Mechanisms for acquisition and transmission of successful antibiotic resistant pneumococcal clones pre- and post-vaccination

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.

To understand the molecular mechanisms of emergence, persistence and transmission of antibiotic resistant pneumococci arising before and after the introduction of conjugated polysaccharide vaccines (PCV). To this end, mouse models will be used to study the transmission, colonization and disease capability of antimicrobial resistant pneumococcal lineages. The overall aim being to identify the specific drivers of antibiotic resistant clones and their role in invasive pneumococcal disease and the host immune response in selection and transmission of antibiotic resistant pneumococci.

Exploitation and dissemination

Publications and Conferences
Results will be disseminated to the research community through presentations at International conferences (such as American Society of Microbiology, Europneumo, and ISPPD), consortia, national meetings and through publication in scientific journals. We will take open access publishing routes where available. In addition to primary research papers, we would publish review articles that may reach a wider audience and encourage greater uptake of our findings. Any publications reporting significant developments in understanding and application that arise from this work will be accompanied by appropriate press releases administered through the different universities participating in this proposal in liaison with relevant partners. Press releases will help ensure the research is presented accurately in the press. In addition, our research will be communicated to the general public through the universities web pages and in particular, important discoveries will be published there.


Public engagement and Media
Direct public engagement will also be done through public events in microbiology and infectious diseases such as through the Institute of Infection and Global Health (IGH) in the UK. AK co-chairs the Institute of Infection and Global Health Public Involvement Panel and will use this experience to continue to deliver outputs to a wide audience. An exhibit will be developed around antimicrobial resistance transmission and alternative strategies to counteract these both through the development of novel therapeutics and mechanisms to extend the lifetime of existing antimicrobials. This exhibit will be supported by the IGH science communications officer. Furthermore, articles to various local and national media outlets will be encouraged and the project will be showcased by a dedicated website. This website will detailing the project's context, key aims, key outputs and team members. Links to and from this page will be sought from collaborators websites and complementary national and international initiatives.
The participating universities social media channels, including Facebook and Twitter, will be used to disseminate research updates, promote events, post photographs and build relationships with target audiences. Also, by the end of the project we plan to organize a conference where we also invite external guests for a wider distribution of our results.

Exploitation of results: We intend that our findings should be exploited quickly and easily by the healthcare sector to improve patient health and welfare. This will be achieved by high impact scientific publication and through clinical links in the UK, Sweden, Germany and worldwide, and through informal meetings. Also, we will when appropriate file patents for further exploitation together with industry. A consortium agreement (CA) will be written to regulate intellectual property rights, ownerships of data and knowledge transfer. In general, the data will be owned by the participant/s that generated them, with joined ownerships if several participants contribute. The researchers will keep track of the results by keeping laboratory notebooks. Overall, we expect this project to lead to worldwide academic research advancement in terms of knowledge enhancement, developing new techniques in a cross disciplinary approach, training of highly skilled researchers and establishment of new academics in the area of antibiotic resistance. Furthermore, this project will impact on public awareness and engagement with research, healthcare issues and will contribute to improved health and well-being for those with respiratory diseases.