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Abstract
The capacity of Mycobacterium tuberculosis (Mtb) to sense, respond and adapt to a variable and hostile environment within the host makes it one of the most successful human pathogens. During different stages of infection, Mtb is surrounded by a plethora of lipid molecules and current evidence points out the relevance of fatty acids during the infectious process. In this study, we have compared the transcriptional response of Mtb to hypoxia in cultures supplemented with a mix of even long-chain fatty acids or dextrose as main carbon sources. Using RNA sequencing, we have identified differential expressed genes in early and late hypoxia, defined according to the in vitro Wayne and Hayes model, and compared the results with the exponential phase of growth in both carbon sources. We show that the number of genes over-expressed in the lipid medium was quite low in both, early and late hypoxia, relative to conditions including dextrose, with the exception of transcripts of stable and non-coding RNAs, which were more expressed in the fatty acid medium. We found that sigB and sigE were over-expressed in the early phase of hypoxia, confirming their pivotal role in early adaptation to low oxygen concentration independently of the carbon source. A drastic contrast was found with the transcriptional regulatory factors at early hypoxia. Only 2 transcriptional factors were over-expressed in early hypoxia in the lipid medium compared to 37 that were over-expressed in the dextrose medium. Instead of Rv0081, known to be the central regulator of hypoxia in dextrose, Rv2745c (ClgR), seems to play a main role in hypoxia in the fatty acid medium. The low level of genes associated to the stress-response during their adaptation to hypoxia in fatty acids, suggests that this lipid environment makes hypoxia a less stressful condition for the tubercle bacilli. Taken all together, these results indicate that the presence of lipid molecules shapes the metabolic response of Mtb to an adaptive state for different stresses within the host, including hypoxia. This fact could explain the success of Mtb to establish long-term survival during latent infection.
Highlights
It is estimated that more than two billion people in the world have latent tuberculosis infection (LTBI), an asymptomatic and non-infectious form of the disease where the causative agent, Mycobacterium tuberculosis (Mtb), is primarily in a dormant state (Dye et al, 1999; Getahun et al, 2015)
NRP1 phase was reached at day four after exponential phase in both fatty acids and dextrose medium (FNRP1 and Dextrose nonreplicative persistence 1 (DNRP1)); NRP2 phase was reached at day eight (FNRP2 and Dextrose non-replicative persistence 2 (DNRP2))
The high mapping reads against intergenic regions (IGRs) in the presence of fatty acids, especially in long chain fatty acid non-replicative persistence 2 (FNRP2), is similar to the IGRs expression observed in the stationary phase of bacilli growing in long chain fatty acids (LC-FA) (Rodríguez et al, 2014) when bacteria develop the dormant phenotype
Summary
It is estimated that more than two billion people in the world have latent tuberculosis infection (LTBI), an asymptomatic and non-infectious form of the disease where the causative agent, Mycobacterium tuberculosis (Mtb), is primarily in a dormant state (Dye et al, 1999; Getahun et al, 2015). Several studies have shown that the dormant bacillus must face different hostile microenvironments within the host to survive, including hypoxia, lack of nutrients, and acidic pH (Deb et al, 2009; Flentie et al, 2016) These wide spectra of host-induced stresses could explain the existence of several subpopulations of the tubercle bacilli, with diverse physiological states and with heterogeneous metabolic activities (Prosser et al, 2017). Most studies adopt the in vitro Wayne and Hayes method to study dormancy in Mtb, which mimic the hypoxic conditions inside a granuloma (Wayne and Hayes, 1996) In this model, oxygen is gradually eliminated from an exponential Mtb culture, originally in Dubos medium with dextrose as the carbon source. These conditions allow Mtb to adapt to what those authors called non-replicating persistence (NRP) states 1 and 2, with a remaining of 1 and 0.06% of oxygen, respectively
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