Whole transcriptomic and proteomic analyses of an isogenic M. tuberculosis clinical strain with a naturally occurring 15 Kb genomic deletion.

Carla Duncan,Frances B Jamieson,Helle Bielefeldt-Ohmann,Angelo Izzo,Linda Izzo,Carolina Mehaffy,Jolynn Troudt,Igor Mokrousov

doi:10.1371/journal.pone.0179996

Carla Duncan, Frances B Jamieson + Show 6 more

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https://doi.org/10.1371/journal.pone.0179996

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Abstract

Tuberculosis remains one of the most difficult to control infectious diseases in the world. Many different factors contribute to the complexity of this disease. These include the ability of the host to control the infection which may directly relate to nutritional status, presence of co-morbidities and genetic predisposition. Pathogen factors, in particular the ability of different Mycobacterium tuberculosis strains to respond to the harsh environment of the host granuloma, which includes low oxygen and nutrient availability and the presence of damaging radical oxygen and nitrogen species, also play an important role in the success of different strains to cause disease. In this study we evaluated the impact of a naturally occurring 12 gene 15 Kb genomic deletion on the physiology and virulence of M. tuberculosis. The strains denominated ON-A WT (wild type) and ON-A NM (natural mutant) were isolated from a previously reported TB outbreak in an inner city under-housed population in Toronto, Canada. Here we subjected these isogenic strains to transcriptomic (via RNA-seq) and proteomic analyses and identified several gene clusters with differential expression in the natural mutant, including the DosR regulon and the molybdenum cofactor biosynthesis genes, both of which were found in lower abundance in the natural mutant. We also demonstrated lesser virulence of the natural mutant in the guinea pig animal model. Overall, our findings suggest that the ON-A natural mutant is less fit to cause disease, but nevertheless has the potential to cause extended transmission in at-risk populations.

Highlights

Mycobacterium tuberculosis (Mtb), the causal agent of tuberculosis (TB) is the leading cause of death due to an infectious disease, surpassing HIV in 2014 [1]
Animals infected with the ON-A natural mutant (NM) displayed less lung involvement, necrosis and fibrosis at day 60 p.i. compared to the ON-A wild type (WT) infected animals (S1 Fig)
It is important to highlight that the last time point (90 d.p.i) included animals euthanized at days 78 (n = 2) and 108 (n = 3) for the NM as opposed to animals in the WT group which had to be euthanized at earlier time points, at days 63 (n = 1), 73 (n = 1), 82 (n = 1) and 96 (n = 2) due to increase in malaise and other signs and symptoms of disease

Summary

Introduction

Mycobacterium tuberculosis (Mtb), the causal agent of tuberculosis (TB) is the leading cause of death due to an infectious disease, surpassing HIV in 2014 [1]. We hypothesize that in certain high risk populations in which factors such as nutrition, recreational drug use and the presence of co-morbidities increase the likelihood of active TB disease, Mtb strains that may not be as fit to cause disease, such as the ON-A natural mutant, can still adapt and even thrive resulting in extended transmission. To address this hypothesis we performed a systems biology study focusing on both proteomic and transcriptomic analyses, supplemented with data from in vivo infections using the guinea pig animal model of TB. The comprehensive approach allowed us to assess the physiological status and virulence of the ON-A natural mutant and ON-A wild type strains

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