Browsing by Subject "Poliomyelitis"
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Gastrointestinal Influences on Poliovirus Replication, Dissemination and Pathogenesis in Mice(2011-12-12) Kuss, Sharon Kay; Pfeiffer, Julie K.Enteric viruses are transmitted between individuals by fecal-oral spread. After oral acquisition, enteric viruses encounter a complex environment within the gastrointestinal (GI) tract, including pH changes, mucus, resident bacteria and a variety of epithelial and immune cell types. Little is known about how factors within and comprising the GI tract influence viral replication, dissemination and pathogenesis. In order to assess the influence of the intestinal environment on enteric viruses, poliovirus was used as a model enteric virus. Following infection within the GI tract, poliovirus has the capacity to spread to the central nervous system (CNS). Poliovirus infection of the CNS is uncommon, but it can result in acute flaccid paralysis known as poliomyelitis in humans. Poliomyelitis can be mimicked in mice susceptible to poliovirus. Initial studies were performed in mice to examine poliovirus infection within and dissemination from the GI tract to extra-intestinal tissues, including blood and the CNS. By monitoring spread of a marked poliovirus population in susceptible mice, many host barriers to intra-host viral trafficking were identified. Type I interferon responses and intestinal epithelial cell integrity are host barriers that were found to restrict poliovirus. Infecting cells within the GI tract was also difficult for poliovirus, which further limited dissemination from the intestine to the blood and CNS. Bottlenecks were imposed on poliovirus while trafficking through and disseminating from the GI tract, possibly providing an explanation for the low incidence of poliomyelitis disease onset in humans following poliovirus infection. Because the GI tract was a substantial barrier to poliovirus, studies were undertaken to characterize factors that limit poliovirus dissemination from the GI tract. The naturally-residing microbiota are amongst many other factors present within the GI tract that may influence poliovirus infection. Although suspected to limit poliovirus, intestinal microbiota augmented poliovirus infection in mice and cell culture by enhancing viral infectivity. The studies described herein demonstrate how host complexity imparts detrimental and beneficial influences on poliovirus acquired by the natural fecal-oral route.Item The meaning of aging for women with childhood onset disabilities(2004) Harrison, Tracie Culp; Stuifbergen, Alexa KramerItem Mechanisms controlling virulence thresholds of mixed viral populations and identification of novel host barriers to poliovirus neuropathogenesis(2012-07-20) Lancaster, Karen; Pfeiffer, Julie K.;Neurotropic 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. [Keywords: poliovirus, neurotropic, interferon, retrograde, axonal, transport, virulence, threshold, virus, barrier]