The Prophage and Plasmid Mobilome as a Likely Driver of Mycobacterium abscessus Diversity

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. IMPORTANCE Mycobacterium 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.

Genome reorganization during emergence of host-associated Mycobacterium abscessus

“…We did not attempt to identify plasmids, as short-read sequencing data are unreliable for this purpose [75]. Plasmids are likely to be another mechanism of LGT, as previous studies have identified conjugative plasmids in M. abscessus [8,[14][15][16].…”

“…abscessus recombines more frequently than the other subspecies [13]. M. abscessus encodes a diverse array of plasmids and prophages [8,[14][15][16]; the extent to which distinct mechanisms of lateral gene transfer (LGT) shape diversity of M. abscessus is unknown.…”

Genetic diversification of persistent Mycobacterium abscessus within cystic fibrosis patients

“…The genome from isolate 09–13-3 comprised a chromosome of a size of 4.949.160 bp and a plasmid of 24.978 bp. This plasmid (pMabs-09-13, plasmid map in Supplementary Figure S2 A) exhibits an identity of 99.86% (with a coverage of 100%) to plasmids pGD42-1 (accession CP065281.1), pGD69A-1 (accession CP065270.1), and pGD69B-1 (accession CP065267.1) described by Dedrick et al [ 24 ]. Supplementary Figure S2 B shows an alignment of plasmids pMabs-09-13 and pGD42-1.…”

Wildy Prize Lecture, 2020–2021: Who wouldn’t want to discover a new virus?

“…The question now is whether this success can be translated into other patients with similar M. abscessus infections. We are finding that there is enormous variation among M. abscessus clinical isolates in their phage infection profiles, and it will require considerable effort to assemble a phage cocktail that acts broadly across this strain variation [ 61, 62 ]. Nonetheless, if phages can be matched to a patient’s bacterial isolate, the prospects of providing substantial clinical benefits are considerable.…”