A type VII secretion system in Group B Streptococcus mediates cytotoxicity and virulence.
A type VII secretion system in Group B Streptococcus mediates cytotoxicity and virulence.
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B 族链球菌中的 VII 型分泌系统介导细胞毒性和毒力。
DOI：
10.1371/journal.ppat.1010121
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发表时间：
2021-12
期刊：
影响因子：
6.7
通讯作者：
Doran KS
中科院分区：
文献类型：
--
作者：
Spencer BL;Tak U;Mendonça JC;Nagao PE;Niederweis M;Doran KS
VII型分泌系统（T7SS）已在放线菌门和厚壁菌门中被发现，并在一些属中被证明分泌具有毒力、宿主毒性和/或细菌间杀伤功能的效应蛋白。生物信息学分析表明，B群链球菌（GBS）分离物编码至少四种不同的T7SS机制亚型，其中三种编码具有WXG和LXG基序的相邻推测的T7SS效应物。然而，T7SS在GBS发病机制中的作用尚不清楚。在这里，我们评估了最丰富的GBS T7SS亚型在GBS发病过程中的作用。在小鼠血源性脑膜炎模型中，与感染亲本GBS菌株的小鼠相比，感染GBS缺乏功能性T7SS或缺乏分泌的WXG100效应物EsxA的小鼠表现出更低的死亡率、更低的组织细菌负荷和更少的脑炎症。我们进一步表明，这种T7SS诱导脑内皮细胞毒性，而EsxA以WXG基序依赖的方式促进了这些细胞毒性表型。最后，我们确定EsxA是一种孔隙形成蛋白，从而证明了非分枝杆菌EsxA同源物在孔隙形成中的第一个作用。这项工作揭示了T7SS在宿主- gbs相互作用中的重要性，并对T7SS效应物在其他革兰氏阳性细菌中的作用具有启示意义。B族链球菌（GBS）是一种重要的人类病原体，是新生儿和某些成年人群（包括孕妇、老年人和糖尿病患者）侵袭性疾病的主要原因。在怀孕期间，无症状的GBS在女性生殖道定域可传播给胎儿或新生儿，并可在GBS破坏血脑屏障（BBB）时导致新生儿脑膜炎。GBS编码VII型分泌系统（T7SS），该系统可能允许输出促进血脑屏障破坏的蛋白质和/或毒素；然而，GBS T7SS尚未被研究过。在这里，我们发现GBS编码四种类型的T7SSs，最普遍的亚型对GBS脑膜炎的进展很重要，可能是通过诱导大脑中的炎症和细胞死亡。我们还发现分泌的T7SS效应蛋白EsxA参与了GBS的发病机制，并能在脂质膜上形成孔隙。这是革兰氏阳性细菌中esxa介导的孔形成的首次证明。
Type VII secretion systems (T7SS) have been identified in Actinobacteria and Firmicutes and have been shown to secrete effector proteins with functions in virulence, host toxicity, and/or interbacterial killing in a few genera. Bioinformatic analysis indicates that isolates of Group B Streptococcus (GBS) encode at least four distinct subtypes of T7SS machinery, three of which encode adjacent putative T7SS effectors with WXG and LXG motifs. However, the function of T7SS in GBS pathogenesis is unknown. Here we assessed the role of the most abundant GBS T7SS subtype during GBS pathogenesis. In a murine model of hematogenous meningitis, mice infected with GBS lacking a functional T7SS or lacking the secreted WXG100 effector EsxA exhibited less mortality, lower bacterial burdens in tissues, and decreased inflammation in the brain compared to mice infected with the parental GBS strain. We further showed that this T7SS induces cytotoxicity in brain endothelium and that EsxA contributes to these cytotoxicity phenotypes in a WXG motif-dependent manner. Finally, we determined that EsxA is a pore-forming protein, thus demonstrating the first role for a non-mycobacterial EsxA homolog in pore formation. This work reveals the importance of a T7SS in host–GBS interactions and has implications for T7SS effector function in other Gram-positive bacteria. Group B Streptococcus (GBS) is an important human pathogen that is a leading cause of invasive disease in newborns and certain adult populations, including pregnant women, the elderly, and those with diabetes. During pregnancy, asymptomatically colonizing GBS in the female genital tract can be transmitted to the fetus or newborn and can result in neonatal meningitis upon GBS disruption of the blood-brain barrier (BBB). GBS encodes a type VII secretion system (T7SS), which may allow export of proteins and/or toxins that promote BBB disruption; however, the GBS T7SS has not been studied. Here we show that GBS encodes four types of T7SSs and that the most prevalent subtype is important for GBS meningitis progression, possibly by inducing inflammation and cell death in the brain. We also show that a secreted T7SS effector protein, EsxA, contributes to GBS pathogenesis and can form pores in lipid membranes. This is the first demonstration of EsxA-mediated pore-formation in Gram-positive bacteria.
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影响因子：
5.7
作者：
Cruciani M;Etna MP;Camilli R;Giacomini E;Percario ZA;Severa M;Sandini S;Rizzo F;Brandi V;Balsamo G;Polticelli F;Affabris E;Pantosti A;Bagnoli F;Coccia EM
通讯作者：
Coccia EM
影响因子：
3.7
作者：
Green ER;Mecsas J
通讯作者：
Mecsas J
影响因子：
4.5
作者：
Chatterjee A;Willett JLE;Dunny GM;Duerkop BA
通讯作者：
Duerkop BA
影响因子：
4.8
作者：
Delahay, RM;Knutton, S;Frankel, G
通讯作者：
Frankel, G
影响因子：
3.4
作者：
Derrick, Steven C.;Morris, Sheldon L.
通讯作者：
Morris, Sheldon L.