Mycobacterium intracellulare ABSURDO is a novel clinical isolate with three colony morphotypes that vary in pathogenicity and sequence at the PKS and MtrA loci

Mycobacterium intracellulare is a nontuberculous mycobacteria (NTM) species which can cause serious and sometimes fatal disease in immunocompromised individuals. Other NTM species, including M. avium and M. abscessus, commonly exhibit two colony morphotypes (smooth and rough) which vary in appearance and liquid growth properties. Here we characterize a novel clinical isolate of M. intracellulare which exhibits three (not two) colony morphotypes which differ in appearance, liquid growth properties, acid-fastness and in vivo survival following infection of mice via an inhalational exposure model. The genome of this isolate, which we have termed ABSURDO, as well as the genome of each morphotype components, aligns with that of M. intracellulare yet contains [~]16% more protein coding sequences than the M. intracellulare type strain ATCC 13590T. Variation analysis of each morphotype genome revealed that across the three morphotypes there were only two mutations which had a high likelihood of causing a phenotype due to a genetic change: one in the gene encoding modular polyketide synthase (PKS), and another in the two component system response regulator MtrA. Neither of these genes have been previously implicated in the morphotype shifting of an NTM. In summary, M. intracellulare ABSURDO is a novel pathogenic isolate with a genome that aligns with (but is nevertheless larger than) the M. intracellulare type strain and comprises three morphotype components which differ in two genes that have not been implicated in NTM appearance, acid-fastness, in vitro and in vivo growth.