Hong Hyejeong, Dill-McFarland Kimberly A, Simmons Jason D, Peterson Glenna J, Benchek Penelope, Mayanja-Kizza Harriet, Boom W Henry, Stein Catherine M, Hawn Thomas R
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.
medRxiv. 2023 Aug 29:2023.08.28.23294698. doi: 10.1101/2023.08.28.23294698.
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 media 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.
结核分枝杆菌（Mtb）感染后结局的异质性是一个与宿主 - 病原体数千年共同进化相关的难题。我们假设人类髓系细胞含有基因编码的、针对Mtb的特异性反应，这些反应调节结核病（TB）发病机制中的关键步骤。我们利用来自80名乌干达肺结核病例家庭接触者的RNAseq，绘制了Mtb感染单核细胞中的全基因组表达定量性状位点（eQTL），以鉴定单核细胞特异性、依赖Mtb的eQTL及其与细胞因子表达以及对结核菌素皮肤试验（TST）和干扰素 - γ释放试验（IGRA）转换的临床抗性的关联。在Mtb感染的单核细胞中鉴定出顺式eQTL（n = 1,567）（FDR<0.01），包括16个基因中的29个eQTL，这些基因是依赖Mtb的（Mtb：基因型相互作用显著[FDR<0.1]，但在培养基条件下未分类为eQTL [FDR≥0.01]）。一部分eQTL与Mtb诱导的细胞因子表达（n = 8）和/或对TST/IGRA转换的临床抗性（n = 1）相关。一个依赖Mtb的eQTL基因的表达与Mtb感染和DNA配体诱导的细胞中的诱导相关。网络和富集分析确定脂肪酸代谢是与eQTL基因相关的一条途径。这些发现表明单核细胞基因含有依赖Mtb的eQTL，包括与细胞因子表达和/或对TST/IGRA转换的临床抗性相关的一个子集，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。
