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Adaptation of M. tuberculosis to impaired host immunity in HIV-infected patients.

Adaptation of M. tuberculosis to impaired host immunity in HIV-infected patients.
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Walter ND, de Jong BC, Garcia BJ, Dolganov GM, Worodria W, Byanyima P, Musisi E, Huang L, Chan ED, Van TT, Antonio M, Ayorinde A, Kato-Maeda M, Nahid P, Leung AM, Yen A, Fingerlin TE, Kechris K, Strong M, Voskuil MI, Davis JL, Schoolnik GK,


Walter ND, de Jong BC, Garcia BJ, Dolganov GM, Worodria W, Byanyima P, Musisi E, Huang L, Chan ED, Van TT, Antonio M, Ayorinde A, Kato-Maeda M, Nahid P, Leung AM, Yen A, Fingerlin TE, Kechris K, Strong M, Voskuil MI, Davis JL, Schoolnik GK, (click to view)

Walter ND, de Jong BC, Garcia BJ, Dolganov GM, Worodria W, Byanyima P, Musisi E, Huang L, Chan ED, Van TT, Antonio M, Ayorinde A, Kato-Maeda M, Nahid P, Leung AM, Yen A, Fingerlin TE, Kechris K, Strong M, Voskuil MI, Davis JL, Schoolnik GK,

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The Journal of infectious diseases 2016 8 17() pii

Abstract
INTRODUCTION
 It is unknown whether immunosuppression influences the physiologic state of Mycobacterium tuberculosis (M.tb) in vivo We evaluated the impact of host immunity by comparing M.tb and human transcription in sputum between HIV-infected and uninfected tuberculosis patients.

METHODS
 We collected pre-treatment sputum from Gambians and Ugandans with acid-fast bacillus smear-positive pulmonary tuberculosis. We quantified expression of 2,179 M.tb genes and 234 human immune genes via qRT-PCR. We summarized genes significantly increased or decreased in key functional categories.

RESULTS
 24 of 65 TB patients were HIV-infected. M.tb DosR regulon genes were less highly expressed among HIV-infected tuberculosis patients than among HIV-uninfected tuberculosis patients (The Gambia: p<0.0001; Uganda: p=0.037). In human profiling of the same sputa, HIV-infected patients had 3.4-fold lower expression of interferon gamma (p=0.005), 4.9-fold higher expression of arginase-1 (p=0.0006) and 3.4-fold higher expression of interleukin-10 (p=0.0002) than HIV-uninfected tuberculosis patients. CONCLUSIONS
 M.tb in HIV-infected patients had lower expression of the DosR regulon, a critical metabolic and immunomodulatory switch induced by nitric oxide, carbon monoxide and hypoxia. Our human data suggest that decreased DosR expression may result from alternative pathway activation of macrophages with consequent decreased nitric oxide expression and/or by poor granuloma formation with consequent decreased hypoxic stress.

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