Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation.
Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation.
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巨噬细胞对人类和动物适应性结核杆菌的特异性反应揭示了驱动多核细胞形成的病原体和宿主因素
DOI：
10.1371/journal.ppat.1009410
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Gutierrez MG
中科院分区：
文献类型：
--
作者：
Queval CJ;Fearns A;Botella L;Smyth A;Schnettger L;Mitermite M;Wooff E;Villarreal-Ramos B;Garcia-Jimenez W;Heunis T;Trost M;Werling D;Salguero FJ;Gordon SV;Gutierrez MG
结核分枝杆菌复合体（MTBC）是一组引起哺乳动物结核病（TB）的相关病原体。MTBC物种的特点是它们在不同宿主种群中维持生存的能力。虽然牛分枝杆菌（Mbv）在牛和野生动物中维持传播循环并引起人畜共患结核病，但结核分枝杆菌（Mtb）影响人群，很少在牛中引起疾病。宿主和病原体决定因素在MTBC物种之间的宿主趋向性仍然是未知的。巨噬细胞是最初感染时遇到分枝杆菌的主要宿主细胞，我们假设巨噬细胞和分枝杆菌之间的早期相互作用影响物种特异性疾病的结果。为了确定促进宿主趋向性的因素，我们分析了感染Mbv和Mtb的血液来源的原代人巨噬细胞和牛巨噬细胞（分别为hmφ或bmφ）。我们发现Mbv和Mtb驻留在不同的细胞室中，并在hmφ中进行差异复制，而Mbv和Mtb都有效地在bmφ中进行复制。具体来说，我们发现在四种感染组合中，只有bmφ与Mbv的感染促进了多核巨细胞（MNGCs）的形成，这是结核性肉芽肿的标志。在机制上，我们证明来自Mbv的MPB70和Mbv感染的bmφ释放的细胞外囊泡都促进巨噬细胞的多核。重要的是，我们扩展了我们的体外研究，表明来自mbv感染而不是mmb感染牛的肉芽肿含有更多的MNGCs。我们的研究结果表明MNGC的形成与牛宿主Mtb和Mbv的病理对比有关，并确定Mbv中的MPB70和bmφ中的细胞外囊泡是这一过程的介质。鉴定宿主和病原体因素对宿主-病原体相互作用的影响对了解结核病的发病机制和传播至关重要。在解读跨MTBC向宿主性的机制基础时尤其如此。在这里，我们表明，在体外，牛分枝杆菌而不是结核分枝杆菌诱导牛巨噬细胞形成多核细胞。我们确定了宿主和病原体多核细胞形成的机制驱动因素：MPB70作为牛分枝杆菌因子和牛巨噬细胞细胞外囊泡。利用牛实验感染模型，我们证实了体内差异多核细胞的形成。因此，我们已经确定了宿主和病原体因素，有助于宿主趋向性在人/牛结核。此外，这项工作为多核细胞与结核病发病机制的长期联系提供了解释。
The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. The host and pathogen determinants underlying host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection, and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed blood-derived primary human and bovine macrophages (hMϕ or bMϕ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMϕ whereas both Mbv and Mtb efficiently replicate in bMϕ. Specifically, we show that out of the four infection combinations, only the infection of bMϕ with Mbv promoted the formation of multinucleated giant cells (MNGCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMϕ promote macrophage multinucleation. Importantly, we extended our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNGCs. Our findings implicate MNGC formation in the contrasting pathology between Mtb and Mbv for the bovine host and identify MPB70 from Mbv and extracellular vesicles from bMϕ as mediators of this process. The identification of host and pathogen factors contributing to host-pathogen interaction is crucial to understand the pathogenesis and dissemination of tuberculosis. This is particularly the case in deciphering the mechanistic basis for host-tropism across the MTBC. Here, we show that in vitro, M. bovis but not M. tuberculosis induces multinucleated cell formation in bovine macrophages. We identified host and pathogen mechanistic drivers of multinucleated cell formation: MPB70 as the M. bovis factor and bovine macrophage extracellular vesicles. Using a cattle experimental infection model, we confirmed differential multinucleated cell formation in vivo. Thus, we have identified host and pathogen factors that contribute to host tropism in human/bovine tuberculosis. Additionally, this work provides an explanation for the long-standing association of multinucleated cells with tuberculosis pathogenesis.
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