ABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
Monkeypox (Mpox), a zoonotic illness triggered by the monkeypox virus (MPXV), poses a significant threat since it may be transmitted and has no cure. This work introduces a computational method to predict Protein-Protein Interactions (PPIs) during MPXV infection. The objective is to discover prospective drug targets and repurpose current potential Food and Drug Administration (FDA) drugs for therapeutic purposes. In this work, ensemble features, comprising 2-5 node graphlet attributes and protein composition-based features are utilized for Deep Learning (DL) models to predict PPIs. The technique that is used here demonstrated an excellent prediction performance for PPI on both the Human Integrated Protein-Protein Interaction Reference (HIPPIE) and MPXV-Human PPI datasets. In addition, the human protein targets for MPXV have been identified accurately along with the detection of possible therapeutic targets. Furthermore, the validation process included conducting docking research studies on potential FDA drugs like Nicotinamide Adenine Dinucleotide and Hydrogen (NADH), Fostamatinib, Glutamic acid, Cannabidiol, Copper, and Zinc in DrugBank identified via research on drug repurposing and the Drug Consensus Score (DCS) for MPXV. This has been achieved by employing the primary crystal structures of MPXV, which are now accessible. The docking study is also supported by Molecular Dynamics (MD) simulation. The results of our study emphasize the effectiveness of using ensemble feature-based PPI prediction to understand the molecular processes involved in viral infection and to aid in the development of repurposed drugs for emerging infectious diseases such as, but not limited to, Mpox. The source code and link to data used in this work is available at: https://github.com/CMATERJU-BIOINFO/In-Silico-Drug-Repurposing-Methodology-To-Suggest-Therapies-For-Emerging-Threats-like-Mpox .
Subject(s)
Antiviral Agents , Drug Repositioning , Drug Repositioning/methods , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Computational Biology/methods , Host-Pathogen Interactions/drug effects , Molecular Docking Simulation , Monkeypox virus/drug effects , Monkeypox virus/metabolism , Computer Simulation , Protein Interaction Maps/drug effectsABSTRACT
Multiple omics analyzes of Vaccinia virus (VACV) infection have defined molecular characteristics of poxvirus biology. However, little is known about the monkeypox (mpox) virus (MPXV) in humans, which has a different disease manifestation despite its high sequence similarity to VACV. Here, we perform an in-depth multi-omics analysis of the transcriptome, proteome, and phosphoproteome signatures of MPXV-infected primary human fibroblasts to gain insights into the virus-host interplay. In addition to expected perturbations of immune-related pathways, we uncover regulation of the HIPPO and TGF-ß pathways. We identify dynamic phosphorylation of both host and viral proteins, which suggests that MAPKs are key regulators of differential phosphorylation in MPXV-infected cells. Among the viral proteins, we find dynamic phosphorylation of H5 that influenced the binding of H5 to dsDNA. Our extensive dataset highlights signaling events and hotspots perturbed by MPXV, extending the current knowledge on poxviruses. We use integrated pathway analysis and drug-target prediction approaches to identify potential drug targets that affect virus growth. Functionally, we exemplify the utility of this approach by identifying inhibitors of MTOR, CHUK/IKBKB, and splicing factor kinases with potent antiviral efficacy against MPXV and VACV.
Subject(s)
Fibroblasts , Monkeypox virus , Mpox (monkeypox) , Viral Proteins , Humans , Monkeypox virus/genetics , Phosphorylation , Mpox (monkeypox)/virology , Mpox (monkeypox)/metabolism , Fibroblasts/virology , Fibroblasts/metabolism , Viral Proteins/metabolism , Viral Proteins/genetics , Proteome/metabolism , Host-Pathogen Interactions , Signal Transduction , Proteomics/methods , Transcriptome , Antiviral Agents/pharmacology , MultiomicsABSTRACT
Monkeypox virus (MPXV) is an emerging zoonotic pathogen with complex epidemiology necessitating rapid diagnosis and distinguishing between clades and subclades. The emerging Clade Ib lacks the genomic region used in the Clade I-specific assay from the Centers for Disease Control and Prevention. We report an MPXV real-time PCR to specifically detect Clade Ib. The assay demonstrated proficient sensitivity and specificity in 92 samples and can be included along other TaqMan-based assays to detect MPXV and distinguish between clades and subclades.
Subject(s)
Monkeypox virus , Mpox (monkeypox) , Real-Time Polymerase Chain Reaction , Sensitivity and Specificity , Monkeypox virus/genetics , Monkeypox virus/isolation & purification , Monkeypox virus/classification , Real-Time Polymerase Chain Reaction/methods , Mpox (monkeypox)/virology , Mpox (monkeypox)/diagnosis , Humans , Animals , Phylogeny , DNA, Viral/genetics , DNA, Viral/analysisABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
A Mpox é uma doença zoonótica viral, sua transmissão para humanos pode ocorrer por meio do contato com animal ou humano infectado ou material corporal humano contendo o vírus. Os boletins de Mpox estão sendo atualizados mensalmente.
Subject(s)
Monkeypox virusABSTRACT
Monkeypox, caused by the monkeypox virus (MPXV), was historically confined to West and Central Africa but has now spread globally. Recombination and selection play crucial roles in the evolutionary adaptation of MPXV; however, the evolution of MPXV and its relationship with the recent, ground-breaking monkeypox epidemic remains poorly understood. To gain insights into the evolutionary dynamics of MPXV, comprehensive in silico recombination and selection analyses were conducted based on MPXV whole genome sequence data. Three types of recombination were identified: five ancestor-sharing interspecies recombination events, six specific interspecies recombination events and four intraspecies recombination events. The results highlight the prevalent occurrence of recombination in MPXV, with 73.3% occurring in variable regions of the genome. Selection analysis was performed from three dimensions: proteins around recombination regions, proteins from recombinant ancestors and MPXV branches, and whole-genome gene analysis. Results revealed 2 and 7 proteins under positive selection in the first two dimensions, respectively. These proteins are mainly involved in infection immunity, apoptosis regulation and viral virulence. Whole-genome analysis detected 25 genes under positive selection, mainly associated with immune response and viral regulation. Understanding their evolutionary patterns will help predict and prevent cross-species transmission, zoonotic outbreaks and potential human epidemics.
Subject(s)
Evolution, Molecular , Genome, Viral , Monkeypox virus , Mpox (monkeypox) , Phylogeny , Recombination, Genetic , Selection, Genetic , Humans , Monkeypox virus/genetics , Monkeypox virus/classification , Mpox (monkeypox)/virology , Mpox (monkeypox)/epidemiology , Genome, Viral/genetics , Adaptation, Biological , AnimalsABSTRACT
The global monkeypox virus (MPXV) outbreak in 2022 emphasizes the urgent need for effective and accessible new-generation vaccines and neutralizing antibodies. Herein, we identified MPXV-neutralizing antibodies using high-throughput single-cell RNA and V(D)J sequencing of antigen-sorted B cells from patients with convalescent monkeypox. IgG1-expressing B cells were obtained from 34 paired heavy- and light-chain B cell receptor sequences. Subsequently, three potent neutralizing antibodies, MV127, MV128, and MV129, were identified and reacted with the MPXV A35 protein. Among these, MV129, which has a half-maximal inhibitory concentration of 2.68µg/mL against authentic MPXV, was considered to be the putative candidates for MPXV neutralization in response to monkeypox disease.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , B-Lymphocytes , High-Throughput Nucleotide Sequencing , Monkeypox virus , Mpox (monkeypox) , Antibodies, Neutralizing/immunology , Humans , Antibodies, Viral/immunology , Monkeypox virus/immunology , Monkeypox virus/genetics , Mpox (monkeypox)/immunology , Mpox (monkeypox)/virology , B-Lymphocytes/immunology , Immunoglobulin G/immunology , Female , Male , Adult , Neutralization Tests , Middle AgedABSTRACT
The recent outbreak of monkeypox virus (MPXV) was unprecedented in its size and distribution. Those living with uncontrolled HIV and low CD4 T cell counts might develop a fulminant clinical mpox course with increased mortality, secondary infections, and necrotizing lesions. Fatal cases display a high and widespread MPXV tissue burden. The underlying pathomechanisms are not fully understood. We report here the pathological findings of an MPXV-driven abscess in gastrocnemius muscle requiring surgery in an immunocompromised patient with severe mpox. Presence of virus particles and infectivity were confirmed by electron microscopy, expansion microscopy, and virus culture, respectively. MPXV tissue distribution by immunohistochemistry (IHC) showed a necrotic core with infection of different cell types. In contrast, at the lesion rim fibroblasts were mainly infected. Immune cells were almost absent in the necrotic core, but were abundant at the infection rim and predominantly macrophages. Further, we detected high amounts of alternatively activated GPNMB+-macrophages at the lesion border. Of note, macrophages only rarely colocalized with virus-infected cells. Insufficient clearance of infected cells and infection of lesion-associated fibroblasts sustained by the abundance of profibrotic macrophages might lead to the coalescing of lesions and the severe and persistent clinical mpox course observed in immunocompromised patients.
Subject(s)
Immunocompromised Host , Monkeypox virus , Mpox (monkeypox) , Muscle, Skeletal , Humans , Muscle, Skeletal/virology , Muscle, Skeletal/pathology , Muscle, Skeletal/immunology , Mpox (monkeypox)/virology , Mpox (monkeypox)/immunology , Monkeypox virus/immunology , Male , Macrophages/immunology , Macrophages/virology , Fibroblasts/virology , Fibroblasts/immunology , Immunohistochemistry , Abscess/immunology , Abscess/virology , Abscess/pathology , Middle AgedABSTRACT
Mpox (monkeypox) is a neglected tropical disease that has received increased attention since the multi-nation outbreak that began in 2022. The virus is endemic in West and Central Africa, where the Democratic Republic of the Congo (DRC) is the most affected country. Clade I monkeypox virus (MPXV) infection is endemic in the DRC and has an overall case fatality rate of 10.6% among children and adults. A study conducted in Sankuru Province, DRC, from 2007 to 2011 demonstrated that 75% of pregnant women with mpox had miscarriages or stillbirth. Further analysis of a stillborn fetus showed that MPXV could infect both the placenta and fetus, causing congenital infection. No additional cases of Clade I MPXV in pregnant women were reported until a new outbreak occurred in South Kivu Province during 2023 and 2024. Eight pregnant women having Clade I MPXV infection were identified, of whom four had either miscarriages or stillbirth, representing a 50% fetal mortality rate. These reports confirm previous data from the DRC that indicate the capability of Clade I MPXV to affect the fetus, causing congenital infection and fetal loss in a high percentage of cases. In this article, we review both past and new data from the DRC on the effects of Clade I MPXV during pregnancy and discuss the association of mpox with fetal loss.