Dataset Information

Heme oxygenase-1 inhibition promotes IFN?- and NOS2-mediated control of Mycobacterium tuberculosis infection.

ABSTRACT: Mycobacterium tuberculosis (Mtb) infection induces pulmonary expression of the heme-degrading enzyme heme oxygenase-1 (HO-1). We have previously shown that pharmacological inhibition of HO-1 activity in experimental tuberculosis results in decreased bacterial loads and unexpectedly that this outcome depends on the presence of T lymphocytes. Here, we extend these findings by demonstrating that IFN? production by T lymphocytes and NOS2 expression underlie this T-cell requirement and that HO-1 inhibition potentiates IFN?-induced NOS2-dependent control of Mtb by macrophages in vitro. Among the products of heme degradation by HO-1 (biliverdin, carbon monoxide, and iron), only iron supplementation reverted the HO-1 inhibition-induced enhancement of bacterial control and this reversal was associated with decreased NOS2 expression and NO production. In addition, we found that HO-1 inhibition results in decreased labile iron levels in Mtb-infected macrophages in vitro and diminished iron accumulation in Mtb-infected lungs in vivo. Together these results suggest that the T-lymphocyte dependence of the therapeutic outcome of HO-1 inhibition on Mtb infection reflects the role of the enzyme in generating iron that suppresses T-cell-mediated IFN?/NOS2-dependent bacterial control. In broader terms, our findings highlight the importance of the crosstalk between iron metabolism and adaptive immunity in determining the outcome of infection.

SUBMITTER: Costa DL

PROVIDER: S-EPMC7796944 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Heme oxygenase-1 inhibition promotes IFNγ- and NOS2-mediated control of Mycobacterium tuberculosis infection.

Costa Diego L DL Amaral Eduardo P EP Namasivayam Sivaranjani S Mittereder Lara R LR Fisher Logan L Bonfim Caio C CC Sardinha-Silva Aline A Thompson Robert W RW Hieny Sara E SE Andrade Bruno B BB Sher Alan A

Mucosal immunology 20200829 1

Mycobacterium tuberculosis (Mtb) infection induces pulmonary expression of the heme-degrading enzyme heme oxygenase-1 (HO-1). We have previously shown that pharmacological inhibition of HO-1 activity in experimental tuberculosis results in decreased bacterial loads and unexpectedly that this outcome depends on the presence of T lymphocytes. Here, we extend these findings by demonstrating that IFNγ production by T lymphocytes and NOS2 expression underlie this T-cell requirement and that HO-1 inhi ...[more]

PMID: 32862202

Similar Datasets

Project description:Heme oxygenase-1 (HO-1) is a stress response antioxidant enzyme which catalyzes the degradation of heme released during inflammation. HO-1 expression is upregulated in both experimental and human Mycobacterium tuberculosis infection, and in patients it is a biomarker of active disease. Whether the enzyme plays a protective versus pathogenic role in tuberculosis has been the subject of debate. To address this controversy, we administered tin protoporphyrin IX (SnPPIX), a well-characterized HO-1 enzymatic inhibitor, to mice during acute M. tuberculosis infection. These SnPPIX-treated animals displayed a substantial reduction in pulmonary bacterial loads comparable to that achieved following conventional antibiotic therapy. Moreover, when administered adjunctively with antimycobacterial drugs, the HO-1 inhibitor markedly enhanced and accelerated pathogen clearance. Interestingly, both the pulmonary induction of HO-1 expression and the efficacy of SnPPIX treatment in reducing bacterial burden were dependent on the presence of host T lymphocytes. Although M. tuberculosis expresses its own heme-degrading enzyme, SnPPIX failed to inhibit its enzymatic activity or significantly restrict bacterial growth in liquid culture. Together, the above findings reveal mammalian HO-1 as a potential target for host-directed monotherapy and adjunctive therapy of tuberculosis and identify the immune response as a critical regulator of this function. IMPORTANCE:There is no reliable vaccine against tuberculosis (TB), and conventional antibiotic therapy is administered over at least 6 months. This prolonged treatment period can lead to noncompliance resulting in relapsed infection as well as the emergence of multidrug resistance. Thus, there is an urgent need for improved therapeutic regimens that can more rapidly and efficiently control M. tuberculosis in infected patients. Here, we describe a potential strategy for treating TB based on pharmacological inhibition of the host heme-degrading enzyme HO-1. This approach results in significantly reduced bacterial burdens in mice, and when administered in conjunction with conventional antibiotic therapy, leads to faster, more effective pathogen clearance without detectable direct effects on the mycobacteria themselves. Interestingly, the effects of HO-1 inhibition on M. tuberculosis infection in vivo are dependent on the presence of an intact host immune system. These observations establish mammalian HO-1 as a potential target for host-directed therapy of TB.

Project description:Background: Understanding macrophage behavior is key to decipher Mycobacterium tuberculosis (Mtb) pathogenesis. We studied the phenotype and ability of human monocyte-derived cells polarized with active vitamin D [1,25(OH)2D3] to control intracellular Mtb infection compared with polarization of conventional subsets, classical M1 or alternative M2. Methods: Human blood-derived monocytes were treated with active vitamin D or different cytokines to obtain 1,25(OH)2D3-polarized as well as M1- and M2-like cells or fully polarized M1 and M2 subsets. We used an in vitro macrophage Mtb infection model to assess both phenotype and functional markers i.e., inhibitory and scavenger receptors, costimulatory molecules, cytokines, chemokines, and effector molecules using flow cytometry and quantitative mRNA analysis. Intracellular uptake of bacilli and Mtb growth was monitored using flow cytometry and colony forming units. Results: Uninfected M1 subsets typically expressed higher levels of CCR7, TLR2, and CD86, while M2 subsets expressed higher CD163, CD200R, and CD206. Most of the investigated markers were up-regulated in all subsets after Mtb infection, generating a mixed M1/M2 phenotype, while the expression of CD206, HLADR, and CD80 was specifically up-regulated (P < 0.05) on 1,25(OH)2D3-polarized macrophages. Consistent with the pro-inflammatory features of M1 cells, Mtb uptake and intracellular Mtb growth was significantly (P < 0.01-0.001 and P < 0.05-0.01) lower in the M1 (19.3%) compared with the M2 (82.7%) subsets 4 h post-infection. However, infectivity rapidly and gradually increased in M1 cells at 24-72 h. 1,25(OH)2D3-polarized monocyte-derived cells was the most potent subset to inhibit Mtb growth at both 4 and 72 h (P < 0.05-0.01) post-Mtb infection. This ability was associated with high mRNA levels of pro-inflammatory cytokines and the antimicrobial peptide LL-37 but also anti-inflammatory IL-10, while expression of the immunosuppressive enzyme IDO (indoleamine 2,3-dioxygenase) remained low in Mtb-infected 1,25(OH)2D3-polarized cells compared with the other subsets. Conclusions: Mtb infection promoted a mixed M1/M2 macrophage activation, and 1,25(OH)2D3-polarized monocyte-derived cells expressing LL-37 but not IDO, were most effective to control intracellular Mtb growth. Macrophage polarization in the presence of vitamin D may provide the capacity to mount an antimicrobial response against Mtb and simultaneously prevent expression of inhibitory molecules that could accelerate local immunosuppression in the microenvironment of infected tissue.

Dataset Information

Heme oxygenase-1 inhibition promotes IFN?- and NOS2-mediated control of Mycobacterium tuberculosis infection.

Publications

Heme oxygenase-1 inhibition promotes IFNγ- and NOS2-mediated control of Mycobacterium tuberculosis infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets