Pathogenic Determinants of the Mycobacterium kansasii Complex: An Unsuspected Role for Distributive Conjugal Transfer

Abstract

The Mycobacterium kansasii species comprises six subtypes that were recently classified into six closely related species; Mycobacterium kansasii (formerly M. kansasii subtype 1), Mycobacterium persicum (subtype 2), Mycobacterium pseudokansasii (subtype 3), Mycobacterium ostraviense (subtype 4), Mycobacterium innocens (subtype 5) and Mycobacterium attenuatum (subtype 6). Together with Mycobacterium gastri, they form the M. kansasii complex. M. kansasii is the most frequent and most pathogenic species of the complex. M. persicum is classically associated with diseases in immunosuppressed patients, and the other species are mostly colonizers, and are only very rarely reported in ill patients. Comparative genomics was used to assess the genetic determinants leading to the pathogenicity of members of the M. kansasii complex. The genomes of 51 isolates collected from patients with and without disease were sequenced and compared with 24 publicly available genomes. The pathogenicity of each isolate was determined based on the clinical records or public metadata. A comparative genomic analysis showed that all M. persicum, M. ostraviense, M innocens and M. gastri isolates lacked the ESX-1-associated EspACD locus that is thought to play a crucial role in the pathogenicity of M. tuberculosis and other non-tuberculous mycobacteria. Furthermore, M. kansasii was the only species exhibiting a 25-Kb-large genomic island encoding for 17 type-VII secretion system-associated proteins. Finally, a genome-wide association analysis revealed that two consecutive genes encoding a hemerythrin-like protein and a nitroreductase-like protein were significantly associated with pathogenicity. These two genes may be involved in the resistance to reactive oxygen and nitrogen species, a required mechanism for the intracellular survival of bacteria. Three non-pathogenic M. kansasii lacked these genes likely due to two distinct distributive conjugal transfers (DCTs) between M. attenuatum and M. kansasii, and one DCT between M. persicum and M. kansasii. To our knowledge, this is the first study linking DCT to reduced pathogenicity.

A Murine Model of Mycobacterium kansasii Infection Reproducing Necrotic Lung Pathology Reveals Considerable Heterogeneity in Virulence of Clinical Isolates

“…We observed that VF genes belonging to the functional category “virulence, detoxification, adaptation” have undergone a massive reduction in M. kansasii when compared to M. tuberculosis H37Rv, including the significant decrease in the toxin–antitoxin’s subsystem genes previously reported by Wang et al (2015) . Additionally, in accordance with previous observations ( Wang et al, 2015 ; Tagini et al, 2021 ), our analysis showed the presence of all key RD1 genes, including the ESAT-6 and CFP-10, coding for the essential components of the ESX-1 secretion system, and the loci encoding for the ESX-1 secretion-associated proteins, ESP. These genes were conserved in all genomes of the Brazilian M. kansasii isolates, although some of the isolates exhibited heterogeneity in copy number (data not shown) and numerous SNPs in these genes.…”

Differences in skin test reactions to official and defined antigens in guinea pigs exposed to non-tuberculous and tuberculous bacteria

“…Their ESAT-6 and CFP-10 nucleotide sequences are almost equal (different only in 3 and 2 base positions, respectively) and result in identical amino acid sequences, although expression level is lower in M. persicum . Furthermore, a recent report concluded that the type-VII secretion system ESX-1-related EspACD locus, which is required for the secretion and function of EsxA (ESAT-6) and EsxB (CFP-10), is absent from M. persicum isolates 32 . Despite this, the effect of increasing the challenge dose of this isolate should be investigated also.…”

A Polymorphic Gene within the Mycobacterium smegmatis esx1 Locus Determines Mycobacterial Self-Identity and Conjugal Compatibility

“…The bias for sequencing clinical specimens likely underestimates mosaicism in mycobacterial genomes, as clinical isolates are often derived from clonal expansions that have had little exposure to other mycobacteria and, thus, the opportunity for HGT. Examples of genomic mosaicism have been observed in the genomes of isolates from the Mycobacterium kansasii complex, M. canettii , and M. abscessus ( 15 , 16 ). For M. canettii , there is more direct evidence for DCT, as not only do natural isolates have mosaic genomes ( 17 ), but strains can also be cocultured to produce recombinants with mosaic genomes ( 18 , 19 ).…”