Abstract
BackgroundH37Rv and H37Ra are well-described laboratory strains of Mycobacterium tuberculosis derived from the same parental strain, H37, that show dramatically different pathogenic phenotypes.Methodology/Principal FindingsIn this study, the transcriptomes of the two strains during axenic growth in broth and during intracellular growth within murine bone-marrow macrophages were compared by whole genome expression profiling. We identified and compared adaptations of either strain upon encountering an intracellular environment, and also contrasted the transcriptomes of the two strains while inside macrophages. In the former comparison, both strains induced genes that would facilitate intracellular survival including those involved in mycobactin synthesis and fatty acid metabolism. However, this response was stronger and more extensive for H37Rv than for H37Ra. This was manifested as the differential expression of a greater number of genes and an increased magnitude of expression for these genes in H37Rv. In comparing intracellular transcriptional signatures, fifty genes were found to be differentially expressed between the strains. Of these fifty, twelve were under control of the PhoPR regulon. Further differences between strains included genes whose products were members of the ESAT-6 family of proteins, or were associated with their secretion.Conclusions/SignificanceAlong with the recent identification of single nucleotide polymorphisms in H37Ra when compared to H37Rv, our demonstration of differential expression of PhoP-regulated and ESX-1 region-related genes during macrophage infection further highlights the significance of these genes in the attenuation of H37Ra.
Highlights
Mycobacterium tuberculosis (Mtb) is a bacterium that can be spread via aerosols generated by infected individuals when they sneeze, cough, or even speak
These two strains were derived from the parental strain H37 Mtb that was isolated from the sputum of a patient suffering from chronic pulmonary tuberculosis in 1906 [3]
For bacteria used to infect macrophages, Mtb cultures were grown in Proskauer and Beck media supplemented with 0.05% Tween-80 in 100 mL roller bottle cultures until midlogarithmic phase
Summary
Mycobacterium tuberculosis (Mtb) is a bacterium that can be spread via aerosols generated by infected individuals when they sneeze, cough, or even speak. Mtb has strategies that enable its survival and replication within the host macrophage, though variations in the pathogenicity of strains have been found [2]. Comparing gene expression profiles of these strains during their interaction with macrophages should shed light on the genes that enable intracellular survival and the microenvironments encountered during infection. It should be emphasized that H37Ra is not completely avirulent, only attenuated in its virulence compared to H37Rv. In common animal models for TB such as mice and guinea pigs, H37Ra does establish an infection, and does multiply within these hosts [4,5,6]. H37Rv and H37Ra are well-described laboratory strains of Mycobacterium tuberculosis derived from the same parental strain, H37, that show dramatically different pathogenic phenotypes
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