Data Sheet 1_Longitudinal mitochondrial bioenergetic signatures of blood monocytes and lymphocytes improve during treatment of drug-susceptible pulmonary tuberculosis patients.docx

The impact of human pulmonary tuberculosis (TB) on the bioenergetic metabolism of circulating immune cells remains elusive, as does the resolution of these effects with TB treatment. In this study, the rates of oxidative phosphorylation (OXPHOS) and glycolysis in circulating lymphocytes and monocytes of patients with drug-susceptible TB at diagnosis, 2 months, and 6 months during treatment, and 12 months after diagnosis were investigated using extracellular flux analysis. At diagnosis, the bioenergetic parameters of both blood lymphocytes and monocytes of TB patients were severely impaired in comparison to non-TB and non-HIV-infected controls. However, most bioenergetic parameters were not affected by HIV status or glycemic index. Treatment of TB patients restored the % spare respiratory capacity (%SRC) of the circulating lymphocytes to that observed in non-TB and non-HIV infected controls by 12 months. Treatment also improved the maximal respiration of circulating lymphocytes and the %SRC of circulating monocytes of the TB patients. Notably, the differential correlation of the clinical and bioenergetic parameters of the monocytes and lymphocytes from the controls and TB patients at baseline and month 12 was consistent with improved metabolic health and resolution of inflammation following successful TB treatment. Network analysis of the bioenergetic parameters of circulating immune cells with serum cytokine levels indicated a highly coordinated immune response at month 6. These findings underscore the importance of metabolic health in combating TB, supporting the need for further investigation of the bioenergetic immunometabolism associated with TB infection for novel therapeutic approaches aimed at bolstering cellular energetics to enhance immune responses and expedite recovery in TB patients.

人类肺结核（Tuberculosis, TB）对循环免疫细胞生物能代谢（bioenergetic metabolism）的影响，以及抗结核治疗能否逆转此类影响，目前仍尚不明确。本研究采用细胞外流量分析法（extracellular flux analysis），对确诊时、治疗期间第2、6个月以及确诊后12个月的药物敏感性肺结核患者的循环淋巴细胞与单核细胞的氧化磷酸化（oxidative phosphorylation, OXPHOS）及糖酵解（glycolysis）速率进行了检测。确诊时，与非结核且未感染人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）的对照组相比，结核患者的血液淋巴细胞与单核细胞的生物能参数均出现显著损伤。不过，多数生物能参数并未受HIV感染状态或血糖指数（glycemic index）的影响。至确诊后12个月时，抗结核治疗已使患者循环淋巴细胞的备用呼吸能力百分比（% spare respiratory capacity, %SRC）恢复至非结核且未感染HIV对照组的水平。此外，治疗还改善了结核患者循环淋巴细胞的最大呼吸速率，以及循环单核细胞的备用呼吸能力百分比。值得注意的是，基线与治疗12个月时，对照组与结核患者的单核细胞、淋巴细胞的临床参数与生物能参数之间的相关性差异，与结核治疗成功后代谢健康改善及炎症消退的情况相符。对循环免疫细胞的生物能参数与血清细胞因子水平进行的关联网络分析显示，治疗第6个月时机体存在高度协调的免疫应答。本研究结果凸显了代谢健康在对抗结核中的重要性，同时支持需进一步探究与结核感染相关的生物能免疫代谢，以开发新型治疗策略，通过增强细胞能量代谢来强化免疫应答、加速结核患者的康复进程。