Innate host barriers to viral trafficking and population diversity: lessons learned from poliovirus

Abstract

Poliovirus is an error-prone enteric virus spread by the fecal-oral route and rarely invades the central nervous system (CNS). However, in the rare instances when poliovirus invades the CNS, the resulting damage to motor neurons is striking and often permanent. In the prevaccine era, it is likely that most individuals within an epidemic community were infected; however, only 0.5% of infected individuals developed paralytic poliomyelitis. Paralytic poliomyelitis terrified the public and initiated a huge research effort, which was rewarded with two outstanding vaccines. During research to develop the vaccines, many questions were asked: Why did certain people develop paralysis? How does the virus move from the gut to the CNS? What limits viral trafficking to the CNS in the vast majority of infected individuals? Despite over 100 years of poliovirus research, many of these questions remain unanswered. The goal of this chapter is to review our knowledge of how poliovirus moves within and between hosts, how host barriers limit viral movement, how viral population dynamics impact viral fitness and virulence, and to offer hypotheses to explain the rare incidence of paralytic poliovirus disease.

Figure 1

Architecture of the gastrointestinal epithelium. Virus may access the epithelium through M cells and the lymphatic system, or epithelial cells. IEL, intraepithelial lymphocyte; LPL, lamina propria lymphocyte; DC, dendritic cell; PP, Peyer’s patch.

Figure 2

Identification of poliovirus barriers using a viral population diversity assay. A. Silent mutations in the capsid-coding region (indicated in bold underline) were used to genetically mark ten polioviruses such that host barriers and viral population bottlenecks could be identified in an orally susceptible poliovirus mouse model (CD155^+/+IFNAR^−/−). B. Following infection and isolation of total RNA, the tag region was amplified by RT-PCR, blotted on a membrane, and probed with ³²P-labeled oligonucleotides matching each tag sequence. C. Each probe hybridized specifically with its cognate virus. D. Samples were harvested from mice orally inoculated with the ten-virus pool upon disease onset, and data from the hybridization assay revealed host barrier-mediated viral population restriction during trafficking within the host. Data from two representative mice are shown. AA, amino acid; WT PV, wild-type poliovirus sequence; Sm. Int., small intestine. Data are from (Kuss, Ethredtge, and Pfeiffer, 2008).

Figure 3

Model for poliovirus trafficking in neurons. Poliovirus engages CD155 at the nerve terminal and is endocytosed. The cytoplasmic tail of CD155 interacts with a component of the dynein complex, and the virus-containing endosome moves through retrograde axonal transport to the cell body. Once in the cell body, viral uncoating and replication occur.

Figure 4

Summary of poliovirus trafficking routes and potential host barriers. In most infections, virus follows the course indicated by the bold arrows, entering the mouth, replicating in the intestinal mucosa, with shedding in feces. Virus can also enter the blood. Rarely, virus accesses the CNS through blood or neural routes. Potential host barriers limiting viral movement at each stage are indicated by grey boxes. BBB, blood-brain barrier; IFN, interferon; Ig, immunoglobulin; CNS, central nervous system; ENS, enteric nervous system (i.e., vagus nerve).