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

抗生素耐药性的全球传播是对全球人类健康的重大且日益严重的威胁。对我们的健康构成挑战的威胁包括卡他莫拉氏菌等机会性细菌。这些细菌可以在不引起疾病的情况下在我们身上定居，但有时它们会导致严重的感染，如复发的中耳炎、肺部疾病的恶化和败血症。对某些抗生素的抗药性目前在卡他分支杆菌菌株中普遍存在。迫切需要了解这种被低估的病原体的生物学，以防止抗生素耐药性的进一步传播，并开发新的预防策略。卡特哈里分枝杆菌的种群和基因组动态及其与疾病和良性定植的关系尚不清楚。针对有限基因数量的研究，如多位点序列分型(MLST)，已经为卡他毛虫的种群结构提供了一些见解。然而，遗传可塑性可能允许这些细菌通过基因分期和重组产生一系列的表型，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中的快速适应。本博士旨在从不同的分离地点和疾病状态描述卡他分支杆菌分离株的耐药性，并研究这些分离株的基因组和毒力相关表型。这些特征与感染传播动力学的联系将通过生物信息学的方法进行检验。成功的候选人将通过不同的免疫分析和蛋白质组学来确定关键毒力因子的存在，并用不同的临床分离株感染模拟体内条件的细胞系。将测定临床相关抗生素的最小抑菌浓度(MIC)。对于每个分离物，将确定MLST类型。来自MLST树状图周围的代表性分离株将对其基因组进行测序和分析，此外还将识别任何相关的质粒。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。结果具有翻译上的重要性：我们将提高对体内选择与抗菌素敏感性和毒力相关的理解。此外，我们将确定生态位特异性是否是细菌表型的一个重要考虑因素，然后可能被用于使用抗菌剂。总体而言，该项目将提供多学科培训，并提高我们对摩拉氏菌种群生物学的了解。

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.