Microbial metabolism disrupts cytokine activity to impact host immune response

• 成果类型: Article
• 署名作者: Marshall, Eleanor K. P.; Nunes, Catarina; Burbaud, Sophie; Vincent, Crystal M.; Munroe, Natalie O.; da Silva, Carolina J. Simoes; Wadhawan, Ashima; Pearson, William H.; Sangen, Jasper; Boeck, Lucas; Floto, R. Andres; Dionne, Marc S.; Medzhitov, Ruslan
• 署名单位: Imperial College London; Imperial College London; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); University of Cambridge; University of Basel; Papworth Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13421
• DOI: 10.1073/pnas.2405719121
• 发表日期: 2024-11-12
• 关键词: mycobacterium-tuberculosis; cystic-fibrosis; abscessus; survival; infection; protein; insulin

摘要

Host-pathogen interactions are shaped by the metabolic status of both the host and pathogen. The host must regulate metabolism to fuel the immune response, while the pathogen must extract metabolic resources from the host to enable its own survival. In this study, we focus on the metabolic interactions of Mycobacterium abscessus with Drosophila melanogaster. We identify MAB_1132c as an asparagine transporter required for pathogenicity in M. abscessus. We show that this requirement is specifically associated with damage to the host: flies infected with MAB_1132c knockout bacteria, or with wild- type bacteria grown in asparagine- restricted conditions, are longer lived without showing a significant change in bacterial load. This is associated with a reduction in the host innate immune response, demonstrated by the decreased transcription of antimicrobial peptides as well as a significant reduction in the ability of the infection to disrupt systemic insulin signaling. Much of the increase in host survival during infection with asparagine- limited M. abscessus can be attributed to alterations in unpaired cytokine signaling. This demonstrates that asparagine transport in M. abscessus prior to infection is not required for replicative fitness in vivo but does significantly influence the interaction with the host immune responses.