Burkholderia pseudomallei is the causative agent of melioidosis, a disease with high morbidity that is endemic in South East Asia and northern Australia. An unusual feature of the bacterium is its ability to induce multinucleated giant cell formation (MNGC), which appears to be related to bacterial pathogenicity. The mechanism of MNGC formation is not fully understood, but host cell factors as well as known bacterial virulence determinants are likely to contribute. Since members of the tetraspanin family of membrane proteins are involved in various types of cell:cell fusion, their role in MNGC formation induced by Burkholderia thailandensis, a mildly pathogenic species closely related to B. pseudomallei, was investigated. The effect of antibodies to tetraspanins CD9, CD81, and CD63 in MNGC formation induced by B. thailandensis in infected mouse J774.2 and RAW macrophage cell lines was assessed along with that of recombinant proteins corresponding to the large extracellular domain (EC2) of the tetraspanins. B. thailandensis-induced fusion was also examined in macrophages derived from CD9 null and corresponding WT mice, and in J774.2 macrophages over-expressing CD9. Antibodies to CD9 and CD81 promoted MNGC formation induced by B. thailandensis, whereas EC2 proteins of CD9, CD81, and CD63 inhibited MNGC formation. Enhanced MNGC formation was observed in CD9 null macrophages, whereas a decrease in MNGC formation was associated with overexpression of CD9. Overall our findings show that tetraspanins are involved in MNGC formation induced by B. thailandensis and by implication, B. pseudomallei, with CD9 and CD81 acting as negative regulators of this process.

中文翻译：

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四跨膜蛋白在调节泰国伯克霍尔德杆菌诱导的融合中的作用。

鼻疽伯克霍尔德氏菌是类鼻疽的病原体，类鼻疽是一种发病率很高的疾病，在东南亚和澳大利亚北部流行。该细菌的一个不寻常的特征是它能够诱导多核巨细胞形成（MNGC），这似乎与细菌的致病性有关。MNGC 形成的机制尚不完全清楚，但宿主细胞因素以及已知的细菌毒力决定因素可能有所贡献。由于膜蛋白四跨膜蛋白家族的成员参与多种类型的细胞：细胞融合，因此研究了它们在泰国伯克霍尔德氏菌（一种与类鼻疽伯克霍尔德氏菌密切相关的轻度致病性物种）诱导的 MNGC 形成中的作用。评估了四跨膜蛋白 CD9、CD81 和 CD63 抗体对受感染小鼠 J774.2 和 RAW 巨噬细胞系中由B. thailandensis诱导的 MNGC 形成的影响，以及与对应于大细胞外结构域 (EC2) 的重组蛋白的影响。四跨膜蛋白。还在来自 CD9 缺失和相应 WT 小鼠的巨噬细胞以及过表达 CD9 的 J774.2 巨噬细胞中检查了泰国B. thailandensis诱导的融合。CD9和CD81抗体促进泰国拟杆菌诱导的MNGC形成，而CD9、CD81和CD63的EC2蛋白抑制MNGC形成。在 CD9 缺失巨噬细胞中观察到 MNGC 形成增强，而 MNGC 形成减少与 CD9 过度表达相关。总体而言，我们的研究结果表明，四跨膜蛋白参与由泰国伯氏杆菌和拟鼻疽伯克氏杆菌诱导的 MNGC 形成，其中 CD9 和 CD81 充当该过程的负调节因子。