Abstract
Mycobacterium abscessus is an emerging pathogen that is often refractory to antibiotic control. Treatment is further complicated by considerable variation among clinical isolates in both their genetic constitution and their clinical manifestations. Here, we show that the prophage and plasmid mobilome is a likely contributor to this variation. Prophages and plasmids are common, abundant, and highly diverse, and code for large repertoires of genes influencing virulence, antibiotic susceptibility, and defense against viral infection. At least 85% of the strains we describe carry one or more prophages, representing at least 17 distinct and diverse sequence "clusters," integrated at 18 different attB locations. The prophages code for 19 distinct configurations of polymorphic toxin and toxin-immunity systems, each with WXG-100 motifs for export through type VII secretion systems. These are located adjacent to attachment junctions, are lysogenically expressed, and are implicated in promoting growth in infected host cells. Although the plethora of prophages and plasmids confounds the understanding of M. abscessus pathogenicity, they also provide an abundance of tools for M. abscessus engineering.IMPORTANCEMycobacterium abscessus is an important emerging pathogen that is challenging to treat with current antibiotic regimens. There is substantial genomic variation in M. abscessus clinical isolates, but little is known about how this influences pathogenicity and in vivo growth. Much of the genomic variation is likely due to the large and varied mobilome, especially a large and diverse array of prophages and plasmids. The prophages are unrelated to previously characterized phages of mycobacteria and code for a diverse array of genes implicated in both viral defense and in vivo growth. Prophage-encoded polymorphic toxin proteins secreted via the type VII secretion system are common and highly varied and likely contribute to strain-specific pathogenesis.
Highlights
Mycobacterium abscessus is an emerging pathogen that is often refractory to antibiotic control
Phage specificity is determined by numerous factors, including receptor accessibility, restriction-modification, CRISPR-Cas, and abortive-infection systems, many of which can be expressed from prophages or plasmids [2,3,4,5,6]
Elucidating its pathogenic capacity is complicated by its genetic variability, much of which could be driven by its expansive mobilome of prophages and plasmids, many of which code for genes predicted to influence survival and growth in vivo as well as antibiotic- and phage-resistance profiles (Fig. 4, Fig. 5)
Summary
Mycobacterium abscessus is an emerging pathogen that is often refractory to antibiotic control. Prophages and plasmids are common, abundant, and highly diverse, and code for large repertoires of genes influencing virulence, antibiotic susceptibility, and defense against viral infection. The prophages code for distinct configurations of polymorphic toxin and toxin-immunity systems, each with WXG-100 motifs for export through type VII secretion systems These are located adjacent to attachment junctions, are lysogenically expressed, and are implicated in promoting growth in infected host cells. Because prophages and plasmids are highly mobile, these are key contributors to variations in phage infection among otherwise closely related bacterial strains. A large collection of mycobacteriophages have been isolated on Mycobacterium smegmatis and genomically characterized [8] They are genetically diverse and are currently grouped into 29 clusters (A to Z, AA to AC) according to overall sequence. Very few of the phages infect Mycobacterium abscessus, but a cocktail of three phages within this subset were used for therapy of a disseminated drug-resistant infection in a cystic fibrosis patient with a bilateral lung transplant [15]; two of the phages were engineered to convert from temperate to being obligatorily lytic [15] using a recombineering strategy [16]
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