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Transcriptional Profile of Mycobacterium tuberculosis Replicating in Human Type II Alveolar Epithelial A549 cell line

ABSTRACT: Infection with Mycobacterium tuberculosis (M. tb) is initiated when an aerosol droplet carrying a few bacilli is inhaled into an alveolus. Alveolar epithelial cells (AEC) (type II and type I) are among the first cells encountered by the infecting bacteria and greatly outnumber macrophages in the alveolus. M. tb replicates dramatically (>20,000 fold) in a “non-migrating” compartment in the lung prior to the development of the cell-mediated immune response in aerosol-infected mice (Wolf AJ, 2008). M. tb DNA has been found in type II AEC in autopsied lung tissue of latently infected individuals (Hernandez-Pando R et. al, 2000; Barrios-Payan J et. al 2012), and M. tb-infected AEC in broncho-alveolar lavage (BAL) and in sputum samples from TB patients indicates the infection of these cells in active as well as latent human TB (Eum SY et. al, 2010). M. tb has been shown to infect and replicate in the human type II AEC line, A549, and passaging of M. tb through A549 increases M. tb invasiveness (Bermudez LE et.al, 2002). In this work, we have used DNA microarray analysis to investigate the transcriptome of M. tb replicating in type II AEC (A549) compared to M. tb grown logarithmically in Middlebrook 7H9 broth media in order to identify M. tb adaptations to this intracellular environment as well as M. tb mechanisms/factors contributing to M. tb replication and increased invasiveness in primary infection.

ORGANISM(S): Mycobacterium tuberculosis Homo sapiens

PROVIDER: GSE58466 | GEO | 2015/03/31

SECONDARY ACCESSION(S): PRJNA252698

REPOSITORIES: GEO

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Project description:Introduction: Tuberculosis (TB) is a serious human disease caused by the bacterium Mycobacterium tuberculosis (Mtb). One third of the world’s population is estimated to be latently infected with Mtb. Exact mechanisms and properties of latent TB infection (LTBI) are not fully elucidated. In essence, the pathogen can enter a dormant or latent state characterized by limited growth and metabolism, resulting in absence of clinical symptoms in the host, and most importantly by increased phenotypic tolerance to the commonly used medications, thereby allowing indefinite persistence in the human body. This persistence is the main reason why the current treatment of new-onset pulmonary TB is very long, consisting of a six months therapy of four antibiotics (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first two months, and only rifampicin and isoniazid for the last four months). Current state of the art: To fight TB globally and more efficiently, it is essential to shorten the treatment for TB with new drugs that are efficient also against LTBI. To facilitate discovery of such drugs, in vitro models for LTBI can be used for high throughput screening of chemical libraries. Current in vitro models such as nutrient starvation (Betts et al. 2002), nutrient depletion (Hampshire et al. 2004; Rifat, Bishai, and Karakousis 2009), progressive hypoxia (Wayne and Hayes 1996), nitric oxide treatment (Martin I. Voskuil et al. 2003) and multiple stress (Deb et al. 2009) mimic the dormant state of Mtb, but the technical settings and equipment required for these models obstruct high throughput applications. Proposed model: The streptomycin (STR)-starved 18b model (SS18b) is a simple and drug discovery efficient Mtb latency model successfully applicable to both in vitro and in vivo settings (Zhang et al. 2012). It is based on the Mtb strain 18b, which is a STR-dependent mutant that enters a viable but nonreplicating state in the absence of STR (Hashimoto 1955). Despite the successful model, we know very little about 18b. How well does SS18b mimic the bacterial response to the complex host-pathogen interactions underlying LTBI, and how does the SS18b response compare to that of other dormancy models are still open questions. In this work we analyse the complete genome of 18b and describe the transcriptomic response of 18b to STR depletion.

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Transcriptional Profile of Mycobacterium tuberculosis Replicating in Human Type II Alveolar Epithelial A549 cell line

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