Browsing by Author "Grant, Ashley 1983-"
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Item Arenavirus Attenuation MechanismsGrant, Ashley 1983-; Peters, Clarence J; Paessler, Slobodan L; Aronson, Judy; Sherman, Michael; Feldmann, HeinzArenaviridae 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.Item Countermeasures Against Viral Hemorrhagic FeversGrant, Ashley 1983-; de Boer, Melanie A; Arcari, Christine M; Barrett, Alan DViral hemorrhagic fevers (VHFs) are a group of viruses from four different virus families that are characterized by coagulation abnormalities with often fatal outcomes. VHFs can cause both internal and external bleeding. The virus families include: Filoviridae, Arenaviridae, Bunyaviridae, and Flaviviridae. All these viruses are enveloped and contain a single-stranded RNA genome. However, the viruses differ in their pathogenesis, transmissibility, natural host, and geographical distribution. VHFs usually begin presentation with marked fever, fatigue, dizziness, nausea, vomiting, abdominal pain, muscle aches, loss of strength, and exhaustion. Patients can also experience bleeding under the skin, internal organs, and/or from other orifices (mouth, eyes, or ears). Finally, patients can progress into shock, neurological involvement, coma, delirium, seizures, renal failure and even death. The route of transmission of VHFs depends on the agent. Some VHFs are spread by close contact with infected animals or humans, while others are spread by insects. The main reservoirs can range from rodents to arthropods. Some of the vectors include: the multimammate rat, cotton rat, house mouse, deer mouse, ticks, and mosquitoes. Ebola, Marburg, Lassa, and Crimean-Congo viruses are known to spread from person to person contact. However, airborne transmission of VHFs is thought to be very rare (CDC, 1988, Baron RC, 1983). Transmission is more likely to happen late in infection when patients experience vomiting, diarrhea, shock, and hemorrhage, occurring with high levels of virus present in bodily fluids. Nosocomial transmission can occur through unprotected contact with infectious body fluids, contaminated medical equipment or supplies, or an accidental needle stick. Infections can be significantly reduced with proper hand washing, safe sharp handling, and isolation precautions. Several outbreaks of Ebola have been attributed to improper personal protective precautions or contaminated needles. This capstone determined the countermeasures available against VHFs in clinical trials, the vaccines tested in non-human primates, the tested in non-human primates as well as treatment strategies tested in humans.