Mycobacterium tuberculosis massive gene amplification to overcome loss of ESX-3 secretion system substrates

In a subset of infected mice, suppressor mutants of esxG or esxH deletions were isolated that enabled growth to high titers or restored virulence. Suppression was conferred by mechanisms that cause over-expression of an ESX-3 paralogous region that lacks genes for the secretion apparatus but encodes EsxR and EsxS, apparent ESX-3 orphan substrates that functionally compensate for lack of EsxG or EsxH. The mechanisms include the disruption of a transcriptional repressor and a massive 38- to 60-fold gene amplification. These data identify an iron acquisition regulon, provide new insight into T7SS and reveal a novel mechanism of Mtb chromosome evolution involving accordion-type amplification.