Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Biomedicum, Stockholm, Sweden.
Virulence. 2024 Dec;15(1):2412745. doi: 10.1080/21505594.2024.2412745. Epub 2024 Nov 5.
Group A (GAS) is a versatile pathogen that targets human lymphoid, decidual, skin, and soft tissues. Recent advancements have shed light on its airborne transmission, lymphatic spread, and interactions with neuronal systems. GAS promotes severe inflammation through mechanisms involving inflammasomes, IL-1β, and T-cell hyperactivation. Additionally, it secretes factors that directly induce skin necrosis via Gasdermin activation and sustains survival and replication in human blood through sophisticated immune evasion strategies. These include lysis of erythrocytes, using red cell membranes for camouflage, resisting antimicrobial peptides, evading phagocytosis, escaping from neutrophil extracellular traps (NETs), inactivating chemokines, and cleaving targeted antibodies. GAS also employs molecular mimicry to traverse connective tissues undetected and exploits the host's fibrinolytic system, which contributes to its stealth and potential for causing autoimmune conditions after repeated infections. Secreted toxins disrupt host cell membranes, enhancing intracellular survival and directly activating nociceptor neurons to induce pain. Remarkably, GAS possesses mechanisms for precise genome editing to defend against phages, and its fibrinolytic capabilities have found applications in medicine. Immune responses to GAS are paradoxical: robust responses to its virulence factors correlate with more severe disease, whereas recurrent infections often show diminished immune reactions. This review focuses on the multifaceted virulence of GAS and introduces novel concepts in understanding its pathogenicity.
A 组链球菌（GAS）是一种多面手病原体，靶向人体淋巴组织、胎盘组织、皮肤和软组织。最近的研究进展揭示了其空气传播、淋巴扩散以及与神经元系统相互作用的机制。GAS 通过包含炎性小体、IL-1β和 T 细胞过度激活等机制促进严重炎症。此外，它通过 Gasdermin 激活直接诱导皮肤坏死的因子以及通过复杂的免疫逃避策略在人血中维持生存和复制。这些策略包括红细胞溶解、利用红细胞膜进行伪装、抵抗抗菌肽、逃避吞噬作用、逃避中性粒细胞胞外陷阱（NETs）、失活趋化因子和切割靶向抗体。GAS 还采用分子模拟来逃避结缔组织的检测，并利用宿主的纤维蛋白溶解系统，这有助于其在反复感染后保持隐匿性并引发自身免疫性疾病的潜力。分泌的毒素破坏宿主细胞膜，增强细胞内生存能力，并直接激活伤害感受器神经元以引起疼痛。值得注意的是，GAS 具有精确的基因组编辑机制来防御噬菌体，其纤维蛋白溶解能力在医学中有应用。针对 GAS 的免疫反应是矛盾的：对其毒力因子的强烈反应与更严重的疾病相关，而反复感染通常表现出免疫反应减弱。本综述重点介绍了 GAS 的多方面毒力，并介绍了理解其致病性的新概念。
