Multiple genetic paths including massive gene amplification allow Mycobacterium tuberculosis to overcome loss of ESX-3 secretion system substrates
Abstract
The Mycobacterium tuberculosis ( Mtb ) ESX-3 type VII secretion system plays a critical role in iron acquisition. Infection of mice with highly attenuated Mtb deletion mutants lacking esxG or esxH , genes encoding key ESX-3 substrates, unexpectedly yielded suppressor mutants with restored capacity to grow in vivo and in vitro in the absence of iron supplementation. Whole-genome sequencing identified two mechanisms of suppression, the disruption of a transcriptional repressor that regulates expression of an ESX-3 paralogous region encoding EsxR and EsxS, and a massive 38- to 60-fold gene amplification of this same region. These data are significant because they reveal a previously unrecognized iron acquisition regulon and inform mechanisms of Mtb chromosome evolution.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 22, 2022
- Source ID
- 10.1073/pnas.2112608119
Entities
People
- Amol C. Shetty
- Angèle Bénard
- Bing Chen
- Brian C Weinrick
- Christopher F Basler
- Daisy W Leung
- Emmanuel Asare
- Freddy Sanchez-tumbaco
- Gaya K. Amarasinghe
- Gordon Dougan
- Jiayong Xu
- Joann M. Tufariello
- John Chan
- Lin Wang
- Megan R. Edwards
- Rajagopalan Saranathan
- William Jacobs
Organizations
- Albert Einstein College of Medicine
- Georgia State University
- National Institute of Allergy and Infectious Diseases
- Trudeau Institute
- United States Department of Defense
- Washington University in St. Louis
- Wellcome Sanger Institute