Table_1_The Host Microbiota Contributes to Early Protection Against Lung Colonization by Mycobacterium tuberculosis.XLSX

Tuberculosis (TB), caused by the airborne bacterial pathogen Mycobacterium tuberculosis, remains a major source of morbidity and mortality worldwide. So far, the study of host-pathogen interactions in TB has mostly focused on the physiology and virulence of the pathogen, as well as, on the various innate and adaptive immune compartments of the host. Microbial organisms endogenous to our body, the so-called microbiota, interact not only with invading pathogens, but also with our immune system. Yet, the impact of the microbiota on host defense against M. tuberculosis remains poorly understood. In order to address this question, we adapted a robust and reproducible mouse model of microbial dysbiosis based on a combination of wide-spectrum antibiotics. We found that microbiota dysbiosis resulted in an increased early colonization of the lungs by M. tuberculosis during the first week of infection, correlating with an altered diversity of the gut microbiota during this time period. At the cellular level, no significant difference in the recruitment of conventional myeloid cells, including macrophages, dendritic cells and neutrophils, to the lungs could be detected during the first week of infection between microbiota-competent and -deficient mice. At the molecular level, microbiota depletion did not impact the global production of pro-inflammatory cytokines, such as interferon (IFN)γ, tumor necrosis factor (TNF)α and interleukin (IL)-1β in the lungs. Strikingly, a reduced number of mucosal-associated invariant T (MAIT) cells, a population of innate-like lymphocytes whose development is known to depend on the host microbiota, was observed in the lungs of the antibiotics-treated animals after 1week of infection. These cells produced less IL-17A in antibiotics-treated mice. Notably, dysbiosis correction through the inoculation of a complex microbiota in antibiotics-treated animals reversed these phenotypes and improved the ability of MAIT cells to proliferate. Altogether, our results demonstrate that the host microbiota contributes to early protection of lung colonization by M. tuberculosis, possibly through sustaining the function(s) of MAIT cells. Our study calls for a better understanding of the impact of the microbiota on host-pathogen interactions in TB. Ultimately, this study may help to develop novel therapeutic approaches based on the use of beneficial microbes, or components thereof, to boost anti-mycobacterial immunity.

结核病（TB），由空气传播的细菌病原体分枝杆菌（Mycobacterium tuberculosis）引起，仍然是全球发病率和死亡率的主要原因。迄今为止，对结核病中宿主-病原体相互作用的 研究，主要集中于病原体的生理学和致病性，以及宿主的各种先天性和适应性免疫组成部分。人体内固有的微生物，即所谓的微生物群，不仅与入侵的病原体相互作用，而且与我们的免疫系统相互作用。然而，微生物群对宿主防御结核分枝杆菌的影响仍鲜为人知。为了解答这一问题，我们采用了一种基于广谱抗生素的稳健且可重复的微生物菌群失调小鼠模型。我们发现，微生物菌群失调导致感染第一周内结核分枝杆菌在肺部早期定植增加，这与该时间段肠道微生物群多样性的改变相关。在细胞水平上，在感染第一周内，与微生物菌群功能健全和功能缺陷小鼠相比，在肺部募集的常规髓系细胞，包括巨噬细胞、树突状细胞和中性粒细胞，之间没有发现显著差异。在分子水平上，微生物菌群耗竭对肺部促炎细胞因子（如干扰素γ（IFNγ）、肿瘤坏死因子α（TNFα）和白细胞介素（IL）-1β）的全球产生没有影响。令人惊讶的是，在抗生素处理的动物肺部观察到黏膜相关恒定T（MAIT）细胞数量减少，这是一种已知其发育依赖于宿主微生物群的先天样淋巴细胞群体。这些细胞在抗生素处理的鼠中产生的IL-17A较少。值得注意的是，通过向抗生素处理的动物接种复杂微生物群来纠正菌群失调，这些表型得以逆转，并改善了MAIT细胞的增殖能力。总之，我们的结果表明，宿主微生物群有助于结核分枝杆菌肺部早期定植的保护，可能通过维持MAIT细胞的功能（或功能群）实现。我们的研究呼吁更好地理解微生物群对结核病中宿主-病原体相互作用的影响。最终，这项研究可能有助于开发基于有益微生物或其成分的新型治疗策略，以增强抗分枝杆菌免疫力。