Background The largest West African monkeypox outbreak began September 2017, in Nigeria. Four individuals traveling from Nigeria to the UK (2), Israel, and Singapore became the first human monkeypox cases exported from Africa, and a related nosocomial transmission event in the UK became the first confirmed human-to-human monkeypox transmission event outside of Africa. Methods Epidemiological and molecular data for exported and Nigerian cases were analyzed jointly to better understand the exportations in the temporal and geographic context of the outbreak. Results Isolates from all travelers and a Bayelsa case shared a most recent common ancestor and traveled to Bayelsa, Delta, or Rivers states. Genetic variation for this cluster was lower than would be expected from a random sampling of genomes from this outbreak, but data did not support direct links between travelers. Conclusions Monophyly of exportation cases and the Bayelsa sample, along with the intermediate levels of genetic variation suggest a small pool of related isolates is the likely source for the exported infections. This may be the result of the level of genetic variation present in monkeypox isolates circulating within the contiguous region of Bayelsa, Delta, and Rivers states, or another more restricted, yet unidentified source pool.
The COVID-19 pandemic caused by SARS-CoV-2 imposes an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we show the development of a replication competent recombinant VSV-∆G-spike vaccine, in which the glycoprotein of VSV is replaced by the spike protein of SARS-CoV-2. In-vitro characterization of this vaccine indicates the expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in-vivo model for COVID-19 is implemented. We show that a single-dose vaccination results in a rapid and potent induction of SARS-CoV-2 neutralizing antibodies. Importantly, vaccination protects hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss, and alleviation of the extensive tissue damage and viral loads in lungs and nasal turbinates. Taken together, we suggest the recombinant VSV-∆G-spike as a safe, efficacious and protective vaccine against SARS-CoV-2.
Solid-state NMR measurements have been carried out on frozen solutions of the complex of a 24-residue peptide derived from the third variable (V3) loop of the HIV-1 envelope glycoprotein gp120 bound to the Fab fragment of an anti-gp120 antibody. The measurements place strong constraints on the conformation of the conserved central GPGR motif of the V3 loop in the antibody-bound state. In combination with earlier crystal structures of V3 peptide-antibody complexes and existing data on the cross-reactivity of the antibodies, the solid-state NMR measurements suggest that the Gly-Pro-Gly-Arg (GPGR) motif adopts an antibody-dependent conformation in the bound state and may be conformationally heterogeneous in unbound, full-length gp120. These measurements are the first application of solid-state NMR methods in a structural study of a peptide-protein complex.
Background: Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects ~8 million annually culminating in ~2 million deaths. Moreover, about one third of the population is latently infected, 10% of which develop disease during lifetime. Current approved prophylactic TB vaccines (BCG and derivatives thereof) are of variable efficiency in adult protection against pulmonary TB (0%-80%), and directed essentially against early phase infection.
In a search for novel attenuated vaccine candidates for use against Yersinia pestis, the causative agent of plague, a signature-tagged mutagenesis strategy was used and optimized for a subcutaneously infected mouse model. A library of tagged mutants of the virulent Y. pestis Kimberley53 strain was generated. Screening of 300 mutants through two consecutive cycles resulted in selection of 16 mutant strains that were undetectable in spleens 48 h postinfection. Each of these mutants was evaluated in vivo by assays for competition against the wild-type strain and for virulence following inoculation of 100 CFU (equivalent to 100 50% lethal doses [LD 50 ] of the wild type). A wide spectrum of attenuation was obtained, ranging from avirulent mutants exhibiting competition indices of 10 ؊5 to 10 ؊7 to virulent mutants exhibiting a delay in the mean time to death or mutants indistinguishable from the wild type in the two assays. Characterization of the phenotypes and genotypes of the selected mutants led to identification of virulence-associated genes coding for factors involved in global bacterial physiology (e.g., purH, purK, dnaE, and greA) or for hypothetical polypeptides, as well as for the virulence regulator gene lcrF. One of the avirulent mutant strains (LD 50 , >10 7 CFU) was found to be disrupted in the pcm locus, which is presumably involved in the bacterial response to environmental stress. This Kimberley53pcm mutant was superior to the EV76 live vaccine strain because it induced 10-to 100-fold-higher antibody titers to the protective V and F1 antigens and because it conferred efficacious protective immunity.The three pathogenic Yersinia species, Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica, are closely related but differ in the mode of infection. Both Y. enterocolitica and Y. pseudotuberculosis are fecal-oral pathogens that cause invasive gastrointestinal diseases. On the other hand, infection with Y. pestis, the causative agent of plague, which is transmitted either by an infected-flea bite or as an inhaled aerosol, culminates in a fatal disease. Most of the documented Y. pestis virulence factors are encoded by the 70-kb plasmid common to all three Yersinia pathogenic species (5,12,15,16,36). Only a few virulence factors that are unique to Y. pestis are known to reside on the strain-specific plasmids (pMT1 and pPCP1) (35). The pMT1 virulence plasmid (19,26,34) harbors, in addition to the sequences encoding the known virulence factors murine toxin and fraction 1 (F1) capsular antigen, sequences encoding several hypothetical proteins whose relevance to Y. pestis pathogenesis remains to be determined. Moreover, the recently completed genome sequences of two Y. pestis strains, CO92 and KIM (14, 34), revealed the dynamic nature of the genome, the presence of many pseudogenes, and the existence of genes encoding hypothetical proteins residing in several putative pathogenicity islands, whose effects on Y. pestis pathogenicity remain to be carefully studied (14,34).During the last deca...
Yersinia pestis is the causative agent of plague. Previously we have isolated an attenuated Y. pestis transposon insertion mutant in which the pcm gene was disrupted. In the present study, we investigated the expression and the role of pcm locus genes in Y. pestis pathogenesis using a set of isogenic surE, pcm, nlpD and rpoS mutants of the fully virulent Kimberley53 strain. We show that in Y. pestis, nlpD expression is controlled from elements residing within the upstream genes surE and pcm. The NlpD lipoprotein is the only factor encoded from the pcm locus that is essential for Y. pestis virulence. A chromosomal deletion of the nlpD gene sequence resulted in a drastic reduction in virulence to an LD50 of at least 107 cfu for subcutaneous and airway routes of infection. The mutant was unable to colonize mouse organs following infection. The filamented morphology of the nlpD mutant indicates that NlpD is involved in cell separation; however, deletion of nlpD did not affect in vitro growth rate. Trans-complementation experiments with the Y. pestis nlpD gene restored virulence and all other phenotypic defects. Finally, we demonstrated that subcutaneous administration of the nlpD mutant could protect animals against bubonic and primary pneumonic plague. Taken together, these results demonstrate that Y. pestis NlpD is a novel virulence factor essential for the development of bubonic and pneumonic plague. Further, the nlpD mutant is superior to the EV76 prototype live vaccine strain in immunogenicity and in conferring effective protective immunity. Thus it could serve as a basis for a very potent live vaccine against bubonic and pneumonic plague.
Bacillus anthracis is the causative organism of the potentially fatal disease anthrax. Although primarily a disease of animals, anthrax can also affect humans, and depending on the route of infection, the consequences are sometimes fatal. While the disease is well characterized, it is only in recent years that we have begun to understand the molecular basis of B. anthracis pathogenicity (22,31).Fully virulent forms of B. anthracis carry two large plasmids, pXO1 (ϳ181 kbp) and pXO2 (ϳ97 kbp), which are considered to be major virulence determinants, since strains lacking either one of these plasmids are attenuated in most animal models (38). These two plasmids also distinguish B. anthracis from the other members of the closely related Bacillus cereus group of bacteria (23). Despite the important role of pXO1 and pXO2 in B. anthracis virulence and the recent availability of their sequences (44; GenBank accession no. AF188935), only a few essential virulence genes encoded by these plasmids have been identified and characterized so far. These genes include the pagA, lef, and cya genes encoding the principal virulence factor (the tripartite toxin), which code for the protective antigen (PA) and the lethal and edema factors, respectively, all located on pXO1 (38, 44), and the pXO2 genes capBCAD.The PA is the major immunogenic component of the cellfree vaccines licensed for use in humans (4,11,19,61,63). An inherent limitation of these vaccines is the requirement for numerous immunizations. Additional somatic antigens (spore antigens or antigens expressed during the vegetative stage) appear to improve vaccine potency (9, 11). Identification of such novel antigens is therefore essential for development of second-generation B. anthracis vaccines.Whole-genome sequencing of a microbial pathogen together with in silico and cross-genomic analysis is a powerful tool that allows prediction of genes coding for virulence factors or immunogens, which may be novel drug targets or vaccine candidates (16-18, 20, 51, 52). The first step towards genomic characterization of B. anthracis was the recent sequencing, assembly, and partial annotation of the pXO1 plasmid (from an isolate of the live veterinary spore vaccine strain Sterne [44]). Recently, 143 open reading frames (ORFs) were identified in pXO1, and these ORFs comprised only 61% of the plasmid DNA sequence. For about 70% of the predicted ORF products (108 of 143 ORFs), putative functions could not be assigned (based on sequence similarity alone) as significant similarity to sequences available at that time in open databases was not detected (44).In order to gain further insight into the role of pXO1 in B. anthracis pathogenesis, the bioinformatics analysis of pXO1-derived ORF products was extended to include searches against diverse sequence databases, as well as sequence cluster and sequence motif databases (databases of protein signatures of families, domains, active sites, and secretion and anchoring signals). Comparative genomics was used to facilitate identification of uniq...
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