Table_4_Local Diversification of Methicillin- Resistant Staphylococcus aureus ST239 in South America After Its Rapid Worldwide Dissemination.XLSX

The global spread of specific clones of methicillin-resistant Staphylococcus aureus (MRSA) has become a major public health problem, and understanding the dynamics of geographical spread requires worldwide surveillance. Over the past 20 years, the ST239 lineage of MRSA has been recognized as an emerging clone across the globe, with detailed studies focusing on isolates from Europe and Asia. Less is known about this lineage in South America, and, particularly, Brazil where it was the predominant lineage of MRSA in the early 1990s to 2000s. To gain a better understanding about the introduction and spread of ST239 MRSA in Brazil we undertook a comparative phylogenomic analysis of ST239 genomes, adding seven completed, closed Brazilian genomes. Brazilian ST239 isolates grouped in a subtree with those from South American, and Western, romance-language-speaking, European countries, here designated the South American clade. After an initial worldwide radiation in the 1960s and 1970s, we estimate that ST239 began to spread in South America and Brazil in approximately 1988. This clone demonstrates specific genomic changes that are suggestive of local divergence and adaptational change including agrC single-nucleotide polymorphisms variants, and a distinct pattern of virulence-associated genes (mainly the presence of the chp and the absence of sea and sasX). A survey of a geographically and chronologically diverse set of 100 Brazilian ST239 isolates identified this virulence genotype as the predominant pattern in Brazil, and uncovered an unexpectedly high prevalence of agr-dysfunction (30%). ST239 isolates from Brazil also appear to have undergone transposon (IS256) insertions in or near global regulatory genes (agr and mgr) that likely led to rapid reprogramming of bacterial traits. In general, the overall pattern observed in phylogenomic analyses of ST239 is of a rapid initial global radiation, with subsequent local spread and adaptation in multiple different geographic locations. Most ST239 isolates harbor the ardA gene, which we show here to have in vivo anti-restriction activity. We hypothesize that this gene may have improved the ability of this lineage to acquire multiple resistance genes and distinct virulence-associated genes in each local context. The allopatric divergence pattern of ST239 also may suggest strong selective pressures for specific traits in different geographical locations.

全球范围内特定克隆的耐甲氧西林金黄色葡萄球菌（MRSA）的传播已成为一项重大的公共卫生问题，而对地理传播动态的理解则需要全球范围内的监测。在过去20年间，MRSA的ST239谱系已被全球范围内视为一种新兴克隆。对来自欧洲和亚洲的分离株的详细研究已得到广泛关注。然而，关于这一谱系在南美洲，尤其是巴西的了解相对较少，特别是在20世纪90年代初至21世纪初，它曾是巴西MRSA的主要谱系。为了更好地理解ST239 MRSA在巴西的引入和传播，我们进行了一项比较系统发育基因组分析，其中增加了七个已完成的巴西基因组。巴西的ST239分离株与来自南美洲、西方及罗曼语系欧洲国家的分离株归入一个亚分支，我们将其命名为南美洲亚群。在20世纪60年代和70年代的初步全球辐射之后，我们估计ST239大约在1988年开始在南美洲和巴西传播。这一克隆体表现出特定的基因组变化，这些变化暗示了局部差异和适应性改变，包括agrC单核苷酸多态性变异，以及与致病性相关的基因（主要是chp基因的存在和sea及sasX基因的缺失）的特定模式。对100个地理和历史上多样的巴西ST239分离株的调查发现，这种致病性基因型在巴西是主要模式，并揭示了agr功能障碍（30%）的意外高发病率。巴西的ST239分离株似乎还经历了转座子（IS256）在全球性调控基因（agr和mgr）附近或其中的插入，这可能导致细菌特性的快速重新编程。总的来说，在ST239的系统发育基因组分析中观察到的整体模式是快速初始全球辐射，随后在多个不同地理位置的局部传播和适应。大多数ST239分离株携带ardA基因，我们在此证明该基因具有体内抗限制活性。我们假设该基因可能提高了这一谱系在各个局部环境中获取多种耐药基因和独特的致病性相关基因的能力。ST239的隔离分化模式也可能表明在不同地理位置上对特定特征的强烈选择压力。