Transcriptional profiling of Mycobacterium tuberculosis replicating ex vivo in blood from HIV- and HIV+ subjects

• Published in: PloS one Vol. 9; no. 4; p. e94939
• Main Authors: Ryndak, Michelle B, Singh, Krishna K, Peng, Zhengyu, Zolla-Pazner, Susan, Li, Hualin, Meng, Lu, Laal, Suman
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2014; Public Library of Science (PLoS)
• Subjects: Adaptation; Analysis; Antigens, Bacterial - genetics; Antigens, Bacterial - metabolism; Bacteremia; Bacteria; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bacterial Secretion Systems - genetics; Biology and Life Sciences; Blood; Care and treatment; Cell Wall - metabolism; Cell walls; Control; Dormancy; ESAT-6 antigen; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Plant; Genes, Bacterial; Genetic aspects; Genetic transcription; Genomics; Health care; HIV; HIV Core Protein p24 - metabolism; HIV infection; HIV patients; HIV Seropositivity - blood; HIV Seropositivity - genetics; HIV Seropositivity - microbiology; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immunodeficiency; Immunosurveillance; Infections; Iron; Iron - metabolism; Lung diseases; Lungs; Macrophages - metabolism; Macrophages - microbiology; Medicine and Health Sciences; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - growth & development; Oligonucleotide Array Sequence Analysis; Pathology; Patients; Real-Time Polymerase Chain Reaction; Recombinant Proteins - metabolism; Replication; Reproducibility of Results; Stress, Physiological - genetics; Studies; Transcription; Transcription, Genetic; Tuberculosis; Up-Regulation - genetics; Vaccines; Virulence; Virulence factors; Virus Replication; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094939

Hematogenous dissemination of Mycobacterium tuberculosis (M. tb) occurs during both primary and reactivated tuberculosis (TB). Although hematogenous dissemination occurs in non-HIV TB patients, in ∼80% of these patients, TB manifests exclusively as pulmonary disease. In contrast, extrapulmonary, disseminated, and/or miliary TB is seen in 60-70% of HIV-infected TB patients, suggesting that hematogenous dissemination is likely more common in HIV+ patients. To understand M. tb adaptation to the blood environment during bacteremia, we have studied the transcriptome of M. tb replicating in human whole blood. To investigate if M. tb discriminates between the hematogenous environments of immunocompetent and immunodeficient individuals, we compared the M. tb transcriptional profiles during replication in blood from HIV- and HIV+ donors. Our results demonstrate that M. tb survives and replicates in blood from both HIV- and HIV+ donors and enhances its virulence/pathogenic potential in the hematogenous environment. The M. tb blood-specific transcriptome reflects suppression of dormancy, induction of cell-wall remodeling, alteration in mode of iron acquisition, potential evasion of immune surveillance, and enhanced expression of important virulence factors that drive active M. tb infection and dissemination. These changes are accentuated during bacterial replication in blood from HIV+ patients. Furthermore, the expression of ESAT-6, which participates in dissemination of M. tb from the lungs, is upregulated in M. tb growing in blood, especially during growth in blood from HIV+ patients. Preliminary experiments also demonstrate that ESAT-6 promotes HIV replication in U1 cells. These studies provide evidence, for the first time, that during bacteremia, M. tb can adapt to the blood environment by modifying its transcriptome in a manner indicative of an enhanced-virulence phenotype that favors active infection. Additionally, transcriptional modifications in HIV+ blood may further accentuate M. tb virulence and drive both M. tb and HIV infection.