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Mycobacterium tuberculosis (Mtb) transcriptional adaptations to growth arrest: unveiling the role of iron and carbon sources

J A Cárdenas-Pestana(1,2) S Alebouyeh(3,4) L Vázquez(3,4) R Prados-Rosales(3,4) P Del Portillo(5) M C Menéndez(3,4) M J García(3,4) J Sanz(1,2)

1:Universidad de Zaragoza; 2:Institute for Biocomputation and Physics of Complex Systems (BIFI); 3:Autonomous University of Madrid; 4:Department of Preventive Medicine and Public Health and Microbiology, School of Medicine; 5:Corporación CorpoGen, Bogota, Colombia

Mycobacterium tuberculosis (Mtb) adapts to diverse host environments by transitioning from active growth to dormancy. This process is regulated by transcriptional regulatory programs that are triggered, among other factors, by changes in the availability of different carbon sources and key nutrients like iron. While iron deprivation is a well-known trigger of the transcriptional adaptation to dormancy in Mtb, our understanding on how it interacts with the environmental availability of different carbon sources remains limited. To shed light on this question, we collected RNA-seq data from in vitro cultures of Mtb subject to different iron levels and carbon sources (glycerol, dextrose, and fatty acids), from exponential to stationary growth phases. As a result, we found that gene expression was significantly affected by iron deprivation during the stationary phase while showing minimal sensitivity during exponential growth, where only a limited number of genes coding mycobactins showed iron-dependent expression. These phase-dependent effects of iron deprivation on gene expression translate into an iron-dependent modulation of the magnitude of the response to growth arrest. Unexpectedly, a majority of the effects of iron deprivation on the magnitude of growth arrest responses were positive, implying stronger transcriptional changes during the transition to dormancy in iron-deprived media, particularly in cultures lacking fatty acids as a carbon source. Considering that, our results suggest an "OR-like" logic where bacteria integrate the sensing of both iron deprivation and lipid availability as relevant signaling cues to modulate the magnitude of its transcriptional adaptation to dormancy.

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