Evolutionary Trade-Offs Underlie the Multi-faceted Virulence of Staphylococcus aureus.
Evolutionary Trade-Offs Underlie the Multi-faceted Virulence of Staphylococcus aureus.
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DOI：
10.1371/journal.pbio.1002229
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发表时间：
2015
期刊：
影响因子：
9.8
通讯作者：
Massey RC
中科院分区：
文献类型：
--
作者：
Laabei M;Uhlemann AC;Lowy FD;Austin ED;Yokoyama M;Ouadi K;Feil E;Thorpe HA;Williams B;Perkins M;Peacock SJ;Clarke SR;Dordel J;Holden M;Votintseva AA;Bowden R;Crook DW;Young BC;Wilson DJ;Recker M;Massey RC
细菌毒力是一种多方面的特征，病原体和宿主因素之间的相互作用会影响感染的严重程度和结果。毒素分泌是许多细菌病原体生物学的核心，并被广泛认为在疾病病理学中发挥着至关重要的作用。为了更深入地了解毒性和细菌毒力之间的关系，我们研究了主要人类病原体金黄色葡萄球菌的两个测序集合，发现细菌毒性和疾病严重程度之间存在意想不到的负相关性。通过应用功能基因组学方法，我们确定了几个新的毒性影响基因座，这些基因座负责在这些集合中观察到的广泛的毒性表型。为了了解低毒性分离株引起菌血症的明显较高倾向，我们进行了几次功能测定，我们的研究结果表明，人血清中高毒和低毒分离株之间的宿主内适应度差异是一个促成因素。由于菌血症等侵袭性感染限制了进一步传播的机会，高毒性菌株可能会获得额外的宿主间适应性优势，可能有助于在群体水平上维持毒性。我们的结果清楚地证明了毒性、相对适应性和传播性之间的进化权衡对于理解细菌毒力的多方面性质至关重要。这项研究表明，与预期相反，毒素分泌与主要人类病原体金黄色葡萄球菌的疾病严重程度呈负相关。全球应对日益严重的抗生素耐药性问题和制定替代治疗策略的努力依赖于对机会性病原体何时以及为何导致疾病的更全面的了解。 DNA 测序技术的最新进展为研究传染性生物体开辟了新的机会，但识别解释疾病差异的遗传变异仍然具有挑战性。在这里，我们的目的是了解毒性（许多细菌疾病的已知危险因素）与主要人类病原体金黄色葡萄球菌的感染严重程度之间的复杂关系。与预期相反，我们发现引起最严重疾病的细菌是毒性最小的菌株。我们能够确定导致毒性差异的突变，并鉴定出许多新的毒性影响基因。我们进一步发现，人血清中的细菌适应性可以解释低毒性分离株与严重侵袭性疾病的意外关联。侵袭性金黄色葡萄球菌感染通常被认为是这些细菌的死胡同，因为这些感染很少传播给另一个人。在这里，我们使用一个简单的数学模型表明，这实际上可能有利于剧毒细菌在人群水平上的传播，从而有助于其在全球范围内的成功。因此，我们的工作强调了细菌感染的复杂性，并有助于针对这种重要病原体设计新的治疗和控制策略。
Bacterial virulence is a multifaceted trait where the interactions between pathogen and host factors affect the severity and outcome of the infection. Toxin secretion is central to the biology of many bacterial pathogens and is widely accepted as playing a crucial role in disease pathology. To understand the relationship between toxicity and bacterial virulence in greater depth, we studied two sequenced collections of the major human pathogen Staphylococcus aureus and found an unexpected inverse correlation between bacterial toxicity and disease severity. By applying a functional genomics approach, we identified several novel toxicity-affecting loci responsible for the wide range in toxic phenotypes observed within these collections. To understand the apparent higher propensity of low toxicity isolates to cause bacteraemia, we performed several functional assays, and our findings suggest that within-host fitness differences between high- and low-toxicity isolates in human serum is a contributing factor. As invasive infections, such as bacteraemia, limit the opportunities for onward transmission, highly toxic strains could gain an additional between-host fitness advantage, potentially contributing to the maintenance of toxicity at the population level. Our results clearly demonstrate how evolutionary trade-offs between toxicity, relative fitness, and transmissibility are critical for understanding the multifaceted nature of bacterial virulence. This study shows that, contrary to expectation, toxin secretion inversely correlates with disease severity for the major human pathogen Staphylococcus aureus. Global efforts to counter the growing problem of antibiotic resistance and develop alternative treatment strategies rely on a fuller understanding of when and why opportunistic pathogens cause disease. Recent advances in DNA sequencing technologies have opened up new opportunities to study infectious organisms, yet identifying the genetic variants that explain differences in disease remains challenging. Here we aimed to understand the complex relationship between toxicity—a known risk factor for disease in many bacteria—and infection severity for the major human pathogen S. aureus. Against expectations, we found that the bacteria that caused the most severe disease were the least toxic strains. We were able to determine the mutations responsible for the differences in toxicity and identified a number of novel toxicity-affecting genes. We further discovered that bacterial fitness in human serum could explain the unexpected association of low-toxicity isolates with severe, invasive disease. Invasive S. aureus infections are usually considered a dead end for these bacteria, as these infections are rarely transmitted to another person. Here we show using a simple mathematical model that this might in fact favour transmission of highly toxic bacteria on a population level and thus contribute to their global success. Our work therefore highlights the complexity of bacterial infection and should aid in devising new treatment and control strategies against this important pathogen.