Virologica Sinica最新文献

A switch from avian-type α-2,3 to human-type α-2,6 receptors is an essential element for the initiation of a pandemic from an avian influenza virus. Some H9N2 viruses exhibit a preference for binding to human-type α-2,6 receptors. This identifies their potential threat to public health. However, our understanding of the molecular basis for the switch of receptor preference is still limited. In this study, we employed the random forest algorithm to identify the potentially key amino acid sites within hemagglutinin (HA), which are associated with the receptor binding ability of H9N2 avian influenza virus (AIV). Subsequently, these sites were further verified by receptor binding assays. A total of 12 substitutions in the HA protein (N158D, N158S, A160N, A160D, A160T, T163I, T163V, V190T, V190A, D193N, D193G, and N231D) were predicted to prefer binding to α-2,6 receptors. Except for the V190T substitution, the other substitutions were demonstrated to display an affinity for preferential binding to α-2,6 receptors by receptor binding assays. Especially, the A160T substitution caused a significant upregulation of immune-response genes and an increased mortality rate in mice. Our findings provide novel insights into understanding the genetic basis of receptor preference of the H9N2 AIV.

The long-term effects of combined antiretroviral therapy (ART) on liver fibrosis patterns in adults living with HIV and chronic hepatitis B virus (HBV) are not well understood. Therefore, this study aimed to investigate the trajectories of liver fibrosis and identify the associations of baseline variables with different patterns of liver fibrosis evolution. A total of 333 individuals with HIV/HBV co-infection and undergoing long-term ART were enrolled in this study. Demographic, clinical, and biochemical data were collected at baseline and during annual visits. Group-based trajectory models (GBTMs) were used to detect the patterns of liver fibrosis evolution based on longitudinal data of fibrosis-4 (Fib-4) and aspartate aminotransferase to platelet ratio index (APRI) scores. Logistic regression analysis was performed to identify baseline predictors of liver fibrosis evolution. The median age of all participants was 33 years. Among them, 89.5% initially received TDF-containing ART. GBTMs identified two distinct patterns of liver fibrosis evolution using either APRI or Fib-4 scores. The majority of individuals (78.5% for APRI and 75.3% for Fib-4; pattern A) showed stable or low fibrosis with no progression, while the remaining participants showed regression from high fibrosis levels (21.5% for APRI and 24.7% for Fib-4; pattern B). Pattern A participants were younger and had higher CD4+ cell counts, higher lymphocyte cell counts, higher white blood cell counts, and lower platelet counts at baseline compared to pattern B participants. For HIV/HBV co-infected patients with varying degrees of initial liver fibrosis, long-term ART has shown distinct patterns of alleviating liver fibrosis.

In-utero exposure to Zika virus (ZIKV) could lead to miscarriage, preterm birth and children with congenital Zika syndrome. This study aimed at estimating the burden of ZIKV infection among pregnant women from 21 Feb and 19 April 2022. ELISA and microneutralization test (MNT) were used to detect the presence of ZIKV antibodies. All the ZIKV IgM positive samples were retested for dengue virus (DENV) and ZIKV RNA, and DENV NS1 antigen. Additionally, all the samples with ZIKV neutralizing antibody (nAb) were retested for DENV antigen, antibody and nucleic acid. Of 200 pregnant women, 16.5% were positive for ZIKV IgM, 10% were positive for IgG, and 23% were found to have nAb in their serum. Among the 46 ZIKV nAb-positive women, 52.2% and 10.9% were recent and previous ZIKV infections, respectively, while 6.5% had previous DENV infections. Although no recent DENV infection was detected, recent and previous ZIKV/DENV co-infections were 13.0% and 17.4%, respectively. Two participants had recent secondary ZIKV infections, while 39.1% had prolonged lifelong immunity against the virus. Recent ZIKV infection rates were significantly higher among sexually active females aged 20-29 years than other age groups and women who had no pre-knowledge of the virus. ZIKV infection is not significantly associated with early and late trimester, but the risk of ZIKV infection is highest in the women in first trimester of pregnancy. The grand-multiparous women are at higher risk of ZIKV infections than other categories. In addition, women with and without a history of children with paralysis, brain defects (microcephaly) and stillbirths (claimed by the women) had both recent and past ZIKV infections. Monotypic recent, secondary and past ZIKV and co-infections with DENV and ZIKV were detected among the asymptomatic and symptomatic pregnant women.

Influenza, a highly contagious respiratory infectious disease caused by an influenza virus, is a threat to public health worldwide. Avian influenza viruses (AIVs) have the potential to cause the next pandemic by crossing the species barrier through mutation of viral genome. Here, we investigated the pathogenicity of AIVs obtained from South Korea and Mongolia during 2018-2019 by measuring viral titers in the lungs and extrapulmonary organs of mouse models. In addition, we assessed the pathogenicity of AIVs in ferret models. Moreover, we compared the ability of viruses to replicate in mammalian cells, as well as the receptor-binding preferences of AIV isolates. Genetic analyses were finally performed to identify the genetic relationships and amino acid substitutions between viral proteins during mammalian adaptation. Of the 24 AIV isolates tested, A/Mallard/South Korea/KNU2019-34/2019 (KNU19-34; H1N1) caused severe bodyweight loss and high mortality in mice. The virus replicated in the lungs, kidneys, and heart. Importantly, KNU19-34-infected ferrets showed high viral loads in both nasal washes and lungs. KNU19-34 replicated rapidly in A549 and bound preferentially to human like α2,6-linked sialic acids rather than to avian-like α2,3-linked sialic acids, similar to the pandemic A/California/04/2009 (H1N1) strain. Gene segments of KNU19-34 were distributed in Egypt and Asia lineages from 2015 to 2018, and the virus had several amino acid substitutions compared to H1N1 AIV isolates that were non-pathogenic in mice. Collectively, the data suggest that KNU19-34 has zoonotic potential and the possibility of new mutations responsible for mammalian adaptation.

Traditional Chinese medicine has unique advantages in preventing and treating COVID-19, and Fuzheng Jiedu decoction (FZJDD) was reported to be effective against COVID-19 in clinical trials. To investigate the potential mechanisms and material basis of FZJDD against SARS-CoV-2, we performed SARS-CoV-2 target protein inhibition analyses and a metabolite full spectrum analysis of FZJDD. Interestingly, FZJDD was found to block the binding of SARS-CoV-2 Spike protein with the receptor ACE2 and inhibit the activity of SARS-CoV-2 3CLpro. Moreover, FZJDD can regulate the TNF and the MAPK signaling pathway to inhibit the inflammatory response and alleviate the "cytokine storm". A total of 298 compounds were identified in FZJDD, among them, caffeic acid and octyl gallate were found to be the potential therapeutic agents of FZJDD. Importantly, FZJDD can broadly inhibit coronavirus infection, including SADS-CoV and porcine epidemic diarrhea virus (PEDV) live viruses, SARS-CoV, MERS-CoV, and SARS-CoV-2 mutant pseudotyped viruses, which might be ascribed to the broad-spectrum anti-coronavirus activity of caffeic acid and octyl gallate. In conclusion, this study reveals the mechanisms and material basis of FZJDD against SARS-CoV-2 and identifies the broad-spectrum anti-coronavirus activity of FZJDD for the first time. Our data provide empirical evidence for the development and application of FZJDD.

Virus-encoding RNA-dependent RNA polymerase (RdRp) is essential for genome replication and gene transcription of human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We previously identified the interaction between the catalytic subunit NSP12 of SARS-CoV-2 RdRp and the host protein CREB-regulated transcription coactivator 3 (CRTC3), a member of the CRTC family that regulates cyclic AMP response element-binding protein (CREB)-mediated transcriptional activation. Currently, the implication of CRTC3 in the pathogenesis of HCoVs is poorly understood. Herein, we demonstrated that CRTC3 attenuates RdRp activity and SARS-CoV-2 genome replication, therefore reducing the production of progeny viruses. The interaction of CRTC3 with NSP12 contributes to its inhibitory effect on RdRp activity. Furthermore, we expanded the suppressive effects of two other CRTC family members (CRTC1 and CRTC2) on the RdRp activities of lethal HCoVs, including SARS-CoV-2 and Middle East respiratory syndrome coronavirus (MERS-CoV), along with the CREB antagonization. Overall, our research suggests that CRTCs restrict the replication of HCoVs and are antagonized by CREB, which not only provides new insights into the replication regulation of HCoVs, but also offers important information for the development of anti-HCoV interventions.

Acute respiratory tract infections (ARTIs) are among the leading causes of morbidity and mortality in children worldwide. Human adenovirus (HAdV) infections are estimated to account for at least 5% of pediatric ARTIs. The circulated genotypes of HAdV and the correlation between genotype and clinical manifestations in Wuhan, China, before and after the complete relaxation of nonpharmaceutical interventions against severe acute respiratory syndrome coronavirus 2, remain unknown. Here, 101 HAdV strains were isolated from throat swab samples collected from hospitalized children with ARTIs who tested positive for HAdV nucleic acid. Of these, sixty-six strains from 2022 and 23 strains from 2023 were successfully genotyped and subjected to phylogenetic analysis based on the hexon, penton base, and fiber genes. Six genotypes, B3, C1, C2, C5, C104, and C108 were identified. HAdV-B3 (84.85%) was the most prevalent type in 2022, while HAdV-C (86.96%), including C1, C2, C108, and C104, was the most prevalent in 2023. These strains were phylogenetically related to strains from Japan, China, and the United States in recent years. When comparing clinical characteristics, pediatric patients infected with B3, C1, C2, C5, C104, or C108 exhibited similar clinical manifestations, primarily fever and cough, but varying interleukin (IL)-10 levels. In conclusion, from June 2022 to September 2023, the circulated genotypes of HAdV in Wuhan included B3, C1, C2, C108, C5, and C104. The endemic pattern of HAdV in Wuhan, China, shifted from species B as the dominant type in 2022 to species C in 2023.

On 30 January 2024, China announced the first human case of H10N5 influenza infection. Prior to this, human cases of H10N7 and H10N8 had been reported. It is now appropriate to re-examine the evolution and future epidemiological trends of the H10 and N5 subtypes of avian influenza viruses (AIVs). In this study, we analyzed the reassortment characteristics of the first human-derived H10N5 AIV (A/Zhejiang/ZJU01/2023), as well as the evolutionary dynamics of the wild bird-derived H10 and N5 subtypes of AIVs over the past decade. Our findings indicate that the human-derived H10N5 AIV exhibited low pathogenicity. A/bean_goose/Korea/KNU-10/2022(H10N7) and A/mallard/Novosibirsk_region/962k/2018(H12N5) were identified as the potential reassortment parents. The virus has existed since 2022 and several isolations have been reported in Bangladesh. Phylogenetic analysis showed that H10Ny and HxN5 AIVs in China are clustered differently based on the East Asian-Australian (eastern) and Central Asian-Indian (western) migratory flyways. The H10Ny and HxN5 AIV reassortant strains may cause human infections through accidental spillover. It is possible that another center of AIV evolution, mutation, and reassortment may be developing along the migratory flyways in northeastern Asia, distinct from Europe, the Americas, and China's Yangtze River Delta and Pearl River Delta, which should be closely monitored to ensure the safety of the public.