Journal of Medical Virology最新文献

Rotavirus alphagastroenteritidis (RVA) is the leading cause of acute gastroenteritis in young children worldwide, as well as in a wide range of animal species. In 2020 and 2022, we identified three unusual RVA strains in pediatric gastroenteritis patients in Hokkaido Prefecture, Japan, using next-generation sequencing: one G10P[14] strain (Ni20-23) and two G8P[14] strains (Ni20-37 and To22-1). All three strains possessed the genotype constellation G10/G8-P[14]-I2-R2-C2-M2-A3-N2-T6-E2-H3. Phylogenetic analyses of these 11 genome segments indicated that the strains were artiodactyl-like RVAs. However, no genome segment exhibited > 98% nucleotide identity among the three strains, suggesting that they originated from distinct artiodactyl RVA strains. Furthermore, no previously reported artiodactyl RVA strain showed > 90% nucleotide identity across all 11 segments; thus, the direct animal origins of these strains remain unclear. As observed in these strains, nearly all artiodactyl-like RVAs previously detected in humans have carried the VP4 genotype P[14], indicating a potential role of P[14] in facilitating cross-species transmission. One strain (To22-1/G8P[14]) was detected in a child who had received two doses of Rotarix (G1P[8] monovalent vaccine). Comparative amino acid analysis of VP4 between the To22-1/G8P[14] strain and the P[8] Rotarix vaccine strain revealed substitutions at 18 of 37 (48.6%) known antigenic epitope sites, suggesting a potential antigenic mismatch. Continued surveillance and further studies are warranted to elucidate the mechanisms underlying interspecies transmission of artiodactyl-like P[14] RVAs and to assess the effectiveness of current vaccines against such strains.

The study investigates the potential of involucrasins for COVID-19 prevention through molecular docking using AutoDock Vina and molecular dynamics (MD) simulations with Gromacs 2020. Docking results revealed that involucrasins exhibit strong binding affinity to the SARS-CoV-2 Delta (B.1.617.2) and Omicron (BA.2 RBD) variants of SARS-CoV-2, as well as the angiotensin-converting enzyme 2 (ACE2) protein. MD simulations further confirmed their stable interactions with these targets. Additionally, bilayer interferometry (BLI) assays demonstrated that involucrasins effectively inhibited the binding between the receptor-binding domain (RBD) of the Delta (B.1.617.2) and Omicron (BA.2 RBD) variants and ACE2, highlighting their potential as viral entry blockers. Further immunocytochemistry (ICC) and pseudo-typed lentiviral particle assay indicated that the entry of the SARS-CoV-2 Delta (B.1.617.2) and Omicron (BA.2 RBD) variants into host cells was impeded due to the inhibition of the binding of the spike (S) protein to ACE2 by involucrasins. ROS can contribute to the activation of the caspase-1 signaling pathway through their involvement in inflammasome activation. Involucrasins have an inhibitory effect on ROS generation in response to LPS/ATP stimulation. Meantime, involucrasins reduce the level of caspase-1, IL-1β, and IL-33.

Although toll-like receptor 6 (TLR6) plays an important role in innate immunity and host antiviral responses, its impact on pegylated interferon-alpha (PegIFNα) treatment efficacy in chronic hepatitis B (CHB) remains unclear. We aimed to investigate whether genetic variations of TLR6 are associated with the response to PegIFNα treatment. This study included 945 HBeAg-positive CHB patients treated with PegIFNα for at least 48 weeks and followed for 24 weeks from two multicenter phase IV trials (Cohort 1, n = 238; Cohort 2, n = 707). Across the TLR6 gene, 13 tag-SNPs were selected. Furthermore, a polygenic score (PGS) was developed by incorporating the newly identified variant of TLR6 and two previously reported SNPs (CD55_rs28371597 and CXCR4_rs28367495). Both TLR6 tag-SNPs and PGS were tested their associations with treatment efficacy. Among the 13 tag-SNPs, TLR6_rs7696175 (C > T) was identified as the most significantly associated variant with HBsAg decline at week 72 in both cohorts. The T allele of TLR6_rs7696175 was significantly associated with greater HBsAg decline, especially higher rates of decline ≥ 1 log₁₀ IU/mL and ≥ 2 log₁₀ IU/mL at week 72 (Cohort 1 + 2: p ≤ 0.001 for all associations). Moreover, the PGS integrating TLR6_rs7696175 and two previously reported SNPs significantly improved prediction accuracy for HBsAg decline at week 72 (Cohort 1 + 2: p < 0.001 for all comparisons) and outperformed single SNPs. Overall, this study identifies TLR6_rs7696175 as a novel genetic biomarker and demonstrates the superiority of a compact PGS for predicting HBsAg decline in PegIFNα-treated CHB patients, facilitating personalized treatment for CHB.

Group A rotavirus remains a major pathogen causing infantile diarrhea. Although rotaviruses are known for their zoonotic potential and frequent genomic reassortment, the virological features of newly isolated strains and their suitability as vaccine candidates remain unclear. In this study, a human rotavirus strain of genotype G3P[10] was isolated from the fecal sample of an infant with diarrhea in Xiangyun County, Yunnan Province, China in 2019, and subsequently cultured in MA104 cells in 2021. The strain was designated XYR-19. Its biological characteristics were assessed through morphological examination, serological testing, and molecular analyses. Whole-genome sequencing and bioinformatic approaches were then used to define its genetic profile. Similarly, an inactivated vaccine was prepared based on this strain and evaluated its immunogenicity. Biological characterization confirmed that XYR-19 demonstrated stable structural and replication properties, reaching a viral titer of 7.3 lg CCID₅₀/mL after propagation. Whole-genome sequencing revealed a genotype constellation of G3-P[10]-I8-R3-C3-M3-A9-N3-T3-E3-H6. Comparative analysis indicated that the VP4 and VP7 genes shared 99.41% and 96.57% nucleotide identity, respectively, with the circulating domestic strain bat-derived strain MYAS33, while also harboring distinct mutation sites. Phylogenetic analysis showed that XYR-19 clustered closely with human RVA strain MS2015-1-0001, CMH079, and CMH-S015-19. These findings expand current knowledge of rotavirus epidemiology in the region and provide essential data for tracking local transmission dynamics. Moreover, they offer a valuable basis for future rotavirus vaccine development and for designing strategies aimed at limiting cross-species transmission, ultimately supporting improved prevention and control of infantile diarrhea in the area.

Background and aim: Chronic hepatitis B (CHB) affects over 250 million people globally and is a major contributor to liver complications, including cirrhosis and hepatocellular carcinoma (HCC). Though antiviral therapies suppress HBV, the rising prevalence of metabolic-associated steatotic liver disease (MASLD) poses new challenges. This study assessed how MASLD influences liver-related outcomes, fibrosis progression, and survival in CHB patients undergoing nucleus(t)ide analogs (NAs) therapy, using large-scale data and clinical cohort analysis.

Methods: A retrospective study using the TriNetX US Collaborative Network, CHB patients receiving long-term NA therapy with undetectable serum HBV DNA and concomitant MASLD (CHB-MASLD-NA, n = 5600) were compared with those without MASLD (CHB-non MASLD-NA, n = 11 021), matched 1:1 by propensity scores (n = 4761 each after matching). Primary outcomes included 10-year incidence of HCC and cirrhosis, with survival assessed via Kaplan-Meier curves and hazard ratios (HRs) from Cox models. Separately, a clinical cohort of 64 CHB patients and 137 MASLD-only patients was assessed for steatosis (controlled attenuation parameter, CAP) and fibrosis (liver stiffness).

Results: Analysis revealed that co-existing MASLD significantly compromised clinical outcomes. CHB-MASLD-NA patients faced a substantially higher risk of developing cirrhosis or HCC (HR 1.75, 95% CI 1.53-2.00, p < 0.001) and demonstrated lower 10-year survival rates (61.5% vs. 79.3%, p < 0.001) compared to the non-MASLD group. These findings were corroborated by the clinical cohort, where CHB-MASLD-NA patients exhibited greater liver stiffness (9.85 vs. 4.95 kPa) and a higher prevalence of advanced fibrosis compared to CHB alone and MASLD-only groups (28.0% vs. 14.3% and 4.4%). HBV DNA load was not a significant predictor of outcomes in this population (HR 1.00). Notably, as steatosis worsened, the pro-inflammatory cytokine TNF-α increased more sharply (3.73-fold) than the antiviral cytokine IFN-γ (2.13-fold).

Conclusions: MASLD drives fibrosis and mortality in NA-treated CHB patients, as metabolic inflammation overrides the benefits of viral suppression. Integrated management, combining antiviral therapy, metabolic intervention, and immune monitoring, is essential to accurately assess progression and improve long-term prognosis.

Following rotavirus vaccine implementation in Vietnam, norovirus has gradually become equally an important as a cause of acute gastroenteritis (AGE) in children as rotavirus. This study aimed to investigate the genotype distribution and compare clinical manifestations of norovirus of children < 5 years of age hospitalized with AGE from 2016 to 2021. Of 6,718 specimens collected through active surveillance from 12/2016 to 05/2021, 2,317 (34.5%) were randomly selected for norovirus testing. Among the 477 (20.6%) norovirus-positive specimens identified from the previous surveillance, 390 (81.8%) were successfully genotyped for both partial RdRp and VP1 genes using online typing tools and 47 were selected for whole-genome sequencing. Overall, norovirus genogroup-II (GII) viruses dominated (97.3%) followed by GI (2.5%) and dual GI/GII infections (0.2%), with GII.4Sydney[P16] as the predominant genotype (51.5%) followed by GII.3[P12] (23.9%). Children infected with GII.4Sydney more commonly presented with thirst (65.8% vs 53.7%, p < 0.05) and showed a trend toward higher rates of sunken eyes compared with other genotypes (48.1% vs 38.1%, p = 0.053). A shift in predominant strain from GII.4Sydney[P31] viruses (50.8%) in 2016-2017 to GII.4-Sydney[P16] (51.9%-68.9% in 2018-2021) was observed. Two cases in 2017 were typed as GII.4Hong Kong[P31]. Compared to GII.4 Sydney[P31], GII.4Hong Kong had 12 amino acid substitutions in the P1-P2 domains. This study highlights the evolving genetic diversity of norovirus genotypes in Vietnam. The shift of the predominant strain from GII.4Sydney[P31] to GII.4Sydney[P16] in 2018 and detection of GII.4 Hong Kong[P31] in 2017 emphasizes the need for continuous molecular surveillance to inform public health prevention strategies.

Human parainfluenza viruses (HPIVs) commonly cause croup and lower respiratory tract infections in young children. Despite typically self-limiting with mild symptoms, the innate immune responses to HPIVs remain poorly understood, especially across all four types in human nasal epithelial cells (hNECs), the primary infection site. This study aims to investigate and compare viral replication kinetics and host immune responses in hNECs infected with HPIV types 1 to 4.The hNECs were infected in vitro, and viral replication kinetics, mucociliary function, cell tropism, and innate immune responses were assessed over 72 h. The viral RNA and progeny of HPIV types 1 to 4 were detected by 8 h postinfection (hpi). All HPIV types predominantly targeted ciliated cells of which a significant proportion displayed a unique apical distribution. HPIV-3 generated the highest level of progeny virus and could infect a fraction of nasal goblet cells. RIG-I and MDA5 expression was delayed during HPIV-2 and HPIV-3 infection (24 hpi), whereas HPIV-1 and HPIV-4 induced gradual upregulation from 8 hpi. Minimal upregulation of IFN-α1 mRNA was induced across all HPIV types. Expression of type I IFN-β was generally subdued during the earlier stage of infection (24 to 48 hpi) with the four HPIV types. Notably, IFN-β mRNA expression was significantly elevated for HPIV-1 infection at 48-72 hpi, whereas only a small increase was observed at 72 hpi for the other HPIV types. Although expression of type III IFN-λ1 was similarly delayed for all four HPIV types during the earlier stage of infection, a greater upregulation of IFN-λ1 was detected at 48-72 hpi for all HPIV types (especially HPIV-1) as compared to type I IFN expression. For HPIV-1 and HPIV-4, mRNA expression of CXCL10 and MX1 appeared as early as 8 hpi and gradually increased until 72 hpi. However, for HPIV-2 and HPIV-3, mRNA expression of CXCL10 and MX1 was delayed at 8-16 hpi, but subsequently increased significantly at 24-72 hpi. In comparison, IFITM1 mRNA was expressed at relatively weaker levels for the four HPIV types. In conclusion, all four HPIV types exhibit high infectivity and replicative capacity in hNECs while initially evading interferon responses to varying extents. Their innate immune modulation appears to be type-specific, potentially influencing viral virulence, pathogenesis, and progression of airway disease in high-risk patients.

Chikungunya virus (CHIKV) infection has been associated with heightened disease burden and fatality rate, especially post its resurgence in 2006, with presentation of various atypical symptoms. Its re-emergence and the subsequent periodic outbreaks indicate the constant evolution of the virus due to the incorporation of mutations in its genome. This can potentially elicit a differential induction of innate immune response of varying degrees, which has been poorly studied in the case of CHIKV. Leveraging an immunocompetent epithelial model cell line to define the varying internalization and replication of CHIKV and differential induction of innate immune response effectors, we demonstrate that CHIKV outbreak isolates (CHIKV 2006, 2016, 2022 and 2024 outbreak isolates) have differential internalization and replication dynamics and trigger expression of defensins, interferon lambda (IFN-λ), and microRNAs modulating CHIKV infection, in an isolate-dependent manner. We also observed that CHIKV 2024, despite having the highest internalization efficiency, shows delayed initiation of exponential replication, with an unusual "eclipse phase," spanning up to 18 h post-infection. While protein-protein interaction analysis suggested the potential interaction of DEFA5 and DEFB2 with CHIKV envelope glycoprotein, microRNA hybridization analysis revealed the differential hybridization pattern of microRNAs at the target sites of the genome of CHIKV outbreak isolates, with hsa-miR-214-3p showcasing increased yet sustained binding affinity to the post-2006 outbreak isolates of CHIKV. Overall, our study provides transcriptional insights regarding the isolate-dependent modulation of innate immune response by CHIKV, as a result of its evolutionary adaptation. This work also sheds light on the potential usage of human defensins and microRNAs modulating CHIKV infection as peptide-based and RNA-based therapeutics, respectively.

Complement temporal activation kinetics, activation pathways, and their relationship with thromboinflammation and antibody responses in severe vaccination-COVID-19 remains unclear. Based on a vaccinated-infected cohort, we analyzed complement immune responses across mild to critical COVID-19 cases by a dynamic model. Our results showed that complement activation was earlier (7-14 days post symptom onset), more intense and lasted longer in severe and critical vaccination-COVID-19, mediated by alternative and lectin pathways instead of classical pathway. Moreover, complement activation in severe vaccination-COVID-19 was related to thromboinflammation but not to the virus-specific antibody response. Our study elucidated the kinetics of complement activation in vaccination-COVID-19 infection, revealing that Bb in alternative pathway were crucial in severe vaccination-COVID-19. These findings indicate the optimal timing for implementing complement activation-targeted interventions in the management of severe vaccination-COVID-19 and provide more potential therapeutic targets.