Nicholas D Walter1, Bouke C de Jong2, Benjamin J Garcia3, Gregory M Dolganov4, William Worodria5, Patrick Byanyima5, Emmanuel Musisi5, Laurence Huang6, Edward D Chan7, Tran T Van4, Martin Antonio8, Abigail Ayorinde8, Midori Kato-Maeda9, Payam Nahid9, Ann M Leung10, Andrew Yen11, Tasha E Fingerlin12, Katerina Kechris13, Michael Strong3, Martin I Voskuil14, J Lucian Davis15, Gary K Schoolnik4. 1. Pulmonary Section, Denver Veterans Affairs Medical Center Integrated Center for Genes, Environment, and Health Division of Pulmonary Sciences and Critical Care Medicine. 2. New York University, New York Institute of Tropical Medicine, Antwerp, Belgium Medical Research Council Laboratories, Serrekunda, Gambia. 3. Integrated Center for Genes, Environment, and Health Computational Bioscience Program. 4. Department of Microbiology and Immunology. 5. Makerere University-UCSF Research Collaboration, Kampala, Uganda. 6. Division of Pulmonary and Critical Care Medicine HIV/AIDS Division, University of California-San Francisco (UCSF). 7. 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. 8. Medical Research Council Laboratories, Serrekunda, Gambia. 9. Division of Pulmonary and Critical Care Medicine. 10. Department of Radiology, Stanford University Medical Center. 11. Department of Radiology, University of California-San Diego. 12. Integrated Center for Genes, Environment, and Health. 13. Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora. 14. Department of Immunology and Microbiology, University of Colorado-Denver Anschutz Medical Campus. 15. Department of Epidemiology of Microbial Diseases Department of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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