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Frontiers in Molecular Biosciences 2023Cryogenic electron microscopy (cryo-EM) and electron tomography (cryo-ET) have become a critical tool for studying viral particles. Cryo-EM has enhanced our... (Review)
Review
Cryogenic electron microscopy (cryo-EM) and electron tomography (cryo-ET) have become a critical tool for studying viral particles. Cryo-EM has enhanced our understanding of viral assembly and replication processes at a molecular resolution. Meanwhile, cryo-ET has been used to investigate how viruses attach to and invade host cells. These advances have significantly contributed to our knowledge of viral biology. Particularly, prompt elucidations of structures of the SARS-CoV-2 spike protein and its variants have directly impacted the development of vaccines and therapeutic measures. This review discusses the progress made by cryo-EM based technologies in comprehending the severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2), the virus responsible for the devastating global COVID-19 pandemic in 2020 with focus on the SARS-CoV-2 spike protein and the mechanisms of the virus entry and replication.
PubMed: 37867557
DOI: 10.3389/fmolb.2023.1252529 -
Bioorganic & Medicinal Chemistry Letters Aug 2023The protein that forms the inner shell of the HBV virus, known as the capsid core protein, plays a crucial role in allowing chronic HBV infections to persist. Studies...
The protein that forms the inner shell of the HBV virus, known as the capsid core protein, plays a crucial role in allowing chronic HBV infections to persist. Studies have shown that disrupting the assembly of the capsid can effectively combat the virus, and small molecule drugs that target the HBV capsid assembly modulator (CAM) process have been successful in clinical trials. Herein is described a distinct series of di-fluoro azepane CAMs with exceptional potency, pharmacokinetic, and solubility properties.
Topics: Capsid; Hepatitis B virus; Virus Assembly; Antiviral Agents; Capsid Proteins; Virus Replication
PubMed: 37247697
DOI: 10.1016/j.bmcl.2023.129350 -
PloS One 2023The M2-2 protein from the respiratory syncytial virus (RSV) is a 10 kDa protein expressed by the second ORF of the viral gene M2. During infection, M2-2 has been...
The M2-2 protein from the respiratory syncytial virus (RSV) is a 10 kDa protein expressed by the second ORF of the viral gene M2. During infection, M2-2 has been described as the polymerase cofactor responsible for promoting genome replication, which occurs by the induction of changes in interactions between the polymerase and other viral proteins at early stages of infection. Despite its well-explored role in the regulation of the polymerase activity, little has been made to investigate the relationship of M2-2 with cellular proteins. A previous report showed poor recruitment of M2-2 to viral structures, with the protein being mainly localized to the nucleus and cytoplasmic granules. To unravel which other functions M2-2 exerts during infection, we performed proteomic analysis of co-immunoprecipitated cellular partners, identifying enrichment of proteins involved with regulation of translation, protein folding and mRNA splicing. In approaches based on these data, we found that M2-2 expression downregulates eiF2α phosphorylation and inhibits both translation and stress granules assembly. Finally, we also verified that M2-2 is targeted for proteasome degradation, being localized to granules composed of defective ribosomal products at the cytoplasm. These results suggest that besides its functions in the replicative complex, M2-2 may exert additional functions to contribute to successful RSV infection.
Topics: Proteasome Endopeptidase Complex; Proteomics; Stress Granules; Viral Proteins; Respiratory Syncytial Virus, Human; Virus Replication
PubMed: 37490507
DOI: 10.1371/journal.pone.0289100 -
Microorganisms Jul 2023Despite the universal vaccination program, there are still regions and territories with a high prevalence of Hepatitis B Virus infection (HBV), such as the Amazon basin,...
Despite the universal vaccination program, there are still regions and territories with a high prevalence of Hepatitis B Virus infection (HBV), such as the Amazon basin, where several indigenous communities live. Additionally, Hepatitis Delta Virus (HDV) is a defective that requires the hepatitis B surface antigen (HBsAg) for the assembly and release of de novo viral particles. Therefore, hepatitis D could be the result of HBV/HDV coinfection or HDV superinfection in individuals with chronic hepatitis B. Among the high prevalence HDV populations are indigenous communities of America. This study aims to describe and characterize the frequency of HBV and HDV infection, viral genotypes and HBV immune escape mutants in indigenous populations from different regions of Colombia. The diagnosis of hepatitis B and hepatitis D was confirmed by serological markers. Moreover, the HBV and HDV genome were amplified by PCR and RT-PCR, respectively, and, subsequently, the phylogenetic analysis was performed. We characterized 47 cases of chronic hepatitis B, 1 case of reactivation and 2 cases of occult hepatitis B infection (OBI). Furthermore, a high prevalence of HDV infection was identified in the study population (29.33%, 22/75) and the circulation of several HBV genotypes and subgenotypes (F1b, F3, F4, and D). Interestingly, this is the first report of the HDV genotype I circulation in this country. These findings demonstrated that HBV and HDV infections are still public health problems in indigenous communities in Colombia.
PubMed: 37512911
DOI: 10.3390/microorganisms11071739 -
Frontiers in Cell and Developmental... 2023The novel coronavirus disease (COVID-19) continues to endanger human health, and its therapeutic drugs are under intensive research and development. Identifying the... (Review)
Review
The novel coronavirus disease (COVID-19) continues to endanger human health, and its therapeutic drugs are under intensive research and development. Identifying the efficacy and toxicity of drugs in animal models is helpful for further screening of effective medications, which is also a prerequisite for drugs to enter clinical trials. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invades host cells mainly by the S protein on its surface. After the SARS-CoV-2 RNA genome is injected into the cells, M protein will help assemble and release new viruses. RdRp is crucial for virus replication, assembly, and release of new virus particles. This review analyzes and discusses 26 anti-SARS-CoV-2 drugs based on their mechanism of action, effectiveness and safety in different animal models. We propose five drugs to be the most promising to enter the next stage of clinical trial research, thus providing a reference for future drug development.
PubMed: 37691829
DOI: 10.3389/fcell.2023.1238027 -
International Journal of Biological... Sep 2023As an important structural protein in virion morphogenesis, the matrix (M) protein of Newcastle disease virus (NDV) is demonstrated to be a nuclear-cytoplasmic... (Review)
Review
As an important structural protein in virion morphogenesis, the matrix (M) protein of Newcastle disease virus (NDV) is demonstrated to be a nuclear-cytoplasmic trafficking protein and plays essential roles in viral assembly and budding. In recent years, increasing lines of evidence have indicated that the M protein has obvious influence on the pathotypes of NDV, and the interaction of M protein with cellular proteins is also closely associated with the replication and pathogenicity of NDV. Although substantial progress has been made in the past 40 years towards understanding the structure and function of NDV M protein, the available information is scattered. Therefore, this review article summarizes and updates the research progress on the structural feature, virulence and pathotype correlation, and nucleocytoplasmic transport mechanism of NDV M protein, as well as the functions of M protein and cellular protein interactions in M's intracellular localization, viral RNA synthesis and transcription, viral protein synthesis, viral immune evasion, and viral budding and release, which will provide an in-depth understanding of the biological functions of M protein in the replication and pathogenesis of NDV, and also contribute to the development of effective antiviral strategies aiming at blocking the early or late steps of NDV lifecycles.
Topics: Animals; Humans; Newcastle disease virus; Newcastle Disease; Virus Replication; Chickens; Virus Assembly
PubMed: 37532184
DOI: 10.1016/j.ijbiomac.2023.126089 -
Pathogens (Basel, Switzerland) Jan 2024Influenza virus has been one of the most prevalent and researched viruses globally. Consequently, there is ample information available about influenza virus lifecycle... (Review)
Review
Influenza virus has been one of the most prevalent and researched viruses globally. Consequently, there is ample information available about influenza virus lifecycle and pathogenesis. However, there is plenty yet to be known about the determinants of influenza virus pathogenesis and disease severity. Influenza virus exploits host factors to promote each step of its lifecycle. In turn, the host deploys antiviral or restriction factors that inhibit or restrict the influenza virus lifecycle at each of those steps. Two broad categories of host restriction factors can exist in virus-infected cells: (1) encoded by the interferon-stimulated genes (ISGs) and (2) encoded by the constitutively expressed genes that are not stimulated by interferons (non-ISGs). There are hundreds of ISGs known, and many, e.g., Mx, IFITMs, and TRIMs, have been characterized to restrict influenza virus infection at different stages of its lifecycle by (1) blocking viral entry or progeny release, (2) sequestering or degrading viral components and interfering with viral synthesis and assembly, or (3) bolstering host innate defenses. Also, many non-ISGs, e.g., cyclophilins, ncRNAs, and HDACs, have been identified and characterized to restrict influenza virus infection at different lifecycle stages by similar mechanisms. This review provides an overview of those ISGs and non-ISGs and how the influenza virus escapes the restriction imposed by them and aims to improve our understanding of the host restriction mechanisms of the influenza virus.
PubMed: 38392865
DOI: 10.3390/pathogens13020127 -
Genes Jan 2024Porcine epidemic diarrhea (PED) virus (PEDV) is one of the main pathogens causing diarrhea in piglets and fattening pigs. The clinical signs of PED are vomiting, acute... (Review)
Review
Porcine epidemic diarrhea (PED) virus (PEDV) is one of the main pathogens causing diarrhea in piglets and fattening pigs. The clinical signs of PED are vomiting, acute diarrhea, dehydration, and mortality resulting in significant economic losses and becoming a major challenge in the pig industry. PEDV possesses various crucial structural and functional proteins, which play important roles in viral structure, infection, replication, assembly, and release, as well as in escaping host innate immunity. Over the past few years, there has been progress in the study of PEDV pathogenesis, revealing the crucial role of the interaction between PEDV viral proteins and host cytokines in PEDV infection. At present, the main control measure against PEDV is vaccine immunization of sows, but the protective effect for emerging virus strains is still insufficient, and there is no ideal safe and efficient vaccine. Although scientists have persistently delved their research into the intricate structure and functionalities of the PEDV genome and viral proteins for years, the pathogenic mechanism of PEDV remains incompletely elucidated. Here, we focus on reviewing the research progress of PEDV structural and nonstructural proteins to facilitate the understanding of biological processes such as PEDV infection and pathogenesis.
Topics: Animals; Swine; Female; Porcine epidemic diarrhea virus; Coronavirus Infections; Viral Proteins; Diarrhea; Vaccines
PubMed: 38397155
DOI: 10.3390/genes15020165 -
Trends in Genetics : TIG May 2024Positive-strand RNA [(+)RNA] viruses include pandemic SARS-CoV-2, tumor-inducing hepatitis C virus, debilitating chikungunya virus (CHIKV), lethal encephalitis viruses,... (Review)
Review
Positive-strand RNA [(+)RNA] viruses include pandemic SARS-CoV-2, tumor-inducing hepatitis C virus, debilitating chikungunya virus (CHIKV), lethal encephalitis viruses, and many other major pathogens. (+)RNA viruses replicate their RNA genomes in virus-induced replication organelles (ROs) that also evolve new viral species and variants by recombination and mutation and are crucial virus control targets. Recent cryo-electron microscopy (cryo-EM) reveals that viral RNA replication proteins form striking ringed 'crowns' at RO vesicle junctions with the cytosol. These crowns direct RO vesicle formation, viral (-)RNA and (+)RNA synthesis and capping, innate immune escape, and transfer of progeny (+)RNA genomes into translation and encapsidation. Ongoing studies are illuminating crown assembly, sequential functions, host factor interactions, etc., with significant implications for control and beneficial uses of viruses.
PubMed: 38724328
DOI: 10.1016/j.tig.2024.04.003 -
Journal of Molecular Biology Dec 2023Bacteriophages of Borrelia burgdorferi are a biologically important but under-investigated feature of the Lyme disease-causing spirochete. No virulent borrelial viruses...
Bacteriophages of Borrelia burgdorferi are a biologically important but under-investigated feature of the Lyme disease-causing spirochete. No virulent borrelial viruses have been identified, but all B. burgdorferi isolates carry a prophage φBB1 as resident circular plasmids. Like its host, the φBB1 phage is quite distinctive and shares little sequence similarity with other known bacteriophages. We expressed φBB1 head morphogenesis proteins in Escherichia coli which resulted in assembly of homogeneous prolate procapsid structures and used cryo-electron microscopy to determine the three-dimensional structure of these particles. The φBB1 procapsids consist of 415 copies of the major capsid protein and an equal combined number of three homologous capsid decoration proteins that form trimeric knobs on the outside of the particle. One of the end vertices of the particle is occupied by a portal assembled from twelve copies of the portal protein. The φBB1 scaffolding protein is entirely α-helical and has an elongated shape with a small globular domain in the middle. Within the tubular section of the procapsid, the internal scaffold is built of stacked rings, each composed of 32 scaffolding protein molecules, which run in opposite directions from both caps with a heterogeneous part in the middle. Inside the portal-containing cap, the scaffold is organized asymmetrically with ten scaffolding protein molecules bound to the portal. The φBB1 procapsid structure provides better insight into the vast structural diversity of bacteriophages and presents clues of how elongated bacteriophage particles might be assembled.
Topics: Bacteriophages; Borrelia; Capsid; Capsid Proteins; Cryoelectron Microscopy; Virus Assembly
PubMed: 37866476
DOI: 10.1016/j.jmb.2023.168323