Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas.
Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas; Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York.
Am J Pathol. 2020 Apr;190(4):862-873. doi: 10.1016/j.ajpath.2019.12.003. Epub 2020 Mar 19.
Group A streptococcus (GAS) is a major pathogen that impacts health and economic affairs worldwide. Although the oropharynx is the primary site of infection, GAS can colonize the female genital tract and cause severe diseases, such as puerperal sepsis, neonatal infections, and necrotizing myometritis. Our understanding of how GAS genes contribute to interaction with the primate female genital tract is limited by the lack of relevant animal models. Using two genome-wide transposon mutagenesis screens, we identified 69 GAS genes required for colonization of the primate vaginal mucosa in vivo and 96 genes required for infection of the uterine wall ex vivo. We discovered a common set of 39 genes important for GAS fitness in both environments. They include genes encoding transporters, surface proteins, transcriptional regulators, and metabolic pathways. Notably, the genes that encode the surface-exclusion protein (SpyAD) and the immunogenic secreted protein 2 (Isp2) were found to be crucial for GAS fitness in the female primate genital tract. Targeted gene deletion confirmed that isogenic mutant strains ΔspyAD and Δisp2 are significantly impaired in ability to colonize the primate genital tract and cause uterine wall pathologic findings. Our studies identified novel GAS genes that contribute to female reproductive tract interaction that warrant translational research investigation.
A 组链球菌（GAS）是一种主要病原体，对全球健康和经济事务都有影响。虽然口咽部是感染的主要部位，但 GAS 可以定植于女性生殖道，并引起严重疾病，如产褥期败血症、新生儿感染和坏死性子宫肌炎。我们对 GAS 基因如何有助于与灵长类动物生殖道相互作用的了解受到缺乏相关动物模型的限制。通过两次全基因组转座子诱变筛选，我们鉴定出 69 个 GAS 基因，这些基因对于 GAS 在体内定植灵长类阴道黏膜是必需的，还有 96 个基因对于 GAS 在体外感染子宫壁是必需的。我们发现了一组共同的 39 个对 GAS 在两种环境中的适应性都很重要的基因。它们包括编码转运蛋白、表面蛋白、转录调节剂和代谢途径的基因。值得注意的是，编码表面排除蛋白（SpyAD）和免疫原性分泌蛋白 2（Isp2）的基因对于 GAS 在雌性灵长类动物生殖道中的适应性至关重要。靶向基因缺失证实了缺失 spyAD 和缺失 isp2 的同基因突变株在定植灵长类生殖道和引起子宫壁病理发现的能力上显著受损。我们的研究确定了一些新的 GAS 基因，它们有助于生殖道相互作用，值得进行转化研究调查。
