Anti-InlA single-domain antibodies that inhibit the cell invasion of Listeria monocytogenes.

The Journal of Biological Chemistry Pub Date : 2023-10-01 Epub Date: 2023-09-14 DOI:10.1016/j.jbc.2023.105254
Taichi Yamazaki, Satoru Nagatoishi, Tsukushi Yamawaki, Takashi Nozawa, Ryo Matsunaga, Makoto Nakakido, Jose M M Caaveiro, Ichiro Nakagawa, Kouhei Tsumoto
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Abstract

Listeriosis, caused by infection with Listeria monocytogenes, is a severe disease with a high mortality rate. The L. monocytogenes virulence factor, internalin family protein InlA, which binds to the host receptor E-cadherin, is necessary to invade host cells. Here, we isolated two single-domain antibodies (VHHs) that bind to InlA with picomolar affinities from an alpaca immune library using the phage display method. These InlA-specific VHHs inhibited the binding of InlA to the extracellular domains of E-cadherin in vitro as shown by biophysical interaction analysis. Furthermore, we determined that the VHHs inhibited the invasion of L. monocytogenes into host cells in culture. High-resolution X-ray structure analyses of the complexes of VHHs with InlA revealed that the VHHs bind to the same binding site as E-cadherin against InlA. We conclude that these VHHs have the potential for use as drugs to treat listeriosis.

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抗InlA单结构域抗体,可抑制单核细胞增多性李斯特菌的细胞侵袭。
李斯特菌病是由单核细胞增多性李斯特菌感染引起的一种死亡率很高的严重疾病。单核细胞增多性李斯特菌毒力因子,即与宿主受体E-钙粘蛋白结合的家族蛋白InlA,是入侵宿主细胞所必需的。在这里,我们使用噬菌体展示方法从羊驼免疫文库中分离出两种与InlA具有皮摩尔亲和力的单结构域抗体(VHH)。如生物物理相互作用分析所示,这些InlA特异性VHH在体外抑制了InlA与E-钙粘蛋白细胞外结构域的结合。此外,我们确定VHHs在培养中抑制了李斯特菌对宿主细胞的入侵。VHHs与InlA复合物的高分辨率X射线结构分析显示,VHHs结合到与针对InlA的E-钙粘蛋白相同的结合位点。我们得出的结论是,这些VHH有潜力用作治疗李斯特菌病的药物。
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