谷口 孝喜

BACKGROUND: Biliary atresia (BA) is a severe infantile hepatobiliary disorder of unknown etiology. Perinatal rotavirus (RV) infection has been implicated in animal models of BA; however, supporting human data remains limited. The study investigated the serological evidence of recent RV infection in infants with BA using RV-specific immunoglobulin (Ig)-A, a marker of primary infection unaffected by maternal antibodies. METHODS: Serum samples from 17 infants with BA and 30 age-matched controls without gastrointestinal symptoms or prior RV vaccination were retrospectively analyzed. Anti-RV-IgA titers were measured by enzyme-linked immunosorbent assay using purified WA-strain virions. Cytomegalovirus (CMV)-IgM and Epstein-Barr virus (EBV)-viral capsid antigen (VCA)-IgM levels were assessed using commercial enzyme immunoassays. RESULTS: RV-IgA was detected in 70.6% (12/17) of the patients with BA versus 3.4% (1/29) of the controls (p < 0.001). RV-IgA titers were significantly higher in the BA group (median: interquartile range 28.0:26.0-210.0) than in the control group (23.5:22.0-24.8) (p = 0.004). Among patients diagnosed with BA after 14 days of age, 84.6% (11/13) were RV-IgA-positive. CMV-IgM was detected in three patients in the BA group and one individual in the control group, while EBV-VCA-IgM was negative in BA patients and positive in two controls; neither difference was statistically significant. CONCLUSIONS: The study findings support the potential association between RV infection and BA pathogenesis. However, the lack of an epidemiological reduction in BA following the introduction of the RV vaccine warrants caution in other studies. Further prospective multicenter studies are required to elucidate the causal role of RV infection in BA development.

An unusual rotavirus strain with the G3P[10] genotype, designated RVA/Human-wt/THA/PK2016-1-0120/2016/G3P[10] (short name "PK2016-1-0120"), was detected in a stool specimen from a hospitalized 10-year-old boy with acute gastroenteritis in Thailand. In this study, we sequenced and characterized its whole genome. The strain possesses the genotype constellation G3-P[10]-I8-R3-C3-M3-A9-N3-T3-E3-H6, similar to several previously reported bat and bat-like rotavirus strains (MYAS33-like). In line with this, phylogenetic analyses and sequence comparisons indicate that 10 of the 11 genomic segments (VP4, VP6, VP1-VP3, and NSP1-NSP5) are most similar to those found in MYAS33-like strains. In contrast, the VP7 genomic segment of PK2016-1-0120-which defines the G genotype-is most closely related to those of the Indian equine rotavirus strain Erv105 and DS-1-like G3P[8] human strains. These findings imply a history of segment reassortment involving independent acquisition of the VP7 segment. Given that bats are likely donors in interspecies RVA transmission chains, we speculate that this VP7 lineage originated in bats. In summary, our characterization of the novel bat-like human strain PK2016-1-0120 suggests that the VP7 lineage as found in human DS-1-like G3P[8] strains may have originated from a bat-associated rotavirus, offering an alternative model to the previously proposed equine origin.

The live attenuated human rotavirus vaccine strain RIX4414 (Rotarix®) is used worldwide to prevent severe rotavirus-induced diarrhea in infants. This strain was attenuated through the cell culture passaging of its predecessor, human strain 89-12, which resulted in multiple genomic mutations. However, the specific molecular reasons underlying its attenuation have remained elusive, primarily due to the absence of a suitable reverse genetics system enabling precise genetic manipulations. Therefore, we first completed the sequencing of its genome and then developed a reverse genetics system for the authentic RIX4414 virus. Our experimental results demonstrate that the rescued recombinant RIX4414 virus exhibits biological characteristics similar to those of the parental RIX4414 virus, both in vitro and in vivo. This novel reverse genetics system provides a powerful tool for investigating the molecular basis of RIX4414 attenuation and may facilitate the rational design of safer and more effective human rotavirus vaccines.

Vaccine development for herpes simplex virus 2 (HSV-2) has been attempted, but no vaccines are yet available. A plasmid-based reverse genetics system for Rotavirus (RV), which can cause gastroenteritis, allows the generation of recombinant RV containing foreign genes. In this study, we sought to develop simian RV (SA11) as a vector to express HSV-2 glycoprotein D (gD2) and evaluated its immunogenicity in mice. We generated the recombinant SA11-gD2 virus (rSA11-gD2) and confirmed its ability to express gD2 in vitro. The virus was orally inoculated into suckling BALB/c mice and into 8-week-old mice. Serum IgG and IgA titers against RV and gD2 were measured by ELISA. In the 8-week-old mice inoculated with rSA11-gD2, significant increases in not only antibodies against RV but also IgG against gD2 were demonstrated. In the suckling mice, antibodies against RV were induced, but gD2 antibody was not detected. Diarrhea observed after the first inoculation of rSA11-gD2 in suckling mice was similar to that induced by the parent virus. A gD2 expressing simian RV recombinant, which was orally inoculated, induced IgG against gD2. This strategy holds possibility for genital herpes vaccine development.

Human rotavirus strains having the unconventional G3P[6] genotype have been sporadically detected in diarrheic patients in different parts of the world. However, the full genomes of only three human G3P[6] strains from Asian countries (China, Indonesia, and Vietnam) have been sequenced and characterized, and thus the exact origin and evolution of G3P[6] strains in Asia remain to be elucidated. Here, we sequenced and characterized the full genome of a G3P[6] strain (RVA/Human-wt/JPN/SO1199/2020/G3P[6]) found in a stool sample from a 3-month-old infant admitted with acute gastroenteritis in Japan. On full genomic analysis, strain SO1199 was revealed to have a unique Wa-like genogroup configuration: G3-P[6]-I5-R1-C1-M1-A8-N1-T1-E1-H1. VP6 genotype I5 and NSP1 genotype A8 are commonly found in porcine rotavirus strains. Furthermore, phylogenetic analysis demonstrated that all 11 genes of strain SO1199 were closely related to those of porcine and/or porcine-like human rotaviruses and thus appeared to be of porcine origin. Thus, strain SO1199 was shown to possess a porcine-like genomic backbone and thus is likely to be the result of interspecies transmission of a porcine rotavirus strain. Of note is that all 11 genes of strain SO1199 were phylogenetically located in clusters, distinct from those of the previously identified porcine-like human G3P[6] strains from around the world including Asia, suggesting the occurrence of independent porcine-to-human zoonotic transmission events. To our knowledge, this is the first report on full genome-based characterization of a human G3P[6] strain that has emerged in Japan. Our findings revealed the diversity of unconventional human G3P[6] strains in Asia, and provide important insights into the origin and evolution of G3P[6] strains.