Pathogens and disease最新文献

Borrelia burgdorferi, the spirochete that causes Lyme disease, is a diderm organism that is similar to Gram-negative organisms in that it contains both an inner and outer membrane. Unlike typical Gram-negative organisms, however, B. burgdorferi lacks lipopolysaccharide (LPS). Using computational genome analyses and structural modeling, we identified a transport system containing six proteins in B. burgdorferi that are all orthologs to proteins found in the lipopolysaccharide transport (LPT) system that links the inner and outer membranes of Gram-negative organisms and is responsible for placing LPS on the surface of these organisms. While B. burgdorferi does not contain LPS, it does encode over 100 different surface-exposed lipoproteins and several major glycolipids, which like LPS are also highly amphiphilic molecules, though no system to transport these molecules to the borrelial surface is known. Accordingly, experiments supplemented by molecular modeling were undertaken to determine whether the orthologous LPT system identified in B. burgdorferi could transport lipoproteins and/or glycolipids to the borrelial outer membrane. Our combined observations strongly suggest that the LPT transport system does not transport lipoproteins to the surface. Molecular dynamic modeling, however, suggests that the borrelial LPT system could transport borrelial glycolipids to the outer membrane.

Metalloproteins and metal-based inhibitors have been shown to effectively combat infectious diseases, particularly those caused by RNA viruses. In this study, a diverse set of bioinformatics methods was employed to identify metal-binding proteins of human RNA viruses. Seventy-three viral proteins with a high probability of being metal-binding proteins were identified. These proteins included 40 zinc-, 47 magnesium- and 14 manganese-binding proteins belonging to 29 viral species and eight significant viral families, including Coronaviridae, Flaviviridae and Retroviridae. Further functional characterization has revealed that these proteins play a critical role in several viral processes, including viral replication, fusion and host viral entry. They fall under the essential categories of viral proteins, including polymerase and protease enzymes. Magnesium ion is abundantly predicted to interact with these viral enzymes, followed by zinc. In addition, this study also examined the evolutionary aspects of predicted viral metalloproteins, offering essential insights into the metal utilization patterns among different viral species. The analysis indicates that the metal utilization patterns are conserved within the functional classes of the proteins. In conclusion, the findings of this study provide significant knowledge on viral metalloproteins that can serve as a valuable foundation for future research in this area.

Guanylate-Binding Proteins are interferon-inducible GTPases that play a key role in cell autonomous responses against intracellular pathogens. Despite sharing high sequence similarity, subtle differences among GBPs translate into functional divergences that are still largely not understood. A key GBP feature is the formation of supramolecular GBP complexes on the bacterial surface. Such complexes are observed when GBP1 binds lipopolysaccharide (LPS) from Shigella and Salmonella and further recruits GBP2-4. Here, we compared GBP recruitment on two cytosol-dwelling pathogens, Francisella novicida and S. flexneri. Francisella novicida was coated by GBP1 and GBP2 and to a lower extent by GBP4 in human macrophages. Contrary to S. flexneri, F. novicida was not targeted by GBP3, a feature independent of T6SS effectors. Multiple GBP1 features were required to promote targeting to F. novicida while GBP1 targeting to S. flexneri was much more permissive to GBP1 mutagenesis suggesting that GBP1 has multiple domains that cooperate to recognize F. novicida atypical LPS. Altogether our results indicate that the repertoire of GBPs recruited onto specific bacteria is dictated by GBP-specific features and by specific bacterial factors that remain to be identified.

Our editorial focused on the concept of "Making the Invisible Visible in Science, Technology, Engineering, Mathematics, and Medicine (STEMM)." We highlight 11 manuscripts submitted to our research topic, which offer unique and innovative, evidence-backed solutions to improve diversity, equity, and inclusion in STEMM. Notably, often racial, and ethnic minority scientists are forgotten and placed in the background even when they make a significant contribution to research. The manuscripts highlighted here begin to undo this and empower by making the invisible visible.

Coxiella burnetii (Cb) is an obligate intracellular pathogen in nature and the causative agent of acute Q fever as well as chronic diseases. In an effort to identify genes and proteins crucial to their normal intracellular growth lifestyle, we applied a 'reverse evolution' approach where the avirulent Nine Mile Phase II strain of Cb was grown for 67 passages in chemically defined ACCM-D media and gene expression patterns and genome integrity from various passages was compared to passage number one following intracellular growth. Transcriptomic analysis identified a marked downregulation of the structural components of the type 4B secretion system (T4BSS), the general secretory (Sec) pathway, as well as 14 out of 118 previously identified genes encoding effector proteins. Additional downregulated pathogenicity determinants genes included several chaperones, LPS, and peptidoglycan biosynthesis. A general marked downregulation of central metabolic pathways was also observed, which was balanced by a marked upregulation of genes encoding transporters. This pattern reflected the richness of the media and diminishing anabolic, and ATP-generation needs. Finally, genomic sequencing and comparative genomic analysis demonstrated an extremely low level of mutation across passages, despite the observed Cb gene expression changes following acclimation to axenic media.

The rapid occurrence of gonococcal resistance to all classes of antibiotics could lead to untreatable gonorrhea. Thus, development of novel anti-Neisseria gonorrhoeae drugs is urgently needed. Neisseria gonorrhoeae FA1090 is the most used in gonococcal infection mouse models because of its natural resistance to streptomycin. Streptomycin inhibits the urogenital commensal flora that permits gonococcal colonization. However, this strain is drug-susceptible and cannot be used to investigate the efficacy of novel agents against multidrug-resistant N. gonorrhoeae. Hence, to test the in vivo efficacy of new therapeutics against N. gonorrhoeae resistant to the frontline antibiotics, azithromycin, or ceftriaxone, we constructed streptomycin-resistant mutants of N. gonorrhoeae CDC-181 (azithromycin-resistant) and WHO-X (ceftriaxone-resistant). We identified the inoculum size needed to successfully colonize mice. Both mutants, CDC-181-rpsLA128G and WHO-X-rpsLA128G, colonized the genital tract of mice for 14 days with 100% colonization observed for at least 7 days. CDC-181-rpsLA128G demonstrated better colonization of the murine genital tract compared to WHO-X-rpsLA128G. Lower inoculum of WHO-X-rpsLA128G (105 and 106 CFU) colonized mice better than higher inoculum. Overall, our results indicate that CDC-181-rpsLA128G and WHO-X-rpsLA128G can colonize the lower genital tract of mice and are suitable to be used in mouse models to investigate the efficacy of antigonococcal agents.

Nontypeable Haemophilus influenzae (NTHi) is considered a major pathogen underlying middle ear infection. This study aimed to investigate the impact of IL-17 on chronic otitis media (COM) induced by NTHi in mice. NTHi was inoculated into the tympanic bulla with eustachian tubal obstruction. Middle ear effusions (MEEs) and tissues were collected on days 3, 14, and at 1, 2, and 6 months after injection. The expression of interleukin-17A (IL-17A) in MEEs was significantly elevated compared to that in the control group at the translational and transcriptional levels during the experiments. The quantities of IL-17-producing γδ T cells were significantly increased compared to that in the control group during COM, but that of Th17 cells did not. Depletion of γδ T cells by anti-γδ T-cell receptor (TCR) monoclonal antibody (mAb) administration significantly decreased the bacteria counts and the concentrations of IL-1β, IL-6, IL-17A, TNF-α, and IL-10 in MEEs. Our results suggest that IL-17 may play an important role in prolonging the inflammation in the middle ear in COM and that IL-17-producing γδ T cells may contribute to the exacerbated inflammatory response in the middle ear. In this study, anti-γδ TCR mAb administration was found to improve chronic middle ear inflammatory conditions.

Disability remains an underacknowledged and underdiscussed topic in science, technology, engineering, mathematics, and medicine (STEMM). Social stigma and fear of negative outcomes have resulted in a consistent lack of disclosure. Disabilities cause social and professional difficulties for those that have them. While some faculty can be allies, past literature shows that steps must be taken to make disabilities visible in STEMM at both student and faculty levels. Here, we offer suggestions to better support faculty and students in enhancing the outcomes of individuals who have invisible disabilities. Critically, techniques such as abolishing stigma, universal learning, and better mentoring may improve the challenges faced by those who self-identify as an individual with a disability.

Cutaneous leishmaniasis is an infectious disease that may lead to a single or multiple disseminated cutaneous lesions. The mechanisms involved in Leishmania dissemination to different areas of the skin and the internal organs remain poorly understood. Evidence shows that Very Late Antigen-4 (VLA-4)-dependent phagocyte adhesion is impaired by Leishmania infection, which may be related to the mechanisms of parasite dissemination. We investigated factors potentially associated with decreased VLA-4-mediated adhesion in Leishmania-infected macrophages, including lipid raft-mediated VLA-4 mobilization along the cellular membrane, integrin cluster formation at the cell base (adhesion site), and focal adhesion complex assembly. Phagocytes treated with Methyl-β-Cyclodextrin (MβCD) demonstrated reduced adhesion, similarly to Leishmania amazonensis-infected J774 cells. Infected and MβCD-treated macrophages presented decreased VLA-4 mobilization to the adhesion plane, as well as reduced integrin clustering. Leishmania amazonensis-infected cells exhibited talin depletion, as well as a decreased mobilization of adhesion complex proteins, such as talin and viculin, which were associated with lower VLA-4 concentrations at the adhesion site and limited cell-spreading. Our results suggest that Leishmania infection may modulate the firm adhesion phase of the cell-spreading process, which could contribute to the bloodstream dissemination of infected cells.