Phenotypic and Genotypic diversity in Moraxella catarrhalis: Using Population Biology to Understand Antimicrobial Resistance and Pathogenesis

卡他莫拉氏菌的表型和基因型多样性：利用群体生物学了解抗菌素耐药性和发病机制

• 批准号: 2749867
• 金额: --
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2749867
• 关键词: Phenotypic; Genotypic; diversity; Moraxella; catarrhalis

The global spread of antibiotic resistance is a significant and increasing threat to global human health. Challenging threats to our health include opportunistic bacteria such as Moraxella catarrhalis. These bacteria can colonise us without ever causing disease but sometimes they can lead to severe infections such as recurrent otitis media, exacerbation of pulmonary disorders and sepsis. Resistance to some antibiotics is now ubiquitous amongst strains of M. catarrhalis. There is an urgent need to understand the biology of this under-appreciated pathogen to prevent the further spread of antibiotic resistance and to develop novel preventative strategies.The population and genomic dynamics of M. catarrhalis and their relationship with disease versus benign colonisation is poorly understood. Studies focussing on limited gene numbers such as multi-locus sequence typing (MLST) have offered some insights into the population structure of M. catarrhalis. However, genetic plasticity may allow these bacteria to generate a range of phenotypes though gene phasing and recombination, the fittest of which can be selected for in vivo, facilitating rapid adaptation within the different mucosal niches infected by these bacteria.This PhD aims to profile the antibiotic resistance of M. catarrhalis isolates from distinct sites of isolation and disease states and study the genomic and virulence related phenotype of these isolates. Linkage of these traits to the dynamics of infection transmission will be examined through bioinformatic approaches.The successful candidate will determine the presence of key virulence factors by distinct immunoassays and proteomics, as well as infect cell lines mimicking in vivo conditions with a diverse range of clinical isolates. Minimal inhibitory concentrations (MICs) for clinically relevant antibiotics will be assayed. For each isolate the MLST-type will be determined. Representative isolates from around the MLST dendrogram will have their genome sequenced and analysed, additionally any associated plasmids will be identified. Finally, data for MIC, virulence factor presence genomic diversity and cell line infectivity will inform models to investigate potential evolutionary mechanisms of action. The outcomes are of translational importance: we will improve understanding of in vivo selection in relation to antimicrobial susceptibility and virulence. In addition, we will identify if niche specificity is an important consideration for bacterial phenotypes that may then be utilised in using antimicrobials. Overall, this project will provide multi-discipline training and improve our understanding of Moraxella population biology.

抗生素耐药性的全球传播是对全球人类健康的重大和日益严重的威胁。对我们健康的威胁包括机会性细菌，如卡他莫拉菌。这些细菌可以在我们身上定植而不会引起疾病，但有时它们会导致严重的感染，如复发性中耳炎，肺部疾病和败血症的恶化。对某些抗生素的耐药性现在普遍存在于M.粘膜炎。迫切需要了解这种未被充分认识的病原体的生物学，以防止抗生素耐药性的进一步传播，并开发新的预防策略。卡他病及其与疾病和良性定植的关系知之甚少。多位点序列分型（MLST）等研究集中在有限的基因数量上，为了解M.粘膜炎。然而，遗传可塑性可能允许这些细菌通过基因定相和重组产生一系列表型，其中最适合的可以在体内选择，促进这些细菌感染的不同粘膜生态位内的快速适应。卡他菌分离株的分离和疾病状态的不同网站，并研究这些分离株的基因组和毒力相关的表型。这些性状与感染传播动力学的联系将通过生物信息学方法进行研究。成功的候选人将通过不同的免疫测定和蛋白质组学方法确定关键毒力因子的存在，以及用各种临床分离株模拟体内条件的感染细胞系。将测定临床相关抗生素的最小抑菌浓度（MIC）。对于每种分离株，将确定MLST类型。将对MLST树状图周围的代表性分离株进行基因组测序和分析，此外还将鉴定任何相关质粒。最后，MIC、毒力因子存在基因组多样性和细胞系感染性的数据将为模型提供信息，以研究潜在的进化作用机制。结果是翻译的重要性：我们将提高了解体内选择有关的抗菌药物的敏感性和毒力。此外，我们将确定生态位特异性是否是细菌表型的重要考虑因素，然后可以在使用抗菌剂时使用。总的来说，这个项目将提供多学科的培训，提高我们对莫拉菌种群生物学的理解。