Establishment of a Poliovirus Oral Infection System in Human Poliovirus Receptor-Expressing Transgenic Mice That Are Deficient in Alpha/Beta Interferon Receptor

Abstract

Poliovirus (PV) is easily transferred to humans orally; however, no rodent model for oral infections has been developed because of the alimentary tract's low sensitivity to the virus. Here we showed that PV is inactivated by the low pH of the gastric contents in mice. The addition of 3% NaHCO 3 to the viral inoculum increased the titer of virus reaching the small intestine through the stomach after intragastric inoculation of PV. Transgenic mice (Tg) carrying the human PV receptor (hPVR/CD155) gene and lacking the alpha/beta interferon receptor (IFNAR) gene (hPVR-Tg/IfnarKO) were sensitive to the oral administration of PV with 3% NaHCO 3 , whereas hPVR-Tg expressing IFNAR were much less sensitive. The virus was detected in the epithelia of the small intestine and proliferated in the alimentary tract of hPVR-Tg/IfnarKO. By the ninth day after the administration of a virulent PV, the mice had died. These results suggest that IFNAR plays an important role in determining permissivity in the alimentary tract as well as the generation of virus-specific immune responses to PV via the oral route. Thus, hPVR-Tg/IfnarKO are considered to be the first oral infection model for PV, although levels of anti-PV antibodies were not elevated dramatically in serum and intestinal secretions of surviving mice when hPVR-Tg/IfnarKO were administered an attenuated PV.Poliomyelitis is an acute disease of the central nervous system (CNS) caused by poliovirus (PV), a human enterovirus that belongs to the family Picornaviridae. In humans, an infection is initiated by oral ingestion of the virus, followed by multiplication in the alimentary mucosa (2, 38), from which the virus spreads through the bloodstream. Viremia is considered essential for leading to paralytic poliomyelitis in humans. By use of a PV-sensitive mouse model, previous studies (9, 44) demonstrated that after intravenous inoculation, circulating PV crosses the blood-brain barrier at a high rate, and a neural dissemination pathway from the skeletal muscle without injury is not the primary route by which the circulating virus disseminates to the CNS. Along with the blood-brain barrier pathway of dissemination, a neural pathway has been reported for humans (30), primates (11), and PV-sensitive transgenic mice (Tg) carrying the human PV receptor (hPVR/CD155) gene (31,34); this pathway appears to be important in causing provocation poliomyelitis (9).It has been proved that Tg carrying the hPVR gene (hPVRTg) are susceptible to all three PV serotypes, 1, 2, and 3 (22, 35), although mice without the hPVR gene are generally not susceptible to PV. This observation indicates that hPVR is the most important determinant of the host range of PV. After inoculation with PV by the intracerebral, intraspinal, intravenous, or intramuscular route (10,(20)(21)(22)(33)(34)(35), hPVR-Tg develop a flaccid paralysis in their limbs, which is clinically similar to human poliomyelitis. However, in contrast to its behavior in humans, PV does not replicate in the alimentary tracts of hPVR-Tg after oral a...

The TLR3/TICAM-1 Pathway Is Mandatory for Innate Immune Responses to Poliovirus Infection

“…Results were confirmed using IRF-3 2/2 and IRF-7 2/2 mice (26). These results are essentially consistent with previous reports using a PVRtg/ IFNAR 2/2 mouse model (27), in which type I IFN is critical for PV permissiveness, particularly in the intestine of PVRtg mice.…”

“…Possible limitations of this model may include the fact that PV natural infection in humans occurs postinfection of the intestine by a low dose of PVand the PV mouse model is unable to reproduce this infectious route (27). The difference in PV infection between human and the PVRtg mouse might reflect the difference of the IFN-inducing system in humans and mice.…”

“…However, the response to neurovirulence and death by PV infection occurs similarly in mice and humans. PVRtg mice are susceptible to neuronal infection and the IFNAR 2/2 phenotype further enhances systemic PV infection (27,34). The G (Sabin vaccine) and A forms (WT) of PV, which harbor G or A residues in their stem-loop V structures, respectively, show different levels of toxicity or neurovirulence (49).…”

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

“…MYXV infects rabbits but will not replicate efficiently in murine or human cells unless their IFN response is disabled Johnston et al, 2005;reviewed by McFadden, 2005). Neither MeV nor PV will replicate efficiently in mouse models unless the IFN system has been compromised [and, for MeV, only if the appropriate virus receptors are expressed (Mrkic et al, 1998;Ohka et al, 2007;Ohno et al, 2007)]. One restriction on the replication of human RSV in bovine cells, and bovine RSV in human cells, is their inability to circumvent the IFN response efficiently in cells of the other species (Schlender et al, 2000;Bossert & Conzelmann, 2002;Young et al, 2003).…”

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

“…Although murine models have been developed for the study of enterovirusinduced disease (1)(2)(3)(4), many of these models require intraperitoneal (i.p.) infection, thereby bypassing the GI tract, or require ablation of the host innate immune system (5,6). Coupled with species differences between humans and mice, there remains a need to develop human-based platforms to model enterovirus infections of the GI tract.…”