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, 214 (8), 1205-11

Adaptation of Mycobacterium Tuberculosis to Impaired Host Immunity in HIV-Infected Patients

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Adaptation of Mycobacterium Tuberculosis to Impaired Host Immunity in HIV-Infected Patients

Nicholas D Walter et al. J Infect Dis.

Erratum in

  • Erratum.
    J Infect Dis. 2017 Feb 1;215(3):495. doi: 10.1093/infdis/jiw582. J Infect Dis. 2017. PMID: 28362904 Free PMC article. No abstract available.

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.

Keywords: Mycobacterium tuberculosis/genetics; Mycobacterium tuberculosis/physiology; acquired immunodeficiency syndrome/immunology; pulmonary/epidemiology; sputum/microbiology; tuberculosis.

Figures

Figure 1.
Figure 1.
Expression of the Mycobacterium tuberculosis DosR regulon in sputa from human immunodeficiency virus (HIV)–infected vs uninfected patients with tuberculosis in Gambia (A) and Uganda (B). Red indicates decreased expression in HIV-infected individuals, and blue indicates increased expression.
Figure 2.
Figure 2.
Differential expression of human genes associated with granuloma formation and macrophage polarization in human immunodeficiency virus (HIV)–infected versus uninfected patients with tuberculosis, with hypothesized consequences. Red indicates significantly decreased and green significantly increased expression in HIV-infected samples. Mean fold-change in HIV-infected samples relative to uninfected samples is shown in parentheses. Expression of cytokine genes suggests that the presence of HIV infection biases macrophages to the alternatively activated (M2) phenotype, a change anticipated to diminish NO stress. Poor granuloma formation and consequent diminished hypoxic stress may result from (1) CD4+ T-cell depletion, (2) a shift in the residual CD4+ T-cell population from the T-helper type 1 (TH1) interferon γ–producing phenotype toward the TH2 phenotype, or (3) arginase 1–mediated inhibition of T-cell proliferation. DosR regulon proteins induce T-cell and interferon γ responses, enhancing granuloma formation. Decreased expression of the DosR regulon is therefore anticipated to further impair granuloma formation.

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