Multiple Host Barriers Restrict Poliovirus Trafficking in Mice

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.

Expression of Human Decay-Accelerating Factor on Intestinal Epithelium of Transgenic Mice Does Not Facilitate Infection by the Enteral Route

“…Studies of poliovirus infection in mouse models indicate that multiple factors influence infection by the enteral route, including PVR expression, innate immunity, mucosal integrity, and interactions with intestinal flora (40,48,49). A major difference between the mouse models of poliovirus and CVB3 infection is that, unlike poliovirus, CVB3 has a natural receptor in mice, murine CAR; once CVB3 enters the bloodstream, infection can spread readily in the absence of any transgenic receptor.…”

Alphaherpesvirus axon-to-cell spread involves limited virion transmission

“…Studies of the retrograde transneuronal transmission of poliovirus identified a bottleneck during axonal transport (3,26). Kuss et al marked poliovirus genomes with nucleic acid "bar codes" to follow spread of infection of virus populations into the PNS and CNS (27). In these studies, population diversity diminished as the length of axon increased.…”

Dynamics of the Establishment of Systemic Potyvirus Infection: Independent yet Cumulative Action of Primary Infection Sites

“…In some cases, this expansion eventually becomes irremediable on a small spatiotemporal scale; local host defenses are no longer able to contain infection, and the virus is established at the main sites of replication, a state that is generally referred to as systemic infection. In many viral pathosystems, the transition from primary infection to systemic infection is labyrinthine: the host immune system effectuates different defensive mechanisms, and on the other hand, different infection pathways are accessible to the virus (10,23). This great complexity has made it difficult to study interactions within the virus population during the establishment of systemic infection.…”