Defective lytic transglycosylase disrupts cell morphogenesis by hindering cell wall de-O-acetylation in N. meningitidis
- Institut Pasteur, France
- University of Wisconsin-Madison, United States
- Harvard Medical School, United States
Abstract
Lytic transglycosylases (LT) are enzymes involved in peptidoglycan (PG) remodeling. However, their contribution to cell wall-modifying complexes and their potential as antimicrobial drug targets remain unclear. Here, we determined a high-resolution structure of the LT, an outer membrane lipoprotein from Neisseria species with a disordered active site helix (alpha helix 30). We show that deletion of the conserved alpha-helix 30 interferes with the integrity of the cell wall, disrupts cell division, cell separation, and impairs the fitness of the human pathogen Neisseria meningitidis during infection. Additionally, deletion of alpha-helix 30 results in hyperacetylated PG, suggesting this LtgA variant affects the function of the PG de-O-acetylase (Ape 1). Our study revealed that Ape 1 requires LtgA for optimal function, demonstrating that LTs can modulate the activity of their protein-binding partner. We show that targeting specific domains in LTs can be lethal, which opens the possibility that LTs are useful drug-targets.
Data availability
Data Availability: Coordinates and structural data have been submitted to the Protein Data Bank under the accession code 6H5F.
Article and author information
Author details
Allison Hillary Williams
Funding
European Molecular Biology Organization (ALTF 732-2010)
- Allison Hillary Williams
European Research Council (PGN from SHAPE to VIR 202283)
- Ivo Gomperts Boneca
Fondation pour la Recherche Médicale (DBF20160635726)
- Ivo Gomperts Boneca
Institut Carnot-Pasteur (Maladies Infectious fellowship)
- Allison Hillary Williams
Institut Carnot Pasteur Microbes and Sante
- Ignacio Santecchia
Fondation pour la Recherche Médicale (FDT201805005258)
- Ignacio Santecchia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal work in this study was carried out at the Institut Pasteur in strict accordance with the European Union Directive 2010/63/EU (and its revision 86/609/EEC) on the protection of animals used for scientific purposes. The laboratory at the Institut Pasteur has the administrative authorization for animal experimentation (Permit Number 75-1554) and the protocol was approved by the Institut Pasteur Review Board that is part of the Regional Committee of Ethics of Animal Experiments of Paris Region (Permit Number: 99-174). All the invasive procedures were performed under anesthesia and all possible efforts were made to minimize animal suffering.
Copyright
© 2020, Williams et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Defective lytic transglycosylase disrupts cell morphogenesis by hindering cell wall de-O-acetylation in N. meningitidis
eLife 9:e51247.
https://doi.org/10.7554/eLife.51247
Further reading
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- Immunology and Inflammation
- Microbiology and Infectious Disease
Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that displays great variability in clinical phenotype. Many factors have been described to be correlated with its severity, and microbiota could play a key role in the infection, progression, and outcome of the disease. SARS-CoV-2 infection has been associated with nasopharyngeal and gut dysbiosis and higher abundance of opportunistic pathogens. To identify new prognostic markers for the disease, a multicentre prospective observational cohort study was carried out in COVID-19 patients divided into three cohorts based on symptomatology: mild (n = 24), moderate (n = 51), and severe/critical (n = 31). Faecal and nasopharyngeal samples were taken, and the microbiota was analysed. Linear discriminant analysis identified Mycoplasma salivarium, Prevotella dentalis, and Haemophilus parainfluenzae as biomarkers of severe COVID-19 in nasopharyngeal microbiota, while Prevotella bivia and Prevotella timonensis were defined in faecal microbiota. Additionally, a connection between faecal and nasopharyngeal microbiota was identified, with a significant ratio between P. timonensis (faeces) and P. dentalis and M. salivarium (nasopharyngeal) abundances found in critically ill patients. This ratio could serve as a novel prognostic tool for identifying severe COVID-19 cases.
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Background:
In many settings, a large fraction of the population has both been vaccinated against and infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, quantifying the protection provided by post-infection vaccination has become critical for policy. We aimed to estimate the protective effect against SARS-CoV-2 reinfection of an additional vaccine dose after an initial Omicron variant infection.
Methods:
We report a retrospective, population-based cohort study performed in Shanghai, China, using electronic databases with information on SARS-CoV-2 infections and vaccination history. We compared reinfection incidence by post-infection vaccination status in individuals initially infected during the April–May 2022 Omicron variant surge in Shanghai and who had been vaccinated before that period. Cox models were fit to estimate adjusted hazard ratios (aHRs).
Results:
275,896 individuals were diagnosed with real-time polymerase chain reaction-confirmed SARS-CoV-2 infection in April–May 2022; 199,312/275,896 were included in analyses on the effect of a post-infection vaccine dose. Post-infection vaccination provided protection against reinfection (aHR 0.82; 95% confidence interval 0.79–0.85). For patients who had received one, two, or three vaccine doses before their first infection, hazard ratios for the post-infection vaccination effect were 0.84 (0.76–0.93), 0.87 (0.83–0.90), and 0.96 (0.74–1.23), respectively. Post-infection vaccination within 30 and 90 days before the second Omicron wave provided different degrees of protection (in aHR): 0.51 (0.44–0.58) and 0.67 (0.61–0.74), respectively. Moreover, for all vaccine types, but to different extents, a post-infection dose given to individuals who were fully vaccinated before first infection was protective.
Conclusions:
In previously vaccinated and infected individuals, an additional vaccine dose provided protection against Omicron variant reinfection. These observations will inform future policy decisions on COVID-19 vaccination in China and other countries.
Funding:
This study was funded the Key Discipline Program of Pudong New Area Health System (PWZxk2022-25), the Development and Application of Intelligent Epidemic Surveillance and AI Analysis System (21002411400), the Shanghai Public Health System Construction (GWVI-11.2-XD08), the Shanghai Health Commission Key Disciplines (GWVI-11.1-02), the Shanghai Health Commission Clinical Research Program (20214Y0020), the Shanghai Natural Science Foundation (22ZR1414600), and the Shanghai Young Health Talents Program (2022YQ076).
