Department of Pediatrics, University of California, San Diego, California, USA.
School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland, Australia.
mBio. 2018 Jan 30;9(1):e02294-17. doi: 10.1128/mBio.02294-17.
Classification of streptococci is based upon expression of unique cell wall carbohydrate antigens. All serotypes of group A (GAS; ), a leading cause of infection-related mortality worldwide, express the group A carbohydrate (GAC). GAC, the classical Lancefield antigen, is comprised of a polyrhamnose backbone with -acetylglucosamine (GlcNAc) side chains. The immunodominant GlcNAc epitope of GAC is the basis of all rapid diagnostic testing for GAS infection. We previously identified the 12-gene GAC biosynthesis gene cluster and determined that the glycosyltransferase GacI was required for addition of the GlcNAc side chain to the polyrhamnose core. Loss of the GAC GlcNAc epitope in serotype M1 GAS resulted in attenuated virulence in two animal infection models and increased GAS sensitivity to killing by whole human blood, serum, neutrophils, and antimicrobial peptides. Here, we report that the GAC biosynthesis gene cluster is ubiquitous among 520 GAS isolates from global sources, representing 105 GAS serotypes. Isogenic Δ mutants were constructed in M2, M3, M4, M28, and M89 backgrounds and displayed an array of phenotypes in susceptibility to killing by whole human blood, baby rabbit serum, human platelet releasate, human neutrophils, and antimicrobial peptide LL-37. The contribution of the GlcNAc side chain to GAS survival also varied by strain, demonstrating that it is not a prerequisite for virulence in the murine infection model. Thus, the relative contribution of GAC to virulence in non-M1 serotypes appears to depend on the quorum of other virulence factors that each strain possesses. The Lancefield group A carbohydrate (GAC) is the species-defining antigen for group A (GAS), comprising ~50% of the cell wall of this major human pathogen. We previously showed that the GlcNAc side chain of GAC contributes to the innate immune resistance and animal virulence phenotypes of the globally disseminated strain of serotype M1 GAS. Here, we use isogenic mutagenesis to examine the role of GAC GlcNAc in five additional medically relevant GAS serotypes. Overall, the GlcNAc side chain of GAC contributes to the innate immune resistance of GAS, but the relative contribution varies among individual strains. Moreover, the GAC GlcNAc side chain is not a universal prerequisite for GAS virulence in the animal model.
链球菌的分类基于其独特的细胞壁碳水化合物抗原的表达。所有 A 组（GAS）血清型，一种全球感染相关死亡率的主要原因，都表达 A 组碳水化合物（GAC）。GAC，经典的 Lancefield 抗原，由带有 -乙酰葡萄糖胺（GlcNAc）侧链的多聚鼠李糖骨干组成。GAC 的免疫显性 GlcNAc 表位是所有用于检测 GAS 感染的快速诊断测试的基础。我们之前确定了 12 基因 GAC 生物合成基因簇，并确定糖基转移酶 GacI 是将 GlcNAc 侧链添加到多聚鼠李糖核心所必需的。M1 GAS 血清型中 GAC 的 GlcNAc 表位丢失导致在两种动物感染模型中的毒力减弱，并增加了 GAS 对全人血、血清、中性粒细胞和抗菌肽的敏感性。在这里，我们报告 GAC 生物合成基因簇在来自全球来源的 520 个 GAS 分离株中普遍存在，代表 105 个 GAS 血清型。在 M2、M3、M4、M28 和 M89 背景下构建了同基因Δ突变体，并在对全人血、幼兔血清、人血小板释放物、人中性粒细胞和抗菌肽 LL-37 的杀伤敏感性方面表现出一系列表型。GlcNAc 侧链对 GAS 存活的贡献也因菌株而异，表明它不是在小鼠感染模型中毒力的先决条件。因此，GAC 对非 M1 血清型毒力的相对贡献似乎取决于每个菌株所具有的其他毒力因子的群体。Lancefield 组 A 碳水化合物（GAC）是 A 组（GAS）的种定义抗原，占这种主要人类病原体细胞壁的约 50%。我们之前表明，GAC 的 GlcNAc 侧链有助于全球传播的 M1 血清型 GAS 的固有免疫抵抗和动物毒力表型。在这里，我们使用同基因诱变来检查 GAC GlcNAc 在另外五个具有医学意义的 GAS 血清型中的作用。总体而言，GAC 的 GlcNAc 侧链有助于 GAS 的固有免疫抵抗，但在各个菌株之间的相对贡献有所不同。此外，GAC 的 GlcNAc 侧链不是 GAS 在动物模型中毒力的普遍先决条件。
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