New insights into the transposition mechanisms of IS6110 and its dynamic distribution between Mycobacterium tuberculosis Complex lineages.

Jesús Gonzalo-Asensio,Carlos Martín,Nacho Aguiló,Carlos Lampreave,Isabel Otal,Santiago Uranga,Irene Pérez,Alberto Cebollada,Ana Picó,Sofía Samper,Carmen Buchrieser

doi:10.1371/journal.pgen.1007282

Jesús Gonzalo-Asensio, Carlos Martín + Show 9 more

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https://doi.org/10.1371/journal.pgen.1007282

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Journal: PLoS Genetics	Publication Date: Apr 12, 2018
Citations: 57	License type: CC BY 4.0

Abstract

The insertion Sequence IS6110, only present in the pathogens of the Mycobacterium tuberculosis Complex (MTBC), has been the gold-standard epidemiological marker for TB for more than 25 years, but biological implications of IS6110 transposition during MTBC adaptation to humans remain elusive. By studying 2,236 clinical isolates typed by IS6110-RFLP and covering the MTBC, we remarked a lineage-specific content of IS6110 being higher in modern globally distributed strains. Once observed the IS6110 distribution in the MTBC, we selected representative isolates and found a correlation between the normalized expression of IS6110 and its abundance in MTBC chromosomes. We also studied the molecular regulation of IS6110 transposition and we found a synergistic action of two post-transcriptional mechanisms: a -1 ribosomal frameshift and a RNA pseudoknot which interferes translation. The construction of a transcriptionally active transposase resulted in 20-fold increase of the transposition frequency. Finally, we examined transposition in M. bovis and M. tuberculosis during laboratory starvation and in a mouse infection model of TB. Our results shown a higher transposition in M. tuberculosis, that preferably happens during TB infection in mice and after one year of laboratory culture, suggesting that IS6110 transposition is dynamically adapted to the host and to adverse growth conditions.

Highlights

Tuberculosis (TB) is the largest infectious cause of death in history having claimed more deaths than smallpox, malaria, plague, influenza and AIDS together [1]
Upon examination of fully sequenced and assembled M. tuberculosis Complex (MTBC) genomes, we observe that the M. bovis AF2122/97 reference strain contains a single IS6110 while M. africanum and M. tuberculosis have higher copy numbers of this element (Fig 1A)
When interrogating M. canettii, considered as the most ancestral linage known from which all MTBC members emerged, we only found potentially functional IS6110 sequences in subgroups STB-A, -D, and–L

Summary

Introduction

Tuberculosis (TB) is the largest infectious cause of death in history having claimed more deaths than smallpox, malaria, plague, influenza and AIDS together [1]. The adaptation of M. tuberculosis to the host is extremely complex. The essential, yet unanswered question, on the natural history of TB is when M. tuberculosis decides to establish either LTBI in the host, resembling the lysogenic cycle of lambda phage, or to cause pulmonary TB disease, like the lytic cycle of lambda phage. In this latter case, M. tuberculosis decide to kill the host with the aim of achieving transmission to new hosts [3]

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