Mycobacterium abscessus virulence traits unraveled by transcriptomic profiling in amoeba and macrophages

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Abstract
Free-living amoebae are thought to represent an environmental niche in which amoeba-resistant bacteria may evolve towards pathogenicity. To get more insights into factors playing a role for adaptation to intracellular life, we characterized the transcriptomic activities of the emerging pathogen Mycobacterium abscessus in amoeba and murine macrophages (Mϕ) and compared them with the intra-amoebal transcriptome of the closely related, but less pathogenic Mycobacterium chelonae. Data on up-regulated genes in amoeba point to proteins that allow M. abscessus to resist environmental stress and induce defense mechanisms, as well as showing a switch from carbohydrate carbon sources to fatty acid metabolism. For eleven of the most upregulated genes in amoeba and/or Mϕ, we generated individual gene knock-out M. abscessus mutant strains, from which ten were found to be attenuated in amoeba and/or Mϕ in subsequence virulence analyses. Moreover, transfer of two of these genes into the genome of M. chelonae increased the intra-Mϕ survival of the recombinant strain. One knock-out mutant that had the gene encoding Eis N-acetyl transferase protein (MAB_4532c) deleted, was particularly strongly attenuated in Mϕ. Taken together, M. abscessus intra-amoeba and intra-Mϕ transcriptomes revealed the capacity of M. abscessus to adapt to an intracellular lifestyle, with amoeba largely contributing to the enhancement of M. abscessus intra-Mϕ survival. The emerging pathogen Mycobacterium abscessus differs from other rapidly growing mycobacteria by its ability to survive phagocytosis by human macrophages. These virulence traits render M. abscessus pathogenic in vulnerable hosts with structural lung disease. How patients become infected with M. abscessus remains unclear, as M. abscessus is not or only very rarely isolated from the environment. Co-culturing of M. abscessus and amoeba increases the virulence of the bacteria for subsequent mouse infection, but little is known about M. abscessus virulence in general. Until now, the prediction of M. abscessus virulence factors was essentially based on the comparative analysis of the genome of M. abscessus with that of Mycobacterium chelonae, a closely related mycobacterium that occasionally causes opportunistic human infections, but to a much lesser extent than M. abscessus. Here, by transcriptomic and functional approaches, we decipher a global view on M. abscessus adaptation to intracellular life.
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Funding Information
  • Association Vaincre la Mucoviscidose (RF20150501377)
  • Agence Nationale de la Recherche (ANR-10-LABX-62-IBEID)
  • Agence Nationale de la Recherche (ANR-16-CE15-0003)
  • Agence Nationale de la Recherche (ANR-16-CE35-0009)
  • Fondation pour la Recherche Médicale (DEQ20130326471)

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