Arenavirus Attenuation Mechanisms
Grant, Ashley 1983-
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Arenaviridae derives from the Latin word ‘arena’ meaning ‘sand’. When scientists first looked at arenavirus virions by transmission electron microscopy, they saw pleomorphic particles that had a sandy appearance. This sandy appearance was due to host ribosomes being incorporated into the virions. Numerous studies were performed in the 1970s determining arenavirus structure, assembly, and biophysical properties. Several phenomena were noted including the presence of host proteins in the virus particles and a large variation in particle size. Arenavirus research is important because of the nature of these viruses as both emerging zoonotic pathogens and the potential biowarfare/bioterrorism threat. For example, the Soviet Union produced mass quantities of arenaviruses as part of their offensive weapons program (Alibek and Handelman, 1999). Junín virus, the etiological agent of Argentine hemorrhagic fever (AHF), causes up to 30% mortality in humans and is considered a National Institute of Allergy and Infectious Disease (NIAID) Category A Pathogen (Charrel and de Lamballerie, 2003). AHF affects numerous Argentineans each year and has shown potential to infect many more. The geographical distribution of the potential rodent hosts far exceeds the region Junín virus is currently localized to. For this and other reasons we must continue to learn more about arenaviruses. Several features of arenaviruses distinguish them from other viral hemorrhagic fevers. For instance, pathogenic arenaviruses can cause significant morbidity and mortality in humans with little evidence of cellular damage. In this dissertation we will demonstrate that pathogenic arenaviruses can infect cells, cause little cellular damage, and effectively replicate going unnoticed by the adaptive immune system. On the other hand, attenuated virus infection can cause cellular death and signals the immune system for clearance of infected cells. Furthermore, animals infected with the vaccine strain of Junín virus appear to have detectable cell death in the spleen, however, it is unclear if those cells are productively infected. The virions that bud from cells infected with an arenavirus vaccine strain are covered with an indicator of apoptosis, phosphatidylserine. We further demonstrate that phosphatidylserine targeting antibodies are ineffective at protecting a small animal model against the disease or death due to virulent Junín virus infection.