Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, United States.
Department of Medicine, University of Washington, Seattle, WA, United States.
Front Immunol. 2024 Mar 7;15:1359178. doi: 10.3389/fimmu.2024.1359178. eCollection 2024.
The heterogeneity of outcomes after (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis.
We mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion.
cis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR<0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR<0.1], but not classified as eQTL in uninfected condition [FDR≥0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression of , an Mtb-dependent eQTL gene, was associated with induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes.
These findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis.
暴露于 （Mtb） 后结果的异质性是与宿主-病原体共同进化几千年相关的难题。我们假设人类髓样细胞中含有针对 Mtb 的遗传编码反应，这些反应调节结核病（TB）发病机制中的关键步骤。
我们通过对 80 名乌干达肺结核病例家庭接触者的 Mtb 感染单核细胞进行 RNAseq 全基因组表达数量性状基因座（eQTL）作图，以鉴定单核细胞特异性、Mtb 依赖性 eQTL 及其与细胞因子表达以及结核菌素皮肤试验（TST）和干扰素-γ释放试验（IGRA）转化的临床耐药性的关联。
在 Mtb 感染的单核细胞中鉴定出顺式 eQTL（n=1567）（FDR<0.01），包括 16 个基因中的 29 个 eQTL，这些基因对 Mtb 具有依赖性（对 Mtb：基因型相互作用具有显著意义 [FDR<0.1]，但在未感染条件下未被归类为 eQTL [FDR≥0.01]）。eQTL 的一部分与 Mtb 诱导的细胞因子表达（n=8）和/或 TST/IGRA 转化的临床耐药性（n=1）相关。作为 Mtb 依赖性 eQTL 基因的 的表达与 Mtb 感染和 DNA 配体诱导细胞中的 诱导相关。网络和富集分析确定脂肪酸代谢是与 eQTL 基因相关的途径。
这些发现表明单核细胞基因包含 Mtb 依赖性 eQTL，其中一部分与细胞因子表达和/或 TST/IGRA 转化的临床耐药性相关，为调节对 Mtb 感染和 TB 发病机制易感性的免疫遗传途径提供了见解。
