Summary auto-generated
This study investigates how poliovirus selection occurs in the central nervous system (CNS) during vaccine-associated paralytic poliomyelitis (VAPP), which occasionally develops in recipients of oral poliovirus vaccine. The researchers analyzed viruses from stool and cerebrospinal fluid samples of two VAPP patients, finding that multiple diverse viral genotypes were present in stool but different genotypes appeared in the CNS. Notably, one CNS isolate corresponded to a less neurovirulent virus from the stool mixture. To understand this selection mechanism, the team used transgenic mice susceptible to poliovirus and inoculated them intraperitoneally with mixtures of two phenotypically different viruses with known neurovirulence levels. Results showed that when both viruses were present at sublethal doses, individual mice were stochastically (randomly) infected by either virus variant. This random selection pattern suggests that CNS infection is not solely determined by a virus's neurovirulence but may involve probabilistic factors. The findings suggest that in humans, CNS infection with less neurotropic viruses can occur from an extraneural pool containing both highly and moderately virulent variants, explaining why some VAPP cases involve less neurovirulent strains.
Key findings
- Multiple poliovirus genotypes circulate in the gastrointestinal tract during VAPP, but the CNS can be infected by a single genotype that may not be the most neurovirulent variant present.
- In transgenic mouse models, mixed poliovirus infections of the CNS showed stochastic selection patterns at sublethal doses, with individual animals randomly infected by either virus variant regardless of relative neurovirulence.
- Neurovirulence alone does not determine which virus variant reaches the CNS; selection appears to involve probabilistic factors beyond inherent pathogenicity.
- The H (hot/highly neurovirulent) virus phenotype dominated in mixtures at high doses, while the C (cold/less virulent) virus could establish CNS infection in lower-dose mixture scenarios.
- These findings explain how vaccine-derived polioviruses with reduced neurovirulence can paradoxically cause paralytic disease in VAPP recipients.
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Abstract
Mixed infections occur in the natural environment, and also result from the use of mixed live vaccines. Some recipients of the trivalent oral poliovirus vaccine develop vaccine-associated paralytic poliomyelitis (VAPP). Numerous serotypes and recombinant genotypes of vaccine-derived polioviruses may be found in stool samples from such cases. To investigate the relationship between the multiplication of various genotypes at the primary replication site in the gut and the infection outcome in the central nervous system (CNS), the viruses excreted on consecutive days by two patients with VAPP were compared with the viruses isolated from the CNS. The genotypes from stools were numerous and varied with time in both cases, suggesting a multiplication of the viruses in multiple foci in the gut. Where the CNS isolated virus clearly corresponded to one of the many viruses detected in stool, this virus was unexpectedly less neurovirulent than others isolated from stool. To assess the mechanism by which viruses with different degrees of neurovirulence are selected in the CNS, transgenic mice sensitive to poliovirus infection were inoculated extraneurally with mixtures of two phenotypically different viruses at different neuropathogenic doses. The virus(es) inducing neurological disease was then isolated from the CNS. At less than 100% input neuropathogenic dose of both inoculated viruses, individual mice were affected stochastically by the virus variants from the mixture. Extrapolated to humans, this selection pattern might explain the occurrence of CNS infections with less neurotropic viruses derived from an extraneural pool containing also highly neurotropic viruses.