for elderly and immunocompromised individuals and particularly infants make development of antivirals targeting HMPV of high significance. HMPV constitutes a quarter of all respiratory hospitalizations among infants, placing it second only to RSV, in addition to becoming a greater concern in concentrated populations of seniors. For these susceptible populations, the consequences of infection have a much greater probability of leading to pneumonia, bronchiolitis and even death. These studies investigate events throughout the infectious cycle of HMPV. They describe specific amino acids that modulate the triggering of viral fusion activity in response to low pH. They also include a report on the dynamic and variable control exercised over gene transcription by viral promoters. Finally, the interplay between viral nonstructural proteins and their distinct roles in both replication and assembly are examined. Ultimately, this work seeks to elucidate the goings-on within an HMPV-infected cell at multiple points throughout the process.

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