Stream Alexandra, Dahesh Samira, Thomas Lamar, Gao Nina J, Bjånes Elisabet, Kang Kalisa, Koh Truman, Kapoor Neeraj, Nizet Victor
Medical Scientist Training Program, University of California, San Diego School of Medicine, La Jolla, California, USA.
Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California, USA.
mBio. 2025 Jul 9;16(7):e0068325. doi: 10.1128/mbio.00683-25. Epub 2025 Jun 11.
Group A (GAS; ) is a significant human pathogen responsible for a wide range of diseases, including invasive conditions with high mortality rates, for which no FDA-approved vaccine exists. The membrane-bound protein dhesion and ivision protein (SpyAD) is highly conserved among all sequenced GAS isolates and has emerged as a promising vaccine antigen, but its precise role in GAS pathogenesis remains unclear. Here, we investigate the contribution of SpyAD in establishing and maintaining infection in M1T1 GAS, a persistent and globally disseminated strain that is the most frequently isolated serotype in both invasive and noninvasive infections. We found that SpyAD is critical for GAS invasion of immortalized human pharyngeal and vaginal epithelial cells, as loss of SpyAD significantly impaired bacterial invasion. SpyAD deficiency also resulted in impaired biofilm formation. These features suggest that SpyAD facilitates bacterial persistence and contributes to GAS virulence. In addition, SpyAD enhanced GAS resistance to neutrophil-mediated killing, potentially through phagocytosis-dependent mechanisms. experiments demonstrated that SpyAD deficiency leads to decreased bacterial burden and prolonged survival in a murine model of systemic infection, as well as reduced colonization of the murine vaginal mucosa, further highlighting its role in GAS virulence. These findings underscore the importance of SpyAD as a factor in GAS pathogenesis in the M1T1 strain and support its potential as a target for vaccine development.IMPORTANCEGroup A (GAS) infections remain prevalent worldwide, with recent surges in severe invasive cases causing high morbidity and mortality. To effectively combat these invasive infections, a more thorough understanding of GAS pathogenesis-particularly mechanisms of immune invasion and evasion-is critical. In this study, we address this need by elucidating the role of the candidate GAS vaccine antigen SpyAD in these key processes in the highly prevalent M1T1 GAS strain. SpyAD enables GAS to evade neutrophil killing and facilitates epithelial cell invasion, likely helping the bacterium circumvent immune defenses. Moreover, SpyAD is important for systemic infection and vaginal mucosal infection . Vaccination targeting SpyAD may generate opsonophagocytic antibodies to improve GAS clearance and fortify protection against invasive disease.
A组链球菌（GAS）是一种重要的人类病原体，可导致多种疾病，包括死亡率很高的侵袭性疾病，目前尚无美国食品药品监督管理局（FDA）批准的疫苗。膜结合蛋白粘附与分裂蛋白（SpyAD）在所有已测序的GAS分离株中高度保守，已成为一种有前景的疫苗抗原，但其在GAS致病机制中的精确作用仍不清楚。在此，我们研究了SpyAD在M1T1 GAS（一种持续存在且在全球传播的菌株，是侵袭性和非侵袭性感染中最常分离出的血清型）建立和维持感染中的作用。我们发现SpyAD对永生化人咽和阴道上皮细胞的GAS侵袭至关重要，因为SpyAD的缺失显著损害了细菌侵袭。SpyAD缺陷还导致生物膜形成受损。这些特征表明SpyAD促进细菌持续存在并有助于GAS的毒力。此外，SpyAD增强了GAS对中性粒细胞介导杀伤的抵抗力，可能是通过依赖吞噬作用的机制。实验表明，在系统性感染的小鼠模型中，SpyAD缺陷导致细菌载量减少和存活时间延长，以及小鼠阴道黏膜定植减少，进一步突出了其在GAS毒力中的作用。这些发现强调了SpyAD作为M1T1菌株中GAS致病因素的重要性，并支持其作为疫苗开发靶点的潜力。重要性A组链球菌（GAS）感染在全球仍然普遍存在，最近严重侵袭性病例的激增导致了高发病率和死亡率。为了有效对抗这些侵袭性感染，更深入地了解GAS致病机制——特别是免疫侵袭和逃避机制——至关重要。在本研究中，我们通过阐明候选GAS疫苗抗原SpyAD在高度流行的M1T1 GAS菌株这些关键过程中的作用来满足这一需求。SpyAD使GAS能够逃避中性粒细胞的杀伤并促进上皮细胞侵袭，可能有助于细菌规避免疫防御。此外，SpyAD对系统性感染和阴道黏膜感染很重要。针对SpyAD的疫苗接种可能产生调理吞噬抗体，以改善GAS清除并加强对侵袭性疾病的保护。
