Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom;
Genome Res. 2014 May;24(5):839-49. doi: 10.1101/gr.165415.113. Epub 2014 Apr 9.
Microbial virulence is a complex and often multifactorial phenotype, intricately linked to a pathogen's evolutionary trajectory. Toxicity, the ability to destroy host cell membranes, and adhesion, the ability to adhere to human tissues, are the major virulence factors of many bacterial pathogens, including Staphylococcus aureus. Here, we assayed the toxicity and adhesiveness of 90 MRSA (methicillin resistant S. aureus) isolates and found that while there was remarkably little variation in adhesion, toxicity varied by over an order of magnitude between isolates, suggesting different evolutionary selection pressures acting on these two traits. We performed a genome-wide association study (GWAS) and identified a large number of loci, as well as a putative network of epistatically interacting loci, that significantly associated with toxicity. Despite this apparent complexity in toxicity regulation, a predictive model based on a set of significant single nucleotide polymorphisms (SNPs) and insertion and deletions events (indels) showed a high degree of accuracy in predicting an isolate's toxicity solely from the genetic signature at these sites. Our results thus highlight the potential of using sequence data to determine clinically relevant parameters and have further implications for understanding the microbial virulence of this opportunistic pathogen.
微生物的毒力是一种复杂的、通常多因素的表型，与病原体的进化轨迹密切相关。毒性，即破坏宿主细胞膜的能力，以及黏附性，即黏附人体组织的能力，是许多细菌病原体（包括金黄色葡萄球菌）的主要毒力因子。在这里，我们检测了 90 株耐甲氧西林金黄色葡萄球菌（MRSA）分离株的毒性和黏附性，发现尽管黏附性的变化很小，但分离株之间的毒性差异超过一个数量级，这表明这两个特征受到不同的进化选择压力的影响。我们进行了全基因组关联研究（GWAS），并鉴定了大量与毒性显著相关的基因座，以及一个可能的遗传相互作用网络。尽管毒性调控存在明显的复杂性，但基于一组显著的单核苷酸多态性（SNP）和插入缺失事件（indels）的预测模型，仅根据这些位点的遗传特征就能高度准确地预测分离株的毒性。因此，我们的研究结果强调了利用序列数据来确定临床相关参数的潜力，并进一步深入了解这种机会致病菌的微生物毒力。
