Gibbs Kyle D, Wang Liuyang, Yang Zhuo, Anderson Caroline E, Bourgeois Jeffrey S, Cao Yanlu, Gaggioli Margaret R, Biel Martin, Puertollano Rosa, Chen Cheng-Chang, Ko Dennis C
Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA.
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Cell Genom. 2023 Apr 4;3(5):100290. doi: 10.1016/j.xgen.2023.100290. eCollection 2023 May 10.
Human genetic diversity can reveal critical factors in host-pathogen interactions. This is especially useful for human-restricted pathogens like serovar Typhi ( Typhi), the cause of typhoid fever. One key defense during bacterial infection is nutritional immunity: host cells attempt to restrict bacterial replication by denying bacteria access to key nutrients or supplying toxic metabolites. Here, a cellular genome-wide association study of intracellular replication by . Typhi in nearly a thousand cell lines from around the world-and extensive follow-up using intracellular Typhi transcriptomics and manipulation of magnesium availability-demonstrates that the divalent cation channel mucolipin-2 (MCOLN2 or TRPML2) restricts Typhi intracellular replication through magnesium deprivation. Mg currents, conducted through MCOLN2 and out of endolysosomes, were measured directly using patch-clamping of the endolysosomal membrane. Our results reveal Mg limitation as a key component of nutritional immunity against Typhi and as a source of variable host resistance.
人类遗传多样性能够揭示宿主与病原体相互作用中的关键因素。这对于诸如伤寒杆菌（伤寒血清型）这类仅感染人类的病原体而言尤为有用，伤寒杆菌是伤寒热的病原体。细菌感染过程中的一种关键防御机制是营养免疫：宿主细胞试图通过阻止细菌获取关键营养物质或提供有毒代谢产物来限制细菌复制。在此，对来自世界各地近千种细胞系中伤寒杆菌的细胞内复制进行了全基因组关联研究，并利用细胞内伤寒杆菌转录组学以及对镁可利用性的调控进行了广泛的后续研究，结果表明二价阳离子通道黏脂素-2（MCOLN2 或 TRPML2）通过剥夺镁来限制伤寒杆菌的细胞内复制。通过对溶酶体膜进行膜片钳直接测量了通过 MCOLN2 并流出内溶酶体的镁电流。我们的研究结果揭示了镁限制是针对伤寒杆菌的营养免疫的关键组成部分，也是宿主抗性差异的一个来源。
