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ELife Mar 2024Marburg virus (MARV) is one of the filovirus species that cause deadly hemorrhagic fever in humans, with mortality rates up to 90%. Neutralizing antibodies represent...
Marburg virus (MARV) is one of the filovirus species that cause deadly hemorrhagic fever in humans, with mortality rates up to 90%. Neutralizing antibodies represent ideal candidates to prevent or treat virus disease. However, no antibody has been approved for MARV treatment to date. In this study, we identified a novel human antibody named AF-03 that targeted MARV glycoprotein (GP). AF-03 possessed a high binding affinity to MARV GP and showed neutralizing and protective activities against the pseudotyped MARV in vitro and in vivo. Epitope identification, including molecular docking and experiment-based analysis of mutated species, revealed that AF-03 recognized the Niemann-Pick C1 (NPC1) binding domain within GP1. Interestingly, we found the neutralizing activity of AF-03 to pseudotyped Ebola viruses (EBOV, SUDV, and BDBV) harboring cleaved GP instead of full-length GP. Furthermore, NPC2-fused AF-03 exhibited neutralizing activity to several filovirus species and EBOV mutants via binding to CI-MPR. In conclusion, this work demonstrates that AF-03 represents a promising therapeutic cargo for filovirus-caused disease.
Topics: Humans; Marburgvirus; Antibodies, Viral; Molecular Docking Simulation; Glycoproteins; Hemorrhagic Fever, Ebola; Ebolavirus
PubMed: 38526940
DOI: 10.7554/eLife.91181 -
Microbial Genomics Sep 2023Respiratory syncytial virus (RSV), or human orthopneumovirus, is a major cause of acute lower respiratory infection (ALRI), particularly in young children, causing...
Respiratory syncytial virus (RSV), or human orthopneumovirus, is a major cause of acute lower respiratory infection (ALRI), particularly in young children, causing significant morbidity and mortality. We used pathogen genomics to characterize the population structure and genetic signatures of RSV isolates circulating in children in New South Wales between 2016 and 2018 and to understand the evolutionary dynamics of these strains in the context of publicly available RSV genomes from the region and globally. Whole-genome phylogenetic analysis demonstrated the co-circulation of a few major RSV clades in the paediatric population from Sydney. The whole-genome-based genotypes A23 (RSV-A ON1-like genotype) and B6 (RSV-B BA9-like genotype) were the predominant RSV-A and RSV-B genotypes circulating during the study period, respectively. These genotypes were characterized with high levels of diversity of predicted N- and O-linked glycosylation patterns in both the G and F glycoproteins. Interestingly, a novel 72-nucleotide triplication in the sequence that corresponds to the C-terminal region of the gene was identified in four of the A23 genotype sequenced in this study. Consistently, the population dynamics analysis demonstrated a continuous increase in the effective population size of A23 and B6 genotypes globally. Further investigations including functional mapping of mutations and identifying the impact of sequence changes on virus fitness are highly required. This study highlights the potential impact of an integrated approach that uses WG-based phylogeny and studying selective pressure events in understanding the emergence and dissemination of RSV genotypes.
Topics: Child; Humans; Child, Preschool; Phylogeny; Genomics; Respiratory Syncytial Viruses; Genotype; Australia; Respiratory Tract Infections
PubMed: 37656160
DOI: 10.1099/mgen.0.001095 -
The American Journal of Pathology Dec 2023The pathophysiology of long-recognized hematologic abnormalities in Ebolavirus (EBOV) disease (EVD) is unknown. From limited human sampling (of peripheral blood), it has...
The pathophysiology of long-recognized hematologic abnormalities in Ebolavirus (EBOV) disease (EVD) is unknown. From limited human sampling (of peripheral blood), it has been postulated that emergency hematopoiesis plays a role in severe EVD, but the systematic characterization of the bone marrow (BM) has not occurred in human disease or in nonhuman primate models. In a lethal rhesus macaque model of EVD, 18 sternal BM samples exposed to the Kikwit strain of EBOV were compared to those from uninfected controls (n = 3). Immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy showed that EBOV infects BM monocytes/macrophages and megakaryocytes. EBOV exposure was associated with severe BM hypocellularity, including depletion of myeloid, erythroid, and megakaryocyte hematopoietic cells. These depletions were negatively correlated with cell proliferation (Ki67 expression) and were not associated with BM apoptosis during disease progression. In EBOV-infected rhesus macaques with terminal disease, BM showed marked hemophagocytosis, megakaryocyte emperipolesis, and the release of immature hematopoietic cells into the sinusoids. Collectively, these data demonstrate not only direct EBOV infection of BM monocytes/macrophages and megakaryocytes but also that disease progression is associated with hematopoietic failure, notably in peripheral cytopenia. These findings inform current pathophysiologic unknowns and suggest a crucial role for BM dysfunction and/or failure, including emergency hematopoiesis, as part of the natural history of severe human disease.
Topics: Animals; Humans; Ebolavirus; Macaca mulatta; Hemorrhagic Fever, Ebola; Bone Marrow; Disease Progression
PubMed: 37689386
DOI: 10.1016/j.ajpath.2023.08.010 -
Virologica Sinica Dec 2023As one of the deadliest viruses, Ebola virus (EBOV) causes lethal hemorrhagic fevers in humans and nonhuman primates. The suppression of innate immunity leads to robust...
As one of the deadliest viruses, Ebola virus (EBOV) causes lethal hemorrhagic fevers in humans and nonhuman primates. The suppression of innate immunity leads to robust systemic virus replication of EBOV, leading to enhanced transmission. However, the mechanism of EBOV-host interaction is not fully understood. Here, we identified multiple dysregulated genes in early stage of EBOV infection through transcriptomic analysis, which are highly clustered to Jak-STAT signaling. EBOV VP35 and VP30 were found to inhibit type I interferon (IFN) signaling. Moreover, exogenous expression of VP35 blocks the phosphorylation of endogenous STAT1, and suppresses nuclear translocation of STAT1. Using serial truncated mutations of VP35, N-terminal 1-220 amino acid residues of VP35 were identified to be essential for blocking on type I IFN signaling. Remarkably, VP35 of EBOV suppresses type I IFN signaling more efficiently than those of Bundibugyo virus (BDBV) and Marburg virus (MARV), resulting in stable replication to facilitate the pathogenesis. Altogether, this study enriches understanding on EBOV evasion of innate immune response, and provides insights into the interplay between filoviruses and host.
Topics: Humans; Animals; Viral Proteins; Hemorrhagic Fever, Ebola; Viral Regulatory and Accessory Proteins; Immunity, Innate; Ebolavirus; Virus Replication; Interferon Type I
PubMed: 37839549
DOI: 10.1016/j.virs.2023.10.004 -
European Journal of Pharmaceutical... Dec 2023Chronic respiratory diseases and infections are among the largest contributors to death globally, many of which still have no cure, including chronic obstructive... (Review)
Review
Chronic respiratory diseases and infections are among the largest contributors to death globally, many of which still have no cure, including chronic obstructive pulmonary disorder, idiopathic pulmonary fibrosis, and respiratory syncytial virus among others. Pulmonary therapeutics afford untapped potential for treating lung infection and disease through direct delivery to the site of action. However, the ability to innovate new therapeutic paradigms for respiratory diseases will rely on modeling the human lung microenvironment and including key cellular interactions that drive disease. One key feature of the lung microenvironment is the air-liquid interface (ALI). ALI interface modeling techniques, using cell-culture inserts, organoids, microfluidics, and precision lung slices (PCLS), are rapidly developing; however, one major component of these models is lacking-innate immune cell populations. Macrophages, neutrophils, and dendritic cells, among others, represent key lung cell populations, acting as the first responders during lung infection or injury. Innate immune cells respond to and modulate stromal cells and bridge the gap between the innate and adaptive immune system, controlling the bodies response to foreign pathogens and debris. In this article, we review the current state of ALI culture systems with a focus on innate immune cells and suggest ways to build on current models to add complexity and relevant immune cell populations.
Topics: Humans; Lung; Pulmonary Disease, Chronic Obstructive; Macrophages; Respiratory Syncytial Virus, Human; Immunity; Immunity, Innate
PubMed: 37770004
DOI: 10.1016/j.ejps.2023.106596 -
Human Vaccines & Immunotherapeutics Dec 2023Human metapneumovirus (HMPV) is one of the main pathogens causing severe respiratory infections in children, as a common cause of immunodeficiency-related deaths in...
Human metapneumovirus (HMPV) is one of the main pathogens causing severe respiratory infections in children, as a common cause of immunodeficiency-related deaths in children and elderly individuals, the prevalence of HMPV has been showing an increasing trend during the last years. However, no vaccines or effective treatment plans are available currently. In this present, based on candidate proteins highly associated with viral virulence and has promising protective potential, we screened for immunodominant cytotoxic T cells, helper T cells, and Linear B-cell epitopes from the most promising candidate Fusion protein, together with G, SH, M, and M2. All epitopes were predicted to have strong antigenicity by Vaxijen and pose no potential toxicity, allergenicity, or hormonology to human proteins by Toxinpred, Allerpred, and Blast analysis, meanwhile, high conservancy is demanded to cover different subtypes. adjuvants β-defensin II and Pam2Cys was attached with EAAAK linkers to improve vaccine's efficiency. Then, calculation of physicochemical properties proved the protein vaccine as a product can stably exist in the human body. Besides, we assessed the docking between the vaccine and immune receptors to evaluate its ability to stimulate immune responses, and the dynamic simulation further confirmed that the vaccine can tightly bind with immune receptors, which approved that the construction has the potential to induce strong humoral and cellular immune response. Finally, the vaccine was constructed into a multi-epitope mRNA vaccine, the immune simulations suggest that this is a vaccine candidate for controlling HMPV infection.
Topics: Child; Humans; Aged; Metapneumovirus; mRNA Vaccines; Epitopes, B-Lymphocyte; T-Lymphocytes, Cytotoxic; Respiratory Tract Infections; Epitopes, T-Lymphocyte; Computational Biology; Vaccines, Subunit
PubMed: 38172569
DOI: 10.1080/21645515.2023.2293300 -
Journal of Virology Feb 2024Nipah virus (NiV) and Hendra virus (HeV) are pathogenic paramyxoviruses that cause mild-to-severe disease in humans. As members of the genus, NiV and HeV use an...
Nipah virus (NiV) and Hendra virus (HeV) are pathogenic paramyxoviruses that cause mild-to-severe disease in humans. As members of the genus, NiV and HeV use an attachment (G) glycoprotein and a class I fusion (F) glycoprotein to invade host cells. The F protein rearranges from a metastable prefusion form to an extended postfusion form to facilitate host cell entry. Prefusion NiV F elicits higher neutralizing antibody titers than postfusion NiV F, indicating that stabilization of prefusion F may aid vaccine development. A combination of amino acid substitutions (L104C/I114C, L172F, and S191P) is known to stabilize NiV F in its prefusion conformation, although the extent to which substitutions transfer to other henipavirus F proteins is not known. Here, we perform biophysical and structural studies to investigate the mechanism of prefusion stabilization in F proteins from three henipaviruses: NiV, HeV, and Langya virus (LayV). Three known stabilizing substitutions from NiV F transfer to HeV F and exert similar structural and functional effects. One engineered disulfide bond, located near the fusion peptide, is sufficient to stabilize the prefusion conformations of both HeV F and LayV F. Although LayV F shares low overall sequence identity with NiV F and HeV F, the region around the fusion peptide exhibits high sequence conservation across all henipaviruses. Our findings indicate that substitutions targeting this site of conformational change might be applicable to prefusion stabilization of other henipavirus F proteins and support the use of NiV as a prototypical pathogen for henipavirus vaccine antigen design.IMPORTANCEPathogenic henipaviruses such as Nipah virus (NiV) and Hendra virus (HeV) cause respiratory symptoms, with severe cases resulting in encephalitis, seizures, and coma. The work described here shows that the NiV and HeV fusion (F) proteins share common structural features with the F protein from an emerging henipavirus Langya virus (LayV). Sequence alignment alone was sufficient to predict which known prefusion-stabilizing amino acid substitutions from NiV F would stabilize the prefusion conformations of HeV F and LayV F. This work also reveals an unexpected oligomeric interface shared by prefusion HeV F and NiV F. Together, these advances lay a foundation for future antigen design targeting henipavirus F proteins. In this way, Nipah virus can serve as a prototypical pathogen for the development of protective vaccines and monoclonal antibodies to prepare for potential henipavirus outbreaks.
Topics: Humans; Glycoproteins; Hendra Virus; Henipavirus; Henipavirus Infections; Nipah Virus; Peptides; Viral Fusion Proteins; Viral Proteins
PubMed: 38214525
DOI: 10.1128/jvi.01372-23 -
The Journal of Infectious Diseases Nov 2023Vesicular stomatitis virus-Ebola virus (VSV-EBOV) vaccine has been successfully used in ring vaccination approaches during EBOV disease outbreaks demonstrating its...
Vesicular stomatitis virus-Ebola virus (VSV-EBOV) vaccine has been successfully used in ring vaccination approaches during EBOV disease outbreaks demonstrating its general benefit in short-term prophylactic vaccination, but actual proof of its benefit in true postexposure prophylaxis (PEP) for humans is missing. Animal studies have indicated PEP efficacy when VSV-EBOV was used within hours of lethal EBOV challenge. Here, we used a lower EBOV challenge dose and a combined intravenous and intramuscular VSV-EBOV administration to improve PEP efficacy in the rhesus macaque model. VSV-EBOV treatment 1 hour after EBOV challenge resulted in delayed disease progression but little benefit in outcome. Thus, we could not confirm previous results indicating questionable benefit of VSV-EBOV for EBOV PEP in a nonhuman primate model.
Topics: Humans; Animals; Ebolavirus; Macaca mulatta; Hemorrhagic Fever, Ebola; Vesiculovirus; Vesicular stomatitis Indiana virus; Ebola Vaccines
PubMed: 37474155
DOI: 10.1093/infdis/jiad280 -
Virus Genes Aug 2023Human metapneumovirus (HMPV) is a major pathogen of acute respiratory tract infections (ARTIs) in children. Whole genome sequence analyses could help understand the...
Human metapneumovirus (HMPV) is a major pathogen of acute respiratory tract infections (ARTIs) in children. Whole genome sequence analyses could help understand the evolution and transmission events of this virus. In this study, we sequenced HMPV whole genomes to improve the identification of molecular epidemiology in Beijing, China. Nasopharyngeal aspirates of hospitalized children aged < 14 years old with ARTIs were screened for HMPV infection using qPCR. Fourteen pairs of overlapping primers were used to amplify whole genome sequences of HMPV from positive samples with high viral loads. The epidemiology of HMPV was analysed and 27 HMPV whole genome sequences were obtained. Sequence identity and the positional entropy analyses showed that most regions of HMPV genome are conserved, whereas the G gene contained many variations. Phylogenetic analysis identified 25 HMPV sequences that belonged to a newly defined subtype A2b1; G gene sequences from 24 of these contained a 111-nucleotide duplication. HMPV is an important respiratory pathogen in paediatric patients. The new subtype A2b1 with a 111-nucleotide duplication has become predominate in Beijing, China.
Topics: Whole Genome Sequencing; Metapneumovirus; Evolution, Molecular; Humans; Male; Female; Infant; Child, Preschool; Child; Adolescent; Paramyxoviridae Infections; Phylogeny
PubMed: 37150780
DOI: 10.1007/s11262-023-02001-2 -
International Journal of Infectious... Jan 2024This meta-analysis aimed to assess the prevalence of respiratory viruses among children under the special conditions of the COVID-19 pandemic. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This meta-analysis aimed to assess the prevalence of respiratory viruses among children under the special conditions of the COVID-19 pandemic.
METHODS
Five databases were systematically searched to assess the pooled prevalence of various respiratory viruses in different age groups, regions, seasons, and in patients with and without confirmed SARS-CoV-2 coinfection. Moreover, we looked at the virus distribution in the first and second half of the pandemic and countries with distinct economic status. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed, and the systematic review was registered on PROSPERO (CRD42022379297).
RESULTS
Enterovirus/rhinovirus and human respiratory syncytial virus (HRSV) were the most prevalent pathogens among children. The prevalence of HRSV increased in the second half of the pandemic. The prevailing viruses vary according to the SARS-CoV-2-coinfection status, season, region, and country´s economic status.
CONCLUSION
This meta-analysis shows the epidemiology of respiratory viruses other than SARS-CoV-2 in children aged 0 to 12 years during the COVID-19 pandemic. Because major events, such as a pandemic, can alter epidemiology patterns, it is important to know them to improve health education measures, develop vaccines and medicines for vulnerable groups, as a guide for prevention strategies, and help with clinical decisions.
Topics: Child; Humans; SARS-CoV-2; COVID-19; Pandemics; Coinfection; Rhinovirus; Enterovirus Infections; Respiratory Syncytial Virus, Human; Respiratory Tract Infections
PubMed: 37951460
DOI: 10.1016/j.ijid.2023.10.023