Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France.
Front Immunol. 2018 Nov 14;9:2656. doi: 10.3389/fimmu.2018.02656. eCollection 2018.
Tuberculosis (TB), caused by the airborne bacterial pathogen , 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 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 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 , 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）是由空气中的细菌病原体引起的，仍然是全球发病率和死亡率的主要来源。到目前为止，对宿主-病原体相互作用的研究主要集中在病原体的生理学和毒力上，以及宿主的各种先天和适应性免疫区室上。我们体内的微生物，即所谓的微生物组，不仅与入侵的病原体相互作用，还与我们的免疫系统相互作用。然而，微生物组对宿主防御的影响仍知之甚少。为了解决这个问题，我们适应了一种基于广谱抗生素组合的强大且可重复的微生物失调小鼠模型。我们发现，微生物组失调导致在感染的第一周， 更早期地在肺部定植，这与在此期间肠道微生物组多样性的改变有关。在细胞水平上，在感染的第一周，能够检测到在具有和缺乏微生物组的小鼠中，常规髓样细胞（包括巨噬细胞、树突状细胞和中性粒细胞）向肺部的募集没有显著差异。在分子水平上，微生物组耗竭并不影响肺部促炎细胞因子（如干扰素（IFN）γ、肿瘤坏死因子（TNF）α 和白细胞介素（IL）-1β）的总体产生。引人注目的是，在感染后 1 周，抗生素处理动物的肺部观察到黏膜相关不变 T（MAIT）细胞数量减少，MAIT 细胞是一种先天样淋巴细胞，其发育已知依赖于宿主微生物组。这些细胞在抗生素处理的小鼠中产生的 IL-17A 较少。值得注意的是，通过在抗生素处理的动物中接种复杂的微生物组来纠正失调现象，逆转了这些表型，并改善了 MAIT 细胞的增殖能力。总之，我们的研究结果表明，宿主微生物组有助于 早期保护肺部免受定植，可能是通过维持 MAIT 细胞的功能。我们的研究呼吁更好地了解微生物组对结核病中宿主-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使用有益微生物或其成分来增强抗分枝杆菌免疫的新型治疗方法。
