title: Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients.
abstract: It is unknown whether immunosuppression influences the physiologic state of Mycobacterium tuberculosis in vivo. We evaluated the impact of host immunity by comparing M. tuberculosis and human gene transcription in sputum between human immunodeficiency virus (HIV)-infected and uninfected patients with tuberculosis.
  
  
  
  We collected sputum specimens before treatment from Gambians and Ugandans with pulmonary tuberculosis, revealed by positive results of acid-fast bacillus smears. We quantified expression of 2179 M. tuberculosis genes and 234 human immune genes via quantitative reverse transcription-polymerase chain reaction. We summarized genes from key functional categories with significantly increased or decreased expression.
  
  
  
  A total of 24 of 65 patients with tuberculosis were HIV infected. M. tuberculosis DosR regulon genes were less highly expressed among HIV-infected patients with tuberculosis than among HIV-uninfected patients with tuberculosis (Gambia, P < .0001; Uganda, P = .037). In profiling of human genes from the same sputa, HIV-infected patients had 3.4-fold lower expression of IFNG (P = .005), 4.9-fold higher expression of ARG1 (P = .0006), and 3.4-fold higher expression of IL10 (P = .0002) than in HIV-uninfected patients with tuberculosis.
  
  
  
  M. tuberculosis in HIV-infected patients had lower expression of the DosR regulon, a critical metabolic and immunomodulatory switch induced by NO, carbon monoxide, and hypoxia. Our human data suggest that decreased DosR expression may result from alternative pathway activation of macrophages, with consequent decreased NO expression and/or by poor granuloma formation with consequent decreased hypoxic stress.
authors.affiliation: Pulmonary Section, Denver Veterans Affairs Medical Center Integrated Center for Genes, Environment, and Health Division of Pulmonary Sciences and Critical Care Medicine.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Walter
authors.affiliation: New York University, New York Institute of Tropical Medicine, Antwerp, Belgium Medical Research Council Laboratories, Serrekunda, Gambia.
authors.forename: Bouke C
authors.initials: BC
authors.lastname: de Jong
authors.affiliation: Integrated Center for Genes, Environment, and Health Computational Bioscience Program.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Garcia
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dolganov
authors.affiliation: Makerere University-UCSF Research Collaboration, Kampala, Uganda.
authors.forename: William
authors.initials: W
authors.lastname: Worodria
authors.affiliation: Makerere University-UCSF Research Collaboration, Kampala, Uganda.
authors.forename: Patrick
authors.initials: P
authors.lastname: Byanyima
authors.affiliation: Makerere University-UCSF Research Collaboration, Kampala, Uganda.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Musisi
authors.affiliation: Division of Pulmonary and Critical Care Medicine HIV/AIDS Division, University of California-San Francisco (UCSF).
authors.forename: Laurence
authors.initials: L
authors.lastname: Huang
authors.affiliation: Pulmonary Section, Denver Veterans Affairs Medical Center Department of Academic Affairs and Medicine, National Jewish Health, Denver Division of Pulmonary Sciences and Critical Care Medicine.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Chan
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Tran T
authors.initials: TT
authors.lastname: Van
authors.affiliation: Medical Research Council Laboratories, Serrekunda, Gambia.
authors.forename: Martin
authors.initials: M
authors.lastname: Antonio
authors.affiliation: Medical Research Council Laboratories, Serrekunda, Gambia.
authors.forename: Abigail
authors.initials: A
authors.lastname: Ayorinde
authors.affiliation: Division of Pulmonary and Critical Care Medicine.
authors.forename: Midori
authors.initials: M
authors.lastname: Kato-Maeda
authors.affiliation: Division of Pulmonary and Critical Care Medicine.
authors.forename: Payam
authors.initials: P
authors.lastname: Nahid
authors.affiliation: Department of Radiology, Stanford University Medical Center.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leung
authors.affiliation: Department of Radiology, University of California-San Diego.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yen
authors.affiliation: Integrated Center for Genes, Environment, and Health.
authors.forename: Tasha E
authors.initials: TE
authors.lastname: Fingerlin
authors.affiliation: Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kechris
authors.affiliation: Integrated Center for Genes, Environment, and Health Computational Bioscience Program.
authors.forename: Michael
authors.initials: M
authors.lastname: Strong
authors.affiliation: Department of Immunology and Microbiology, University of Colorado-Denver Anschutz Medical Campus.
authors.forename: Martin I
authors.initials: MI
authors.lastname: Voskuil
authors.affiliation: Department of Epidemiology of Microbial Diseases Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: J Lucian
authors.initials: JL
authors.lastname: Davis
authors.affiliation: Department of Microbiology and Immunology.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schoolnik
mesh_terms: D000222:Adaptation, Physiological / Q000276:immunology*; D000328:Adult; D001426:Bacterial Proteins / Q000235:genetics; D004268:DNA-Binding Proteins; D005714:Gambia; D006099:Granuloma / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D006801:Humans; D000860:Hypoxia / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology*; D009589:Nitrogen Oxides / Q000276:immunology; D011494:Protein Kinases / Q000235:genetics; D018085:Regulon / Q000235:genetics / Q000276:immunology; D013183:Sputum / Q000382:microbiology; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D014454:Uganda
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C542863:DosR protein, Mycobacterium tuberculosis; D009589:Nitrogen Oxides; D011494:Protein Kinases
keywords: Mycobacterium tuberculosis/genetics; Mycobacterium tuberculosis/physiology; acquired immunodeficiency syndrome/immunology; pulmonary/epidemiology; sputum/microbiology; tuberculosis