A conserved 3D pattern in a Streptococcus pyogenes M protein immunogen elicits M-type crossreactivity.
A conserved 3D pattern in a Streptococcus pyogenes M protein immunogen elicits M-type crossreactivity.
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DOI：
10.1016/j.jbc.2023.104980
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发表时间：
2023-08
影响因子：
4.8
通讯作者：
Ghosh, Partho
中科院分区：
文献类型：
--
作者：
Wang, Kuei-Chen;Kuliyev, Eziz;Nizet, Victor;Ghosh, Partho
卷曲螺旋形成广泛和潜在致命的细菌病原体化脓性链球菌（链球菌A）的M蛋白是调理抗体的免疫显性靶标。然而，如由其高变区（HVR）所定义的，M蛋白的抗原序列变异性为>220个M类型，这被认为限制了M蛋白作为疫苗免疫原，因为抗体应答中的类型特异性。令人惊讶的是，临床疫苗试验中的多HVR免疫原显示出引起M型交叉反应性。这种交叉反应性的基础尚不清楚，但可能部分是由于抗体识别许多M蛋白HVR中保守的3D模式，该模式赋予与人补体C4b结合蛋白（C4BP）的结合。为了验证这一假设，我们研究了携带3D模式的单个M蛋白免疫原是否会引起对携带3D模式的其他M类型的交叉反应。我们发现，当与来自蛋白质GCN 4的卷曲螺旋稳定序列融合时，具有3D模式的化脓性链球菌M2蛋白的34个氨基酸序列保留了完整的C4BP结合能力。我们发现，这种免疫原，称为M2G，引起交叉反应抗体对一些M型携带的3D模式，但不对那些缺乏3D模式。我们进一步表明，M2G抗血清识别的M蛋白显示天然的链球菌A表面上，并促进调理吞噬杀死链球菌A菌株表达这些M蛋白。由于C4BP结合是链球菌A的保守毒力性状，我们建议靶向3D模式可能在疫苗设计中被证明是有利的。
Coiled coil–forming M proteins of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes (strep A) are immunodominant targets of opsonizing antibodies. However, antigenic sequence variability of M proteins into >220 M types, as defined by their hypervariable regions (HVRs), is considered to limit M proteins as vaccine immunogens because of type specificity in the antibody response. Surprisingly, a multi-HVR immunogen in clinical vaccine trials was shown to elicit M-type crossreactivity. The basis for this crossreactivity is unknown but may be due in part to antibody recognition of a 3D pattern conserved in many M protein HVRs that confers binding to human complement C4b-binding protein (C4BP). To test this hypothesis, we investigated whether a single M protein immunogen carrying the 3D pattern would elicit crossreactivity against other M types carrying the 3D pattern. We found that a 34-amino acid sequence of S. pyogenes M2 protein bearing the 3D pattern retained full C4BP-binding capacity when fused to a coiled coil–stabilizing sequence from the protein GCN4. We show that this immunogen, called M2G, elicited cross-reactive antibodies against a number of M types that carry the 3D pattern but not against those that lack the 3D pattern. We further show that the M2G antiserum–recognized M proteins displayed natively on the strep A surface and promoted the opsonophagocytic killing of strep A strains expressing these M proteins. As C4BP binding is a conserved virulence trait of strep A, we propose that targeting the 3D pattern may prove advantageous in vaccine design.
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DOI：
10.1093/cid/cix599
发表时间：
2017-10-16
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Frost HR;Laho D;Sanderson-Smith ML;Licciardi P;Donath S;Curtis N;Kado J;Dale JB;Steer AC;Smeesters PR
通讯作者：
Smeesters PR
影响因子：
7.7
作者：
Kolesinski, Piotr;Wang, Kuei-Chen;Hirose, Yujiro;Nizet, Victor;Ghosh, Partho
通讯作者：
Ghosh, Partho
影响因子：
3.7
作者：
Cunningham, Madeleine W.
通讯作者：
Cunningham, Madeleine W.
影响因子：
5.5
作者：
Dale, James B.;Penfound, Thomas A.;Kotloff, Karen L.
通讯作者：
Kotloff, Karen L.
影响因子：
2.9
作者：
André, I;Persson, J;Linse, S
通讯作者：
Linse, S