Ana Isabel Fernandes, Alexandre Jorge Pinto, Diogo Silvério, Ulrike Zedler, Carolina Ferreira, Iola F Duarte, Ricardo Silvestre, Anca Dorhoi, Margarida Saraiva
{"title":"基因多样的结核分枝杆菌分离株独立于巨噬细胞的代谢重构,操纵炎症小体的激活和 IL-1β 的分泌","authors":"Ana Isabel Fernandes, Alexandre Jorge Pinto, Diogo Silvério, Ulrike Zedler, Carolina Ferreira, Iola F Duarte, Ricardo Silvestre, Anca Dorhoi, Margarida Saraiva","doi":"10.1093/infdis/jiae583","DOIUrl":null,"url":null,"abstract":"The diversity of Mycobacterium tuberculosis (Mtb) impacts the outcome of tuberculosis. We previously showed that Mtb isolates obtained from patients with severe disease induced low inflammasome activation and IL-1β production by infected macrophages. Here we questioned whether this differential modulation of macrophages by Mtb isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting Mtb isolate. Paralleling single-TLR activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and HIF-1α. Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncouples Mtb-inflammasome modulation from the host metabolic reprogramming.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring\",\"authors\":\"Ana Isabel Fernandes, Alexandre Jorge Pinto, Diogo Silvério, Ulrike Zedler, Carolina Ferreira, Iola F Duarte, Ricardo Silvestre, Anca Dorhoi, Margarida Saraiva\",\"doi\":\"10.1093/infdis/jiae583\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The diversity of Mycobacterium tuberculosis (Mtb) impacts the outcome of tuberculosis. We previously showed that Mtb isolates obtained from patients with severe disease induced low inflammasome activation and IL-1β production by infected macrophages. Here we questioned whether this differential modulation of macrophages by Mtb isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting Mtb isolate. Paralleling single-TLR activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and HIF-1α. Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncouples Mtb-inflammasome modulation from the host metabolic reprogramming.\",\"PeriodicalId\":501010,\"journal\":{\"name\":\"The Journal of Infectious Diseases\",\"volume\":\"3 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-11-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Infectious Diseases\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/infdis/jiae583\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Infectious Diseases","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/infdis/jiae583","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring
The diversity of Mycobacterium tuberculosis (Mtb) impacts the outcome of tuberculosis. We previously showed that Mtb isolates obtained from patients with severe disease induced low inflammasome activation and IL-1β production by infected macrophages. Here we questioned whether this differential modulation of macrophages by Mtb isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting Mtb isolate. Paralleling single-TLR activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and HIF-1α. Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncouples Mtb-inflammasome modulation from the host metabolic reprogramming.