Evolutionary Trade-Offs Underlie the Multi-faceted Virulence of <i>Staphylococcus aureus</i>

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.细菌毒力是一种多层面的性状，病原菌与宿主因子间的相互作用会影响感染的严重程度与转归。毒素分泌是诸多病原菌生物学过程的核心环节，且已被广泛认可在疾病病理进程中发挥关键作用。为更深入解析毒素活性与细菌毒力间的关联，我们针对两种已完成全基因组测序的人类主要病原菌——金黄色葡萄球菌（Staphylococcus aureus）的菌株集合展开研究，意外发现细菌毒素活性与疾病严重程度呈负相关。通过功能基因组学方法，我们在上述菌株集合中鉴定出多个可影响毒素活性的全新基因座，其与观察到的多样毒素表型密切相关。为探究低毒素活性菌株为何更易引发菌血症，我们开展了多项功能实验，结果表明：高、低毒素活性菌株在人体血清中的宿主内适应性差异是潜在影响因素之一。由于菌血症等侵袭性感染会限制病原菌的后续传播机会，高毒素活性菌株可获得额外的宿主间适应性优势，这可能有助于毒素活性在种群层面得以维持。本研究结果清晰表明，毒素活性、相对适应性与传播能力之间的进化权衡，对于解析细菌毒力的多面性本质至关重要。