Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA.
Int J Mol Sci. 2024 Jun 21;25(13):6823. doi: 10.3390/ijms25136823.
The World Health Organization (WHO) highlights a greater susceptibility of males to tuberculosis (TB), a vulnerability attributed to sex-specific variations in body fat and dietary factors. Our study delves into the unexplored terrain of how alterations in body fat influence () burden, lung pathology, immune responses, and gene expression, with a focus on sex-specific dynamics. Utilizing a low-dose -HN878 clinical strain infection model, we employ transgenic FAT-ATTAC mice with modulable body fat to explore the impact of fat loss (via fat ablation) and fat gain (via a medium-fat diet, MFD). Firstly, our investigation unveils that infection triggers severe pulmonary pathology in males, marked by shifts in metabolic signaling involving heightened lipid hydrolysis and proinflammatory signaling driven by IL-6 and localized pro-inflammatory CD8 cells. This stands in stark contrast to females on a control regular diet (RD). Secondly, our findings indicate that both fat loss and fat gain in males lead to significantly elevated (1.6-fold ( ≤ 0.01) and 1.7-fold ( ≤ 0.001), respectively) burden in the lungs compared to females during infection (where fat loss and gain did not alter load in the lungs). This upsurge is associated with impaired lung lipid metabolism and intensified mitochondrial oxidative phosphorylation-regulated activity in lung CD8 cells during infection. Additionally, our research brings to light that females exhibit a more robust systemic IFNγ ( ≤ 0.001) response than males during infection. This heightened response may either prevent active disease or contribute to latency in females during infection. In summary, our comprehensive analysis of the interplay between body fat changes and sex bias in infection reveals that alterations in body fat critically impact pulmonary pathology in males. Specifically, these changes significantly reduce the levels of pulmonary CD8 T-cells and increase the burden in the lungs compared to females. The reduction in CD8 cells in males is linked to an increase in mitochondrial oxidative phosphorylation and a decrease in TNFα, which are essential for CD8 cell activation.
世界卫生组织（WHO）强调男性更容易感染结核病（TB），这种易感性归因于体脂和饮食因素的性别特异性差异。我们的研究深入探讨了体脂变化如何影响结核分枝杆菌负担、肺部病理、免疫反应和基因表达，重点关注性别特异性动态。我们利用低剂量 -HN878 临床株感染模型，使用可调节体脂的 FAT-ATTAC 转基因小鼠，探索脂肪减少（通过脂肪消融）和脂肪增加（通过中脂肪饮食，MFD）对结核分枝杆菌感染的影响。首先，我们的研究表明，结核分枝杆菌感染在男性中引发严重的肺部病理，表现为代谢信号的变化，涉及脂质水解的增强和由 IL-6 驱动的促炎信号，以及局部促炎 CD8 细胞。这与接受对照常规饮食（RD）的女性形成鲜明对比。其次，我们的发现表明，男性脂肪减少和脂肪增加分别导致肺部结核分枝杆菌负担显著增加（分别为 1.6 倍（ ≤ 0.01）和 1.7 倍（ ≤ 0.001）），而女性在感染期间脂肪减少和增加并不改变肺部的结核分枝杆菌负荷。这种增加与感染期间肺部 CD8 细胞的肺脂质代谢受损和线粒体氧化磷酸化调节活性增强有关。此外，我们的研究表明，女性在感染期间表现出比男性更强的系统性 IFNγ 反应（ ≤ 0.001）。这种增强的反应可能要么防止活动性疾病，要么导致女性在感染期间潜伏。总之，我们对体脂变化和结核分枝杆菌感染中性别偏见相互作用的综合分析表明，体脂变化对男性肺部病理有重要影响。具体而言，与女性相比，这些变化显著降低了肺部 CD8 T 细胞的水平，并增加了肺部的结核分枝杆菌负担。男性 CD8 细胞减少与线粒体氧化磷酸化增加和 TNFα 减少有关，这对 CD8 细胞的激活至关重要。
