title: Transcriptional profile of Mycobacterium tuberculosis replicating in type II alveolar epithelial cells.
abstract: Mycobacterium tuberculosis (M. tb) infection is initiated by the few bacilli inhaled into the alveolus. Studies in lungs of aerosol-infected mice provided evidence for extensive replication of M. tb in non-migrating, non-antigen-presenting cells in the alveoli during the first 2-3 weeks post-infection. Alveoli are lined by type II and type I alveolar epithelial cells (AEC) which outnumber alveolar macrophages by several hundred-fold. M. tb DNA and viable M. tb have been demonstrated in AEC and other non-macrophage cells of the kidney, liver, and spleen in autopsied tissues from latently-infected subjects from TB-endemic regions indicating systemic bacterial dissemination during primary infection. M. tb have also been demonstrated to replicate rapidly in A549 cells (type II AEC line) and acquire increased invasiveness for endothelial cells. Together, these results suggest that AEC could provide an important niche for bacterial expansion and development of a phenotype that promotes dissemination during primary infection. In the current studies, we have compared the transcriptional profile of M. tb replicating intracellularly in A549 cells to that of M. tb replicating in laboratory broth, by microarray analysis. Genes significantly upregulated during intracellular residence were consistent with an active, replicative, metabolic, and aerobic state, as were genes for tryptophan synthesis and for increased virulence (ESAT-6, and ESAT-6-like genes, esxH, esxJ, esxK, esxP, and esxW). In contrast, significant downregulation of the DevR (DosR) regulon and several hypoxia-induced genes was observed. Stress response genes were either not differentially expressed or were downregulated with the exception of the heat shock response and those induced by low pH. The intra-type II AEC M. tb transcriptome strongly suggests that AEC could provide a safe haven in which M. tb can expand dramatically and disseminate from the lung prior to the elicitation of adaptive immune responses.
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Ryndak
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.affiliation: Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, New York, United States of America; Veterans Affairs New York Harbor Healthcare System, New York, New York, United States of America.
authors.forename: Suman
authors.initials: S
authors.lastname: Laal
mesh_terms: D000220:Adaptation, Biological; D001426:Bacterial Proteins / Q000235:genetics*; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology*; D020869:Gene Expression Profiling / Q000379:methods*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development*; D020411:Oligonucleotide Array Sequence Analysis; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins
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