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

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.