Mechanisms Controlling Virulence Thresholds of Mixed Viral Populations and Identification of Novel Host Barriers to Poliovirus Neuropathogenesis

dc.contributor.advisorPfeiffer, Julie K.en
dc.creatorLancaster, Karenen
dc.description.abstractNeurotropic viruses comprise some of the worlds most widespread and deadly pathogens, including West Nile virus, rabies virus, and poliovirus. Poliovirus, as a model neurotropic virus, is also an RNA virus. RNA viruses have high mutation rates and a propensity to revert attenuating mutations, contributing to disease and complicating treatment and vaccine development. Despite worldwide epidemics in the early nineteenth century, paralysis from poliovirus is a rare event occurring in less than 1% of poliovirus infections. This suggests the presence of viral and host barriers limiting disease. Here we examined viral barriers by exploring the concept of virulence thresholds using mixtures of virulent and attenuated viruses in a transgenic mouse model of poliovirus infection. We determined that 1000-fold excess of an attenuated strain of poliovirus was protective against disease induced by the virulent strain. Protection was induced locally, was a poliovirus specific effect, and inactivated virus conferred protection. Treatment with a poliovirus receptor-blocking antibody phenocopied the protective effect of inactivated viruses in vitro and in vivo, suggesting virulence thresholds may be modulated by competition for viral receptor. Furthermore, we found the attenuated virus became virulent in immune-deficient mice due to enhanced replication and reversion of attenuating mutations. We also identified additional host barriers limiting pathogenesis using a novel hybridization-based viral diversity assay to quantify the efficiency of poliovirus transport from the periphery to the central nervous system. We found viral replication in peripheral axons is limited and the type I interferon response limits viral replication in peripheral tissues, protecting against disease. Significantly, we discovered that retrograde axonal transport of poliovirus in the sciatic nerve was inefficient and only 20% of viral pool members reaching the brain. The efficiency of viral transport increased upon muscle damage, leading to increased viral diversity and pathogenesis. In summary, we identified a viral induced mechanism controlling virulence of mixed viral populations, and characterized three host barriers that restrict poliovirus pathogenesis in the nervous system. The identification of these barriers restricting virulence may help explain the rare incidence of neurological complications following poliovirus infection and aid in our understanding of viral population dynamics and pathogenesis.en
dc.subjectRNA Virusesen
dc.subjectDisease Models, Animalen
dc.titleMechanisms Controlling Virulence Thresholds of Mixed Viral Populations and Identification of Novel Host Barriers to Poliovirus Neuropathogenesisen
dc.type.materialTexten School of Biomedical Sciencesen Microbiologyen Southwestern Medical Centeren of Philosophyen


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