Mechanisms for acquisition and transmission of successful antibiotic resistant pneumococcal clones pre- and postvaccination
AMR in Streptococcus pneumoniae is spread globally by a limited number of clones. PCV vaccination has decreased AMR among vaccine-type strains. AMR now emerges by expansion of non-PCV types. The project focuses on genetic/functional properties of AMR clones with the goal to target their success and transmission in the carrier population. The goals are to: 1) Perform whole genome based analyses on emerging AMR after PCV introduction, comparing with pre-PCV. Sequence data will be correlated to host factors including clinical patient information. Phylogenetic and general machine learning methods will be applied and a data base will be created to identify microbial traits that link success of AMR to transmission, colonization and ability to cause invasive disease 2) A set of animal models will be used to study transmission, colonization and disease capability of AMR clones. Different endogenous and environmental cues will be applied to these studies by altering host immune defense, by sensitizing with influenza A virus, by exposure to long term antibiotics, and by affecting physical or chemical parameters in the environment 3) Drivers affecting transmission/colonization/invasive disease will be identified using appropriate mutants, and monitoring the influence of the host microbiome using germ free mice 4) Resistance transfer and role of competence pili, conjugative transfer and lack of CRISPR/Cas9 interference will be studied in the presence and absence of a respiratory microbiome 5) Clonal elimination will be attempted in mice models using antigens targeting AMR clones and by generating a CRISPR/Cas9 delivery system for interference of AMR clones during carriage.
- Birgitta Henriques Normark, Karolinska Institutet, Sweden (Coordinator)
- Aras Kadioglu, University of Liverpool, United Kingdom (Partner)
- Tim Sparwasser, University Medical Center of the Johannes Gutenberg University, Germany (Partner)
- Jens Lagergren, KTH Royal Institute of Technology, Sweden (Partner)
Pneumococcal infections are major contributors to morbidity and mortality world-wide, even though we have access to antibiotics and intensive care. Pneumococci are the major cause of common milder respiratory tract infections such as otitis and sinusitis, but also to more severe infections such as pneumonia with or without septicaemia and meningitis. Despite causing all these disease with even lethal outcome, pneumococci frequently colonize healthy children from where they may spread to susceptible individuals and cause disease. Resistance to antibiotics is emerging, threatening effective treatment. In this project we have gained important insight into factors that affect transmission of pneumococcal strains, and into the pathogenesis of pneumococcal infections. We have unravelled factors both on the bacterial side and on the host side that are important for the spread and transmission of antimicrobial susceptible and resistant pneumococcal strains using in vitro and in vivo models. Based on this knowledge, potential novel treatment and preventive methods could be developed in the future.
- EMBO Mol Med. 2020. Mannose receptor-derived peptides neutralize pore-forming toxins and reduce inflammation and development of pneumococcal disease
- Cell Microbiol. 2019. Emerging concepts in the pathogenesis of the Streptococcus pneumoniae: From nasopharyngeal colonizer to intracellular pathogen
- Microorganisms, 2020. Lysogeny in Streptococcus pneumoniae
- Journal of Allergy and Clinical Immunology, 2020. Regulating T cell differentiation through the polyamine spermidine
- Nature Microbiology, 2019. Pneumolysin binds to the mannose receptor C type 1 (MRC-1) leading to anti-inflammatory responses and enhanced pneumococcal survival
- J Mol Med, 2021. Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections