MedNexus
2025年 · 第07卷第01期
MedNexus
Antibiotic-resistant bacterial pathogens pose substantial biosafety and health hazards, leading to millions of deaths each year. The evolution of bacterial virulence factors is mainly propelled by horizontal gene transfer (HGT). In addition to traditional antibiotics, antimicrobial strategies targeting biofilm-related virulence factors and quorum sensing (QS)-related virulence factors can effectively restrain drug-resistant bacteria. Future anti-virulence strategies, encompassing natural drugs, antibiotic resistance inhibitors, monoclonal antibodies (mAbs), and vaccines, are in the development pipeline. Consequently, by disrupting virulence factors, these drugs can eliminate the ability of bacterial pathogens to cause disease. In conclusion, this Perspective comprehensively summarizes current anti-bacterial virulence factor strategies and prospects for future cutting-edge approaches, which may address the issues of antibacterial resistance and curtail the spread of pathogens in the future.
Hepatitis B virus (HBV) is categorized into ten distinct genotypes (A - J), with over 40 subgenotypes identified to date. HBV genotype I (HBV-I), an inter-genotypic recombinant, has emerged during the evolution history of HBV. In this study, we conducted a comprehensive analysis of the genomic characteristics of HBV-I in China, employing a range of methodologies including phylogenetic analysis, nucleotide homology assessment, examination of amino acid substitutions within the PreS/S region, recombination detection, and evolutionary analysis. The 12 HBV-I strains, classified into subgenotype I1 and predominantly serotype adw2 (with one exception being ayw1) were preliminarily divided into two clusters based on homology analysis. A higher substitution rate was observed in the antigenic loop of the hepatitis B surface antigen (HBsAg), and the potential immune-escape mutations were found. Molecular clock analysis estimated an average evolutionary rate for HBV-I between 1.17 exp(-4) and 1.61 exp(-4) substitutions/site/year, with the most recent common ancestor traced back to between year 1740 and 1774. The epidemiological surveillance and genomic characterization of HBV genotype I are significant for informing future strategies in the prevention and control of hepatitis B.
To better understand the epidemiological characteristics of human adenovirus (HAdV) infections in China during and after the coronavirus disease 2019 (COVID-19) pandemic, respiratory specimens were collected from 17,562 enrolled patients with acute respiratory infections (ARIs) in 14 sentinel surveillance provinces during 2020–2023. Eight common respiratory viruses were detected using commercially available nucleic acid detection kits. HAdV-positive cases were statistically analyzed for detection rates, geographic distribution, seasonal patterns, demographic characteristics, and co-infection status. The results of this study showed that the overall HAdV detection rate was 5.09 % (894/17,562) during 2020–2023, with a gradual decrease in the annual detection rate from 6.66 % in 2020 to 3.89 % in 2022 and a rebound in 2023 (5.19 %). The overall HAdV detection rate was significantly higher in the southern region (6.15 %) than in the northern region (4.76 %) (P < 0.001). The median age of patients with HAdV infection was 3 years, with infants aged 0–2 years accounting for the majority (41.39 %). HAdV-positive cases were detected throughout the year, with no clear seasonal pattern, and the HAdV epidemic in China during 2020–2023 may have been driven primarily by the virus infection in the southern region. Co-infections were frequent in HAdV-positive cases (overall rate: 36.01 %), primarily consisting of dual infections (79.28 %), with human rhinovirus and human respiratory syncytial virus being the most common coinfecting pathogens. In conclusion, this study suggested the significant regional and temporal variation in HAdV detection rate in China during 2020–2023, and thus ongoing surveillance should be conducted to elucidate the epidemiological dynamics of HAdV infections.
In the past two decades, highly pathogenic coronaviruses (CoVs), such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have constituted a grave threat to human health. Broad-spectrum anti-CoV fusion inhibitors that target the heptapeptide repeat (HR) region within the S2 subunit of SARS-CoV-2 spike (S) protein exhibit inhibitory activity against various CoVs. In this study, we employed EK1, a fusion inhibitor previously characterized for its broad spectrum and potent antiviral activity, as a scaffold for computational design to enhance its inhibitory potential using the Rosetta software suite. We designed EK1 variants and synthesized two N-terminally extended EK1 elongation peptides, and evaluated their inhibitory activity. The results revealed that the designed peptides enhanced inhibitory activity against diverse CoVs. Structural analysis and molecular dynamics simulations demonstrated that EK1 variants formed more robust interactions with HR1 of SARS-CoV-2, and these interactions were conserved across different CoVs. These findings underscore the utility of computational approaches in optimizing therapeutic peptides.
It is crucial to understand how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sheds in human respiratory tract, but this question remains elusive due to technical limitations. In this study, we integrated published human metagenomic data of SARS-CoV-2 and developed a novel algorithm named RedeCoronaVS to systematically dissect SARS-CoV-2 shedding modes with single-cell data as reference. Our study demonstrated that SARS-CoV-2 particles were the dominant mode of viral shedding in the very early infection phase (≤24 h after hospitalization). Within the first week after hospitalization, SARS-CoV-2 replicas within host cells dominated viral shedding alongside viral particles. One week later, viral fragments became the dominant mode in patients with mild or moderate symptoms, while viral replicas still dominated in some patients with severe symptoms. In addition to epithelial cells, SARS-CoV-2 replicas in neutrophils, macrophages, and plasma cells also played significant roles and were associated with sampling time and disease severity.
Treatment of mpox virus (MPXV) is crucial for public health. However, research into drugs for MPXV has fallen behind, particularly in anticipation of sudden outbreaks. This study aimed to identify new inhibitors of Orthopoxvirus using artificial intelligence (AI)-assisted methods. We explored AlphaFold v2.0 to simulate the F13 protein structures of MPXV, vaccinia virus (VACV), and variola virus (VARV). Utilizing MOE2019 software, we identified amino acid binding sites suitable for small molecule docking, focusing on a phosphodiesterase active site pocket in F13. Our efforts led to the identification of JCS-2022, a promising new inhibitor that exhibited docking similarities with the known anti-poxvirus drug tecovirimat. In vitro experiments demonstrated that JCS-2022 had a half maximal effective concentration (EC50) of 0.05430 μmol/L (μM), comparable to tecovirimat’s EC50 of 0.04794 μM. At a dosage of 1.6 μM, JCS-2022 significantly reduced VACV plaque size, indicating effective inhibition of extracellular enveloped virus (EEV) formation. Immunofluorescence analysis confirmed a reduction in VACV-induced actin tail formation. Our findings suggest that JCS-2022 is a strong candidate for development as a small molecule inhibitor against Orthopoxvirus, highlighting the potential of AI-assisted methods in accelerating drug discovery for infectious diseases.
Flaviviruses are zoonotic pathogens transmitted by infected mosquitoes and ticks, posing a persistent threat to global health. These infections lead to a diverse spectrum of diseases, broadly classified into two phenotypes: systemic hemorrhagic conditions, such as dengue and yellow fever, and neurological complications, exemplified by West Nile virus (WNV) and Zika virus (ZIKV) infections. The interactions between flaviviruses and human host cells are pivotal to the viral lifecycle and the activation of host immunity. Investigating the molecular mechanisms of flavivirus-host interactions is essential for understanding viral pathogenesis, managing epidemics, optimizing therapeutic strategies, and enhancing public health security. Flaviviruses utilize various strategies to evade the host immune system, and understanding these mechanisms is critical for the development of antiviral therapeutics. This study employs bibliometric methods, leveraging CiteSpace and VOSviewer software, to analyze literature on flavivirus-host interactions and the associated immune responses. By examining developmental trends and pivotal research areas, this analysis provides insights and guidance for future studies in this field.
Coronaviruses can infect humans, mammals, and birds, leading to respiratory, gastrointestinal, and neurological diseases. These viruses are significant zoonotic pathogens with nine known types capable of infecting humans. The coronavirus genome, approximately 30 kb in size, is the largest known ribonucleic acid (RNA) virus genome, and its complexity makes assembly and manipulation time-consuming and labor-intensive. Reverse genetic systems are widely used to engineer recombinant viruses that can be adapted at Biosafety Level 2 (BSL-2) for studying viral gene function, replication, pathogenesis, vaccines, and therapeutics. The infectious clones, which enabled the recovery of various viruses after DNA recombinant technology, were indispensable tools for the reverse genetics of viruses. Various techniques for constructing infectious clones of human coronaviruses (HCoV) have been developed, encompassing methods such as vaccinia virus vectors method, in vitro ligation, bacterial artificial chromosome systems, yeast artificial chromosome systems, circular polymerase extension reaction, and the recently reported infectious sub-genomic amplicons technology. This review summarizes the status of various techniques for constructing infectious clones of human coronaviruses and related applications.
Over the past decades, oncolytic viruses have emerged as prominent therapeutic agents with significant potential for anticancer treatment. Enteroviruses (EVs) have garnered particular attention due to their specific tropism for various types of tumor cells. The rapid advancement of reverse genetics has enabled its application in the genetic modification of enteroviruses and the investigation of viral infection mechanisms. The utilization of reverse genetics has significantly enhanced our understanding of the infection mechanisms and pathogenesis of enteroviruses, while concurrently facilitating the development of translational therapies related to these viruses. In this review, we summarize the progress in the application of reverse genetics to oncolytic enteroviruses and their potential clinical applications. Specifically, we discuss the characteristics of EVs and the applications of reverse genetics in EV research. We review the utilization of reverse genetics in mechanistic investigations of EVs and in exploring the oncolytic potential of EVs. Further, we discuss the oncolytic roles of specific EVs including EV-A71, coxsackievirus B3 (CV-B3), echovirus 7 (Echo-7), CV-A21, and poliovirus. Our review highlights the advances in oncolytic therapy utilizing EVs with specific tumor tropism, which holds significant potential for immunotherapy.
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