Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Systems Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Cell Rep. 2023 Oct 31;42(10):113189. doi: 10.1016/j.celrep.2023.113189. Epub 2023 Oct 5.
Host-pathogen interactions are complex by nature, and the host developmental stage increases this complexity. By utilizing Caenorhabditis elegans larvae as the host and the bacterium Pseudomonas aeruginosa as the pathogen, we investigated how a developing organism copes with pathogenic stress. By screening 36 P. aeruginosa isolates, we found that the CF18 strain causes a severe but reversible developmental delay via induction of reactive oxygen species (ROS) and mitochondrial dysfunction. While the larvae upregulate mitophagy, antimicrobial, and detoxification genes, mitochondrial unfolded protein response (UPR) genes are repressed. Either antioxidant or iron supplementation rescues the phenotypes. We examined the virulence factors of CF18 via transposon mutagenesis and RNA sequencing (RNA-seq). We found that non-phenazine toxins that are regulated by quorum sensing (QS) and the GacA/S system are responsible for developmental slowing. This study highlights the importance of ROS levels and mitochondrial health as determinants of developmental rate and how pathogens can attack these important features.
宿主-病原体相互作用本质上很复杂，而宿主的发育阶段会增加这种复杂性。本研究通过利用秀丽隐杆线虫幼虫作为宿主和铜绿假单胞菌作为病原体，研究了发育中的生物体如何应对致病应激。通过对 36 株铜绿假单胞菌分离株进行筛选，我们发现 CF18 菌株通过诱导活性氧（ROS）和线粒体功能障碍，导致严重但可逆的发育迟缓。虽然幼虫上调了自噬、抗菌和解毒基因，但线粒体未折叠蛋白反应（UPR）基因受到抑制。抗氧化剂或铁补充均可挽救表型。我们通过转座子诱变和 RNA 测序（RNA-seq）研究了 CF18 的毒力因子。我们发现，群体感应（QS）和 GacA/S 系统调控的非吩嗪毒素是导致发育迟缓的原因。本研究强调了 ROS 水平和线粒体健康作为决定发育速度的重要因素，以及病原体如何攻击这些重要特征。
