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Effect of Iron and carbon sources on in-vitro transcriptional responses to growth arrest of Mycobacterium tuberculosis

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

1:University of Zaragoza; 2:Universidad Autónoma de Madrid; 3:Corporación CorpoGen

The establishment of Mycobacterium tuberculosis (Mtb) long-term infection in vivo depends on several factors, one of which is the availability of key nutrients such as iron (Fe), and long-chain fatty acids (LCFA). The relation between Fe deprivation inside and outside the granuloma, and the capacity of Mtb to accumulate lipids and persist in the absence of growth is not well understood. The current knowledge of how Mtb modifies its lipid composition in response to growth arrest, depending on iron and lipids availability is scarce. To explore these topics, we compare genome-wide transcriptomic profiles of Mtb at exponential and stationary growth phases using cultures with glycerol–dextrose, glycerol, and LCFA as the carbon sources, in the presence or absence of iron. We focused on comparing Fe effects on response to growth arrest with either glycerol–dextrose or glycerol constituting the main carbon source for the bacteria; and the effect of shifting from glycerol and dextrose as main carbon sources to LCFA in the presence of Fe. We found that transcriptomic responses to growth arrest, considered as the transition from exponential to stationary phase are enhanced when culture conditions incorporate nutrient cues characteristic of the phagosomal environment such as low levels of iron and high concentration of LCFAs. Effects of low iron levels and LCFA on responses to growth arrest are significantly correlated and impact key pathways to bacterial survival upon phagocytosis such as energy production and stress responses, suggesting a convergent signaling dynamics of these cues towards the dormant phenotype.

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