Factor H binds to the hypervariable region of many Streptococcus pyogenes M proteins but does not promote phagocytosis resistance or acute virulence.
Factor H binds to the hypervariable region of many Streptococcus pyogenes M proteins but does not promote phagocytosis resistance or acute virulence.
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DOI：
10.1371/journal.ppat.1003323
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Lindahl G
中科院分区：
文献类型：
--
作者：
Gustafsson MC;Lannergård J;Nilsson OR;Kristensen BM;Olsen JE;Harris CL;Ufret-Vincenty RL;Stålhammar-Carlemalm M;Lindahl G
许多病原体表达结合人补体调节因子H（FH）的表面蛋白，如首次描述的化脓性链球菌和抗吞噬M6蛋白。通常认为，FH募集到M蛋白通过保护细菌免受补体沉积和吞噬作用而增强毒力，但FH结合在S.化脓性链球菌的发病机制仍然不清楚和有争议。在这里，我们研究了七种纯化的M蛋白结合FH的能力，发现FH结合M5、M6和M18蛋白，但不结合M1、M3、M4和M22蛋白。广泛的免疫化学分析表明，FH仅结合M蛋白的高变区（HVR），表明选择有利于某些HVR结合FH的能力。这些FH结合HVR可以作为保留结合FH的能力的分离的多肽来研究，这意味着FH结合HVR代表不同的配体结合结构域。在所有人血清蛋白中，分离的HVR特异性地与FH相互作用，与FH中的相同区域相互作用，并显示种属特异性，但表现出很少或没有抗原交叉反应性。虽然这些发现表明，FH募集到一个M蛋白促进毒力，在转基因小鼠中的研究并没有证明在急性感染结合FH的作用。此外，吞噬试验表明，结合FH的能力对S.化脓性细菌可以抵抗人体全血中的杀伤。虽然这些数据为M蛋白的HVR提供了新的线索，但它们表明FH结合可能影响S。化脓性链球菌毒力机制未在目前使用的模型系统中评估。人补体系统在感染后可被迅速激活，从而在先天免疫中起关键作用。然而，激活必须严格控制，以避免对自身组织的攻击。该控制系统的一个关键组成部分是血浆蛋白因子H（FH）。许多病原体结合FH，如第一次描述的化脓性链球菌，并且已经提出这种细菌的表面定位的M蛋白“劫持”FH以逃避吞噬作用。然而，目前尚不清楚FH结合M蛋白是否真的保护S。化脓菌抵抗吞噬作用并促进体内细菌生长。在这里，我们证明，FH结合到一些，但不是所有的M蛋白，仅结合到高变区（HVR），一部分的M蛋白的重要毒力。然而，包括转基因小鼠研究在内的多项证据表明，FH结合能力并不导致急性毒力或吞噬抗性。这些数据揭示了新的光M蛋白的HVR，但强调在确定体内的配体结合区的作用的困难。FH的结合可能有助于S.化脓性链球菌毒力机制未在目前使用的模型中评估。
Many pathogens express a surface protein that binds the human complement regulator factor H (FH), as first described for Streptococcus pyogenes and the antiphagocytic M6 protein. It is commonly assumed that FH recruited to an M protein enhances virulence by protecting the bacteria against complement deposition and phagocytosis, but the role of FH-binding in S. pyogenes pathogenesis has remained unclear and controversial. Here, we studied seven purified M proteins for ability to bind FH and found that FH binds to the M5, M6 and M18 proteins but not the M1, M3, M4 and M22 proteins. Extensive immunochemical analysis indicated that FH binds solely to the hypervariable region (HVR) of an M protein, suggesting that selection has favored the ability of certain HVRs to bind FH. These FH-binding HVRs could be studied as isolated polypeptides that retain ability to bind FH, implying that an FH-binding HVR represents a distinct ligand-binding domain. The isolated HVRs specifically interacted with FH among all human serum proteins, interacted with the same region in FH and showed species specificity, but exhibited little or no antigenic cross-reactivity. Although these findings suggested that FH recruited to an M protein promotes virulence, studies in transgenic mice did not demonstrate a role for bound FH during acute infection. Moreover, phagocytosis tests indicated that ability to bind FH is neither sufficient nor necessary for S. pyogenes to resist killing in whole human blood. While these data shed new light on the HVR of M proteins, they suggest that FH-binding may affect S. pyogenes virulence by mechanisms not assessed in currently used model systems. The human complement system may be rapidly activated upon infection and thereby plays a key role in innate immunity. However, activation must be tightly controlled, to avoid attack on self tissues. A key component of this control system is the plasma protein factor H (FH). Many pathogens bind FH, as first described for Streptococcus pyogenes, and it has been proposed that the surface-localized M protein of this bacterium “hijacks” FH to escape phagocytosis. However, it remains unclear whether FH-binding to M protein indeed protects S. pyogenes against phagocytosis and promotes bacterial growth in vivo. Here, we demonstrate that FH binds to some but not all M proteins and solely binds to the hypervariable region (HVR), a part of M protein important for virulence. Nevertheless, several lines of evidence, including studies with transgenic mice, indicated that FH-binding ability did not contribute to acute virulence or phagocytosis resistance. These data shed new light on the HVR of M proteins but underline the difficulty in determining the in vivo role of a ligand-binding region. Binding of FH may contribute to S. pyogenes virulence by mechanisms not assessed in currently used models.
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影响因子：
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作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1007/978-94-007-0940-9_12
发表时间：
2011-01-01
期刊：
BACTERIAL ADHESION: CHEMISTRY, BIOLOGY AND PHYSICS
影响因子：
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作者：
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通讯作者：
Ghosh, Partho