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Human adenovirus (HAdV) is known to be a common cause of diarrhea in children worldwide. Infection with adenovirus is responsible for 2-10% of diarrheic cases. To increase a better understanding of the prevalence and epidemiology of HAdV infection, a large scale and long-term study was needed. We implemented a multi-year molecular detection and characterization study of HAdV in association with acute gastroenteritis in Chiang Mai, Thailand from 2011 to 2017. Out of 2,312 patients, HAdV was detected in 165 cases (7.2%). The positive rate for HAdV infection was highest in children of 1 and 2 years of age compared to other age groups. HAdV subgroup C (40.6%) was the most prevalent, followed by subgroups F (28.5%), B (20.6%), A and D (4.8% each), and E (0.6%). Of these, HAdV-F41 (22.4%), HAdV-C2 (18.2%), HAdV-B3 (15.2%), and HAdV-C1 (13.3%) were the most common genotypes detected. HAdV infection occurred throughout the year with a higher detection rate between May and July. In conclusion, our study demonstrated the infection rate, seasonal distribution and genotype diversity of HAdV infection in children with diarrhea in Chiang Mai, Thailand over a period of 7 year. Not only enteric adenovirus (F40 and F41) but also non-enteric adenovirus (B3, C1, C2) may play an important role in gastroenteritis in this area. The information will be beneficial for the prevention and control of HAdV outbreaks in the future.

Many different enteric viruses can cause acute gastroenteritis in humans worldwide. While a single virus can indeed cause disease, multiple-virus infections are commonly reported. However, data regarding a comparison between single- and multiple-virus infections upon clinical manifestations of acute gastroenteritis are relatively limited. In this study, a total of 2383 fecal specimens were collected from children with acute gastroenteritis during June 2014–July 2017 in a pediatric clinic in Japan and tested for 11 viruses by multiplex RT-PCR. At least 1 virus was found in 1706 (71.6%) specimens and norovirus GII was the most frequent agent, followed by rotavirus A and other viruses. Multiple-virus infections were identified in 565 cases (33.1%). While major clinical symptoms were found to be significantly different in some single- vs. multiple-virus infections, the disease severity was statistically non-significant. Our study highlights the burden of multiple-virus infections for acute gastroenteritis and the clinical features of patients with multiple-virus infections.

Single-round infectious rotavirus, which lacks a gene essential for virion assembly, serves not only as a safe and effective rotavirus vaccine but also as an orally-administrable viral vector vaccine that induces mucosal immunity. Previously, we generated a single-round infectious rotavirus by partially deleting the viral VP6 gene, and demonstrated its potential as a promising vaccine platform. However, this system has several limitations; namely, low viral protein expression levels and safety concerns. Here, we addressed these challenges by introducing large deletions into the VP7 or VP4 genes, which are dispensable for viral protein expression but essential for virion assembly. These VP7- or VP4-defective viruses exhibited markedly higher protein expression in wild-type MA104 cells than the previously developed VP6-defective virus. In addition, the large deletions reduce the risk of viral reversion, thereby increasing both efficacy and safety. In a mouse model, these viruses induced neutralizing antibodies at levels comparable with those elicited by wild-type rotavirus, indicating their potential as rotavirus vaccines. Moreover, a VP4-defective rotavirus harboring a heterologous gene achieved high expression of heterologous proteins, warranting its application as a viral vector vaccine. To further increase safety, we established a reverse genetics system for the bovine rotavirus WC3 strain, a parental strain of the licensed live attenuated rotavirus vaccine, and successfully generated a single-round VP4-defective rotavirus based on the WC3 backbone. Taken together, these optimizations facilitate development of safe and effective single-round infectious rotavirus platforms suitable for human use.

Norovirus is a major cause of acute gastroenteritis worldwide. Over 30 different genotypes, mostly from genogroup I (GI) and II (GII), have been shown to infect humans. Despite three decades of genome sequencing, our understanding of the role of genomic diversification across continents and time is incomplete. To close the spatiotemporal gap of genomic information of human noroviruses, we conducted a large-scale genome-wide analyses that included the nearly full-length sequencing of 281 archival viruses circulating since the 1970s in over 10 countries from four continents, with a major emphasis on norovirus genotypes that are currently underrepresented in public genome databases. We provided new genome information for 24 distinct genotypes, including the oldest genome information from 12 norovirus genotypes. Analyses of this new genomic information, together with those publicly available, showed that (i) noroviruses evolve at similar rates across genomic regions and genotypes; (ii) emerging viruses evolved from transiently-circulating intermediate viruses; (iii) diversifying selection on the VP1 protein was recorded in genotypes with multiple variants; (iv) non-structural proteins showed a similar branching on their phylogenetic trees; and (v) contrary to the current understanding, there are restrictions on the ability to recombine different genomic regions, which results in co-circulating populations of viruses evolving independently in human communities. This study provides a comprehensive genetic analysis of diverse norovirus genotypes and the role of non-structural proteins on viral diversification, shedding new light on the mechanisms of norovirus evolution and transmission.

Transforming growth factor-beta 1 (TGF-β1) is a pleiotropic growth factor playing various roles in the human body including cell growth and development. More functions of TGF-β1 have been discovered, especially its roles in viral infection. TGF-β1 is abundant at the maternal–fetal interface during pregnancy and plays an important function in immune tolerance, an essential key factor for pregnancy success. It plays some critical roles in viral infection in pregnancy, such as its effects on the infection and replication of human cytomegalovirus in syncytiotrophoblasts. Interestingly, its role in the enhancement of Zika virus (ZIKV) infection and replication in first-trimester trophoblasts has recently been reported. The above up-to-date findings have opened one of the promising approaches to studying the mechanisms of viral infection during pregnancy with links to corresponding congenital syndromes. In this article, we review our current and recent advances in understanding the roles of TGF-β1 in viral infection. Our discussion focuses on viral infection during pregnancy, especially in the first trimester. We highlight the mutual roles of viral infection and TGF-β1 in specific contexts and possible functions of the Smad pathway in viral infection, with a special note on ZIKV infection. In addition, we discuss promising approaches to performing further studies on this topic.

Noroviruses (NoVs) are a global concern, causing widespread outbreaks and sporadic acute gastroenteritis (AGE) cases across all age groups. Recent research has shed light on the emergence of novel recombinant strains of NoV in various countries. To delve deeper into this phenomenon, we extensively analyzed 1,175 stool samples collected from Japanese infants and children with AGE from six different prefectures in Japan over three years, from July 2018 to June 2021. Our investigation aimed to determine the prevalence and genetic characteristics of NoV associated with sporadic AGE while exploring the possibility of detecting NoV recombination events. Among the analyzed samples, we identified 355 cases positive for NoV, 11 cases attributed to GI genotypes, and 344 associated with GII genotypes. Notably, we discovered four distinct GI genotypes (GI.2, GI.3, GI.4, and GI.6) and seven diverse GII genotypes (GII.2, GII.3, GII.4, GII.6, GII.7, GII.14, and GII.17). The predominant genotypes were GII.4 (56.4%; 194 out of 344), followed by GII.2 and GII.3. Through dual genotyping based on sequencing of the ORF1/ORF2 junction region, we identified a total of 14 different RdRp/capsid genotypes. Of particular interest were the prevalent recombinant genotypes GII.4[P31] and GII.2[P16]. Notably, our study revealed a decrease in the number of children infected with NoV during and after the COVID-19 pandemic. These findings underscore the importance of continuous NoV surveillance efforts.

Acute gastroenteritis is one of the major health problems in children aged <5 years around the world. Rotavirus A (RVA) is an important pathogen of acute gastroenteritis. The burden of rotavirus disease in the pediatric population is still high in Bangladesh. This study investigated the prevalence of group A, B, and C rotavirus (RAV, RBV, RCV), norovirus, adenovirus (AdV) and human bocavirus (HBoV) infections in children with acute gastroenteritis in Bangladesh from February 2014 to January 2019. A total of 574 fecal specimens collected from children with diarrhea in Bangladesh during the period of February 2014-January 2019 were examined for RAV, RBV and RCV by reverse transcriptase- multiplex polymerase chain reaction (RT- multiplex PCR). RAV was further characterized to G-typing and P-typing by RT-multiplex PCR and sequencing method. It was found that 24.4% (140 of 574) fecal specimens were positive for RVA followed by AdV of 4.5%. RBV and RCV could not be detected in this study. Genotype G1P[8] was the most prevalent (43%), followed by G2P[4] (18%), and G9P[8] (3%). Among other genotypes, G9P[4] was most frequent (12%), followed by G1P[6] (11%), G9P[6] (3%), and G11P[25] (3%). We found that 7% RVA were nontypeable. Mutations at antigenic regions of the VP7 gene were detected in G1P[8] and G2P[4] strains. Incidence of rotavirus infection had the highest peak (58.6%) during November to February with diarrhea (90.7%) as the most common symptom. Children aged 4–11 months had the highest rotavirus infection percentage (37.9%). By providing baseline data, this study helps to assess efficacy of currently available RVA vaccine. This study revealed a high RVA detection rate, supporting health authorities in planning strategies such as introduction of RVA vaccine in national immunization program to reduce the disease burden.

Rubella infection (RuV) during early pregnancy is a known cause of congenital rubella syndrome (CRS). However, the mechanisms by which the virus crosses the placenta and infects the fetus are not fully understood. It has been known that various kinds of cell stresses can occur during the placenta formation. Previously, we demonstrated that low-glucose-induced endoplasmic reticulum stress could drastically enhance RuV infection in immortalized human first-trimester trophoblast cells. In this study, we investigated the roles of oxidative stress in RuV infection in these cells. Oxidative stress was induced in Swan.71 cells by culturing them in medium containing hydrogen peroxide (H2O2) in various concentrations and durations (50 µM or 100 µM for 24 h, or 150 µM for 1 h). RuV infection with a clinical strain was performed 24 h post-treatment, and capsid proteins were visualized at 24 and 48 h post-infection (hpi) using flow cytometry (FCM) and fluorescence microscopy (IF), respectively. The findings demonstrated that oxidative stress significantly enhanced RuV infection, as evidenced by FCM analysis, showing a twofold increase in infection rate, and confirmed by IF assay. Additionally, significantly increased intracellular viral replication was observed at 3 dpi. These findings suggest that oxidative stress during early pregnancy may promote the maternal-to-fetal transmission of rubella, contributing to the development of CRS.

Diversity in group A rotavirus (RVA) strains after introduction of RV-vaccines remains an emerging concern worldwide. In this study, we investigated the prevalence and distribution of RVA genotypes in Japanese children with acute gastroenteritis (AGE) from 2015 to 2018. In addition, a comparison of the genotypes in pre-vaccination (2006–2012) and post-vaccination (2012–2018) periods was conducted to understand the impact of these vaccines on genotype distribution. Fecal samples were collected regularly from outpatient clinics in six localities: Hokkaido, Tokyo, Shizuoka, Osaka, Kyoto, and Saga. RVA were screened and genotyped by RT-PCR and sequence-based genotyping. During the period 2015–2018, RVA was detected in 307 (19.7%) samples out of 1557 specimens: 29.9% (95% CI: 25.8% to 34.3%), 17.9% (95% CI: 14.7% to 21.5%), and 13% (95% CI: 10.3% to 16.0%) were detected RVA-positive in 2015–2016, 2016–2017 and 2017–2018, respectively. The average detection of RVA in pre-vaccination (2006–2012) and post-vaccination (2012–2018) era remained almost similar (18%-20%). The G2P[4]I2 (52.1%, 95% CI: 43.5%-60.6%) remained the most common genotype in 2015–2016, whereas G8P[8]I2 (55.9%, 95% CI: 45.2%-66.2%) dominated in 2016–2017. In 2017–2018, G9P[8]I2 (42.0%, 95% CI: 30.5%-53.9%) prevailed, followed by G9P[8]I1 (23.0%, 95% CI: 14.0%-34.2%). The detection rate of some common genotypes of pre-vaccination era like G1P[8] and G3P[8] has been reduced after introduction of RV-vaccine, whereas genotypes that were sporadic before the introduction of vaccines like G2P[4], G2P[8], G9P[8] and G8P[8] were emerged/reemerged in post-vaccination period. Our study presented the diversity in circulating RVA genotypes in Japan before and after introduction of RV-vaccines. Sudden emergence of DS-1-like (I2) unusual strains in post-vaccination era remains alarming. Continuous monitoring of RVA genotypes is therefore indispensable to refine future vaccine strategy.

Rotavirus, the leading cause of severe acute gastroenteritis in infants, is responsible for approximately 128,500 infant deaths globally each year. The virus’s surface proteins are highly diverse, comprising approximately 100 genotypes. This diversity affects susceptibility to neutralizing antibodies and the efficacy of vaccines. Here, we found that certain genotypes are highly resistant to serum neutralizing antibodies induced by vaccination and natural infections. Furthermore, we identified a specific region in the viral outer capsid protein that plays a significant role in determining susceptibility to neutralization. These findings may be important for predicting outbreak-causing strains and for developing more effective vaccines, ultimately contributing to the prevention of future outbreaks and improving global infant health.