Institut National de la Recherche Scientifique (INRS) - Centre Armand-Frappier Santé Biotechnologie and Infectiopôle INRS, Laval, Quebec, Canada.
Microbiol Spectr. 2023 Aug 17;11(4):e0509622. doi: 10.1128/spectrum.05096-22. Epub 2023 Jul 5.
Polyclonal B cell activation and the resulting hypergammaglobulinemia are a detrimental consequence of visceral leishmaniasis (VL); however, the mechanisms underlying this excessive production of nonprotective antibodies are still poorly understood. Here, we show that a causative agent of VL, Leishmania donovani, induces CD21-dependent formation of tunneling nanotubule (TNT)-like protrusions in B cells. These intercellular connections are used by the parasite to disseminate among cells and propagate B cell activation, and close contact both among the cells and between B cells and parasites is required to achieve this activation. Direct contact between cells and parasites is also observed , as L. donovani can be detected in the splenic B cell area as early as 14 days postinfection. Interestingly, parasites can also glide from macrophages to B cells via TNT-like protrusions. Taken together, our results suggest that, during infection, B cells may acquire L. donovani from macrophages via TNT-like protrusions, and these connections are subsequently exploited by the parasite to disseminate among B cells, thus propagating B cell activation and ultimately leading to polyclonal B cell activation. Leishmania donovani is a causative agent of visceral leishmaniasis, a potentially lethal disease characterized by strong B cell activation and the subsequent excessive production of nonprotective antibodies, which are known to worsen the disease. How activates B cells is still unknown, particularly because this parasite mostly resides inside macrophages and would not have access to B cells during infection. In this study, we describe for the first time how the protozoan parasite Leishmania donovani induces and exploits the formation of protrusions that connect B lymphocytes with each other or with macrophages and glides on these structures from one cell to another. In this way, B cells can acquire from macrophages and become activated upon contact with the parasites. This activation will then lead to antibody production. These findings provide an explanation for how the parasite may propagate B cell activation during infection.
多克隆 B 细胞激活和由此产生的高免疫球蛋白血症是内脏利什曼病（VL）的有害后果；然而，这种非保护性抗体过度产生的机制仍知之甚少。在这里，我们表明，VL 的病原体利什曼原虫（Leishmania donovani）诱导 B 细胞中依赖 CD21 的形成隧道纳米管（TNT）样突起。这些细胞间连接被寄生虫用于在细胞间传播和传播 B 细胞激活，并且细胞间和 B 细胞与寄生虫之间的紧密接触是实现这种激活所必需的。还观察到细胞与寄生虫之间的直接接触，因为早在感染后 14 天，就可以在脾脏 B 细胞区检测到 L. donovani。有趣的是，寄生虫也可以通过 TNT 样突起从巨噬细胞滑向 B 细胞。总之，我们的结果表明，在感染期间，B 细胞可能通过 TNT 样突起从巨噬细胞中获得 L. donovani，并且寄生虫随后利用这些连接在 B 细胞之间传播，从而传播 B 细胞激活，并最终导致多克隆 B 细胞激活。利什曼原虫（Leishmania donovani）是内脏利什曼病的病原体，这是一种潜在致命的疾病，其特征是强烈的 B 细胞激活和随后产生非保护性抗体，已知这些抗体会使病情恶化。仍然不知道如何激活 B 细胞，特别是因为这种寄生虫主要存在于巨噬细胞内，在感染期间不会接触 B 细胞。在这项研究中，我们首次描述了原生动物寄生虫利什曼原虫（Leishmania donovani）如何诱导和利用突起的形成，这些突起将 B 淋巴细胞彼此连接或与巨噬细胞连接，并在这些结构上从一个细胞滑向另一个细胞。通过这种方式，B 细胞可以从巨噬细胞中获得 L. donovani，并在与寄生虫接触时被激活。这种激活将导致抗体的产生。这些发现为寄生虫在感染期间如何传播 B 细胞激活提供了解释。
