Multiple genetic paths including massive gene amplification allow <i>Mycobacterium tuberculosis</i> to overcome loss of ESX-3 secretion system substrates
Lin Wang, Emmanuel Asare, Amol C. Shetty, Freddy Sanchez-Tumbaco, Megan R. Edwards, Rajagopalan Saranathan, Brian Weinrick, Jiayong Xu, Bing Chen, Angèle Bénard, Gordon Dougan, Daisy W. Leung, Gaya K. Amarasinghe, John Chan, Christopher F. Basler, William R. Jacobs, JoAnn M. Tufariello
Abstract
Significance 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.