Department of Medicine, University of Washington, Seattle, Washington, USA.
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
mSystems. 2024 Sep 17;9(9):e0062824. doi: 10.1128/msystems.00628-24. Epub 2024 Aug 20.
(Mtb) exposure leads to a range of outcomes including clearance, latent TB infection (LTBI), and pulmonary tuberculosis (TB). Some heavily exposed individuals resist tuberculin skin test (TST) and interferon-gamma (IFNγ) release assay (IGRA) conversion (RSTR), which suggests that they employ IFNγ-independent mechanisms of Mtb control. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. Chromatin accessibility did not differ between uninfected RSTR and LTBI monocytes. By contrast, methylation significantly differed at 174 CpG sites and across 63 genomic regions. Consistent with previous transcriptional findings in this cohort, differential methylation was enriched in lipid- and cholesterol-associated pathways including the genes APOC3, KCNQ1, and PLA2G3. In addition, methylation was enriched in Hippo signaling, which is associated with cholesterol homeostasis and includes CIT and SHANK2. Lipid export and Hippo signaling pathways were also associated with gene expression in response to Mtb in RSTR as well as IFN stimulation in monocyte-derived macrophages (MDMs) from an independent healthy donor cohort. Moreover, serum-derived high-density lipoprotein from RSTR had elevated ABCA1-mediated cholesterol efflux capacity (CEC) compared to LTBI. Our findings suggest that resistance to TST/IGRA conversion is linked to regulation of lipid accumulation in monocytes, which could facilitate early Mtb clearance among RSTR subjects through IFNγ-independent mechanisms.IMPORTANCETuberculosis (TB) remains an enduring global health challenge with millions of deaths and new cases each year. Despite recent advances in TB treatment, we lack an effective vaccine or a durable cure. While heavy exposure to often results in latent TB latent infection (LTBI), subpopulations exist that are either resistant to infection or contain Mtb with interferon-gamma (IFNγ)-independent mechanisms not indicative of LTBI. These resisters provide an opportunity to investigate the mechanisms of TB disease and discover novel therapeutic targets. Here, we compare monocyte epigenetic profiles of RSTR and LTBI from a Ugandan household contact cohort. We identify methylation signatures in host lipid and cholesterol pathways with potential relevance to early TB clearance before the sustained IFN responses indicative of LTBI. This adds to a growing body of literature linking TB disease outcomes to host lipids.
（Mtb）暴露可导致多种结果，包括清除、潜伏性结核感染（LTBI）和肺结核（TB）。一些暴露严重的个体抵抗结核菌素皮肤试验（TST）和干扰素-γ（IFNγ）释放试验（IGRA）转换（RSTR），这表明他们采用了 IFNγ 非依赖性的 Mtb 控制机制。在这里，我们比较了乌干达家庭接触队列中 RSTR 和 LTBI 的单核细胞表观遗传谱。未感染的 RSTR 和 LTBI 单核细胞的染色质可及性没有差异。相比之下，甲基化在 174 个 CpG 位点和 63 个基因组区域显著不同。与该队列之前的转录发现一致，差异甲基化在脂质和胆固醇相关途径中富集，包括 APOC3、KCNQ1 和 PLA2G3 基因。此外，甲基化在 Hippo 信号通路中富集，该通路与胆固醇稳态有关，包括 CIT 和 SHANK2。脂质外排和 Hippo 信号通路也与 RSTR 中对 Mtb 的基因表达以及来自独立健康供体队列的单核细胞衍生巨噬细胞（MDM）中 IFN 刺激有关。此外，与 LTBI 相比，RSTR 的血清来源高密度脂蛋白具有更高的 ABCA1 介导的胆固醇流出能力（CEC）。我们的研究结果表明，TST/IGRA 转换的抗性与单核细胞中脂质积累的调节有关，这可能通过 IFNγ 非依赖性机制促进 RSTR 受试者早期清除 Mtb。
结核病（TB）仍然是一个持久的全球健康挑战，每年都有数百万人死亡和新发病例。尽管最近在结核病治疗方面取得了进展，但我们仍然缺乏有效的疫苗或持久的治愈方法。尽管大量接触通常会导致潜伏性结核感染（LTBI），但存在一些人群对感染具有抵抗力或含有不提示 LTBI 的 IFNγ 非依赖性机制的 Mtb。这些抵抗者为研究结核病发病机制和发现新的治疗靶点提供了机会。在这里，我们比较了乌干达家庭接触队列中 RSTR 和 LTBI 的单核细胞表观遗传谱。我们确定了宿主脂质和胆固醇途径中的甲基化特征，这些特征可能与 LTBI 提示的持续 IFN 反应之前的早期 TB 清除有关。这增加了将结核病疾病结果与宿主脂质联系起来的文献数量。
