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

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 HIVuninfected 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.

Hypoxia Sensing and Persistence Genes Are Expressed during the Intragranulomatous Survival of Mycobacterium tuberculosis

“…Because hypoxia was detected in all samples tested, our data strongly suggest that the induction of dormancy is critical in all granuloma stages, a result supported by observations that lesions of macaques with both ATB and LTBI contain hypoxia ( Figures 4B-4D) (16). Our results are also supported by the recent evidence of dosR expression in the lungs of humans with TB (43). Overall, the pathogen's response to hypoxia is a critical component of its intragranulomatous physiology.…”

“…Finally, an unbiased, system-wide proteomic approach found that, upon in vitro hypoxic stress, 20% of all Mtb protein mass is contributed by the fewer than 50 dosR-regulated genes (48). Moreover, the expression of this regulon was recently reported to be strongly induced in human TB and to significantly lower levels in patients with HIV (43). This suggests that the expression of DosR may promote more robust granulomas, a contention supported by data that expression of DosR by WhiB6 promotes granuloma stability in an environment of chronic oxidative/nitrosative stress (49).…”

The Troika Host–Pathogen–Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes

“…Because the risk of developing TB is largely increased in HIV-infected individuals even before CD4 T cell counts decrease ( 16 ), other factors must also play a role. Indeed, a detrimental alternative activation of macrophages, accompanied by less nitric oxide (NO) synthase expression and poorly formed granulomas was described in HIV–TB, which in turn downregulated the Mycobacterium tuberculosis DosR regulon ( 17 ), a set of genes known to be induced during anaerobic dormancy ( 18 ). Therefore, changes in the host immunity resulting from HIV coinfection remodel the bacterial physiology, further rewiring the host tissue microenvironment.…”

Host-pathogen redox dynamics modulate Mycobacterium tuberculosis pathogenesis

“…The authors observed increased expression of genes within the dormancy regulon in the cells collected by bronchoalveolar lavage (BAL) from HIV uninfected patients (Walter et al. 2016 ). The authors propose two possible explanations for this observation.…”

“…Increased expression of the arginase gene and a decreased expression of the gene for inducible nitric oxide synthase in HIV infected patients suggest that macrophages in HIV infected patients were potentially less capable of producing NO, stressing Mtb , and inducing the dormancy regulon in Mtb (Walter et al. 2016 ). Regardless, this finding underscores the importance of the host response on cellular activity of Mtb in human TB.…”