Abstract
Pulmonary disease caused by nontuberculous mycobacteria (NTM) is increasing worldwide. Mycobacterium avium is the most clinically significant NTM species in humans and animals, and comprises four subspecies: M. avium subsp. avium (MAA), M. avium subsp. silvaticum (MAS), M. avium subsp. paratuberculosis (MAP), and M. avium subsp. hominissuis (MAH). To improve our understanding of the genetic landscape and diversity of M. avium and its role in disease, we performed a comparative genome analysis of 79 M. avium strains. Our analysis demonstrated that MAH is an open pan-genome species. Phylogenetic analysis based on single nucleotide variants showed that MAH had the highest degree of sequence variability among the subspecies, and MAH strains isolated in Japan and those isolated abroad possessed distinct phylogenetic features. Furthermore, MAP strains, MAS and MAA strains isolated from birds, and many MAH strains that cause the progression of pulmonary disease were grouped in each specific cluster. Comparative genome analysis revealed the presence of genetic elements specific to each lineage, which are thought to be acquired via horizontal gene transfer during the evolutionary process, and identified potential genetic determinants accounting for the pathogenic and host range characteristics of M. avium.
Highlights
(MAP) causes John’s disease in ruminants; and M. avium subsp. hominissuis (MAH) infects mainly pigs and humans[16,17,18]
To investigate the genomic features of MAH that cause the progression of pulmonary disease, we sequenced the genomes of 46 MAH isolates from 17 patients with progressive disease and 29 patients with stable disease, in addition to the previously determined complete genome sequence of MAH strain TH13524, which was used as a reference genome in the analysis
variable number tandem repeats (VNTR) typing analysis using M. avium tandem repeats (MATR) of isolates from patients with pulmonary MAH disease demonstrated a relationship between VNTR genotype and disease progression
Summary
(MAP) causes John’s disease in ruminants; and M. avium subsp. hominissuis (MAH) infects mainly pigs and humans[16,17,18]. Variable number tandem repeats (VNTR) typing analysis of isolates from patients with pulmonary NTM disease revealed that isolates from patients with progressive pulmonary disease and those with stable pulmonary disease are clustered differently[21,22,23], which suggests the involvement of bacterial factors in the progression of pulmonary NTM disease. We determined the complete genome sequence of strain TH135 isolated from a serious case with worsening pulmonary MAH disease[24], and further demonstrated the presence of a circular plasmid, pMAH13525. This novel plasmid consists of 194,711 nucleotides and has 164 coding sequences (CDSs), some of which encode proteins involved in the pathogenicity of mycobacteria and their resistance to antimicrobial agents. To improve our understanding of the genetic landscape and diversity of M. avium and its role in disease, we performed a comparative genome analysis of 79 M. avium strains including 46 novel MAH genomes
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