Human macrophages play a major role in controlling tuberculosis (TB), but their anti-mycobacterial mechanisms remain unclear among individuals with metabolic alterations like obesity (TB protective) or diabetes (TB risk). To help discern this, we aimed to: i) Evaluate the impact of the host's TB status or their comorbidities on the anti-mycobacterial responses of their monocyte-derived macrophages (MDMs), and ii) determine if the autophagy inducer rapamycin, can enhance these responses. We used MDMs from newly diagnosed TB patients, their close contacts and unexposed controls. The MDMs from TB patients had a reduced capacity to activate T cells (surrogate for antigen presentation) or kill M. tuberculosis (Mtb) when compared to non-TB controls. The MDMs from obese participants had a higher antigen presenting capacity, whereas those from chronic diabetes patients displayed lower Mtb killing. The activation of MDMs with rapamycin led to an enhanced anti-mycobacterial activity irrespective of TB status but was not as effective in patients with diabetes. Further studies are warranted using MDMs from TB patients with or without metabolic comorbidities to: i) elucidate the mechanisms through which host factors affect Mtb responses, and ii) evaluate host directed therapy using autophagy-inducing drugs like rapamycin to enhance macrophage function.

中文翻译：

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人类单核细胞来源的巨噬细胞对结核分枝杆菌的反应因宿主的结核病、糖尿病或肥胖状况而异，并且雷帕霉素可增强这种反应


人类巨噬细胞在控制结核病 (TB) 方面发挥着重要作用，但在肥胖（结核病保护性）或糖尿病（结核病风险）等代谢改变的个体中，其抗分枝杆菌机制仍不清楚。为了帮助认识这一点，我们的目的是：i) 评估宿主的结核病状况或其合并症对其单核细胞衍生巨噬细胞 (MDM) 的抗分枝杆菌反应的影响，以及 ii) 确定自噬诱导剂雷帕霉素是否可以增强这些回应。我们使用了来自新诊断的结核病患者、他们的密切接触者和未暴露对照的 MDM。与非结核病对照相比，结核病患者的 MDM 激活 T 细胞（抗原呈递的替代物）或杀死结核分枝杆菌 (Mtb) 的能力较低。来自肥胖参与者的 MDM 具有较高的抗原呈递能力，而来自慢性糖尿病患者的 MDM 则表现出较低的 Mtb 杀灭能力。无论结核病状况如何，用雷帕霉素激活 MDM 都会增强抗分枝杆菌活性，但对于糖尿病患者则效果不佳。有必要使用患有或不患有代谢合并症的结核病患者的 MDM 进行进一步研究，以：i）阐明宿主因素影响 Mtb 反应的机制，以及 ii）评估使用雷帕霉素等自噬诱导药物增强巨噬细胞功能的宿主定向治疗。