The Structures of Secretory IgA in complex with Streptococcus pyogenes M4 and human CD89 provide insights on mucosal host-pathogen interactions.
The Structures of Secretory IgA in complex with Streptococcus pyogenes M4 and human CD89 provide insights on mucosal host-pathogen interactions.
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分泌性 IgA 与化脓性链球菌 M4 和人 CD89 复合物的结构提供了关于粘膜宿主-病原体相互作用的见解。
DOI：
10.1101/2023.04.21.537878
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Stadtmueller,BethM
中科院分区：
文献类型：
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作者：
Liu,Qianqiao;Stadtmueller,BethM
免疫球蛋白（IG）A在血清中以单体伊加起作用，在粘膜分泌物中以分泌型（S）伊加起作用。宿主伊加Fc受体（Fcα R），包括人FcαR1/CD 89，介导伊加效应子功能;然而，人类病原体化脓性链球菌已进化出表面蛋白毒力因子，包括M4，其也与伊加上的CD 89结合位点结合。尽管人类粘膜作为病原体的储存库，但SIgA与CD 89和M4的相互作用仍然知之甚少。在这里，我们报告了M4-SIgA和CD 89-SIgA复合物的cryo-EM结构，这出乎意料地揭示了M4和CD 89的不同SIgA结合化学计量。结构数据、支持性实验和建模表明，SIgA的拷贝与S.化脓性链球菌M4在细菌表面上采用相似的取向，并留下一个宿主FcαR结合位点开放。结果表明，与SIgA结合宿主和细菌Fcα R相关的未被重视的功能后果与理解宿主-微生物共进化、伊加效应子功能和改善A组链球菌感染的结果相关。
Immunoglobulin (Ig) A functions as monomeric IgA in the serum and Secretory (S) IgA in mucosal secretions. Host IgA Fc receptors (FcαRs), including human FcαR1/CD89, mediate IgA effector functions; however human pathogen Streptococcus pyogenes has evolved surface-protein virulence factors, including M4, that also engage the CD89 binding site on IgA. Despite human mucosa serving as a reservoir for pathogens, SIgA interactions with CD89 and M4 remain poorly understood. Here we report cryo-EM structures of M4-SIgA and CD89-SIgA complexes, which unexpectedly reveal different SIgA-binding stoichiometry for M4 and CD89. Structural data, supporting experiments, and modeling indicate that copies of SIgA bound to S. pyogenes M4 will adopt similar orientations on the bacterium surface and leave one host FcαR binding site open. Results suggest unappreciated functional consequences associated with SIgA binding to host and bacterial FcαRs relevant to understanding host-microbe co-evolution, IgA effector functions and to improving the outcomes of group A Streptococcus infection.