Existing antibiotics are inadequate to defeat tuberculosis (TB), a leading cause of death worldwide. We sought potential targets for host-directed therapies (HDTs) by investigating the host immune response to mycobacterial infection. We used high-throughput CRISPR knockout and CRISPR interference (CRISPRi) screens to identify perturbations that improve the survival of human phagocytic cells infected with Mycobacterium bovis BCG (Bacillus Calmette-Guérin), as a proxy for Mycobacterium tuberculosis (Mtb). Many of these perturbations constrained the growth of intracellular mycobacteria. We identified over 100 genes associated with diverse biological pathways as potential HDT targets. We validated key components of the type I interferon and aryl hydrocarbon receptor signaling pathways that respond to the small-molecule inhibitors cerdulatinib and CH223191, respectively; these inhibitors enhanced human macrophage survival and limited the intracellular growth of Mtb. Thus, high-throughput functional genomic screens, by elucidating highly complex host-pathogen interactions, can serve to identify HDTs to potentially improve TB treatment.

现有的抗生素不足以击败结核病 (TB)，这是全球主要的死亡原因。我们通过研究宿主对分枝杆菌感染的免疫反应来寻找宿主导向疗法 (HDT) 的潜在目标。我们使用高通量 CRISPR 敲除和 CRISPR 干扰 (CRISPRi) 筛选来确定扰动，以提高感染牛分枝杆菌BCG（卡介苗）的人类吞噬细胞的存活率，作为结核分枝杆菌的代理（山）。许多这些扰动限制了细胞内分枝杆菌的生长。我们确定了 100 多个与不同生物途径相关的基因作为潜在的 HDT 目标。我们验证了分别响应小分子抑制剂 cerdulatinib 和 CH223191 的 I 型干扰素和芳烃受体信号通路的关键成分；这些抑制剂增强了人类巨噬细胞的存活并限制了 Mtb 的细胞内生长。因此，通过阐明高度复杂的宿主-病原体相互作用，高通量功能基因组筛选可用于鉴定 HDT，从而潜在地改善结核病治疗。