Multiple Host Barriers Restrict Poliovirus Trafficking in Mice

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Abstract
RNA viruses such as poliovirus have high mutation rates, and a diverse viral population is likely required for full virulence. We previously identified limitations on poliovirus spread after peripheral injection of mice expressing the human poliovirus receptor (PVR), and we hypothesized that the host interferon response may contribute to the viral bottlenecks. Here, we examined poliovirus population bottlenecks in PVR mice and in PVR mice that lack the interferon α/β receptor (PVR-IFNAR−/−), an important component of innate immunity. To monitor population dynamics, we developed a pool of ten marked polioviruses discriminated by a novel hybridization-based assay. Following intramuscular or intraperitoneal injection of the ten-virus pool, a major bottleneck was observed during transit to the brain in PVR mice, but was absent in PVR-IFNAR−/− mice, suggesting that the interferon response was a determinant of the peripheral site-to-brain bottleneck. Since poliovirus infects humans by the fecal–oral route, we tested whether bottlenecks exist after oral inoculation of PVR-IFNAR−/− mice. Despite the lack of a bottleneck following peripheral injection of PVR-IFNAR−/− mice, we identified major bottlenecks in orally inoculated animals, suggesting physical barriers may contribute to the oral bottlenecks. Interestingly, two of the three major bottlenecks we identified were partially overcome by pre-treating mice with dextran sulfate sodium, which damages the colonic epithelium. Overall, we found that viral trafficking from the gut to other body sites, including the CNS, is a very dynamic, stochastic process. We propose that multiple host barriers and the resulting limited poliovirus population diversity may help explain the rare occurrence of viral CNS invasion and paralytic poliomyelitis. These natural host barriers are likely to play a role in limiting the spread of many microbes. RNA viruses are highly error prone, and can use their replication infidelity to adapt to complex environments within an infected host. However, viral populations may experience bottlenecks, which limit their diversity and potentially reduce their virulence. We hypothesized that natural barriers may limit the spread of RNA viruses within an infected host. To test this hypothesis, we engineered a pool of ten marked polioviruses identifiable by a novel assay, infected susceptible mice by injection or oral inoculation, and determined the percentage of the ten viruses that successfully spread to various body sites, including the brain. We found that, on average, only 10%–20% of the input viruses were found in most tissues, suggesting that barriers prevented the spread of the whole population. The importance of one such physical barrier, the colonic epithelium, was demonstrated in experiments where the colon was damaged prior to oral inoculation. Under these conditions, 30%–50% of the input viruses successfully spread to various body sites. We propose that host barriers limit viral spread, and this could possibly explain the rare incidence of paralytic poliomyelitis due to central nervous system invasion.