Abstract
BackgroundHuman tuberculosis, which is caused by the pathogen Mycobacterium tuberculosis, remains a major public health concern. Increasing drug resistance poses a threat of disease resurgence and continues to cause considerable mortality worldwide, which necessitates the development of new drugs with improved efficacy. Thymoquinone (TQ), an essential compound of Nigella sativa, was previously reported as an active anti-tuberculosis agent.MethodsIn this study, the effects of TQ on intracellular mycobacterial replication are examined in macrophages. In addition, its effect on mycobacteria-induced NO production and pro-inflammatory responses were investigated in Mycobacterium tuberculosis (MTB)-infected Type II human alveolar and human myeloid cell lines.ResultsTQ at concentrations ranging from 12.5 to 25 μg/mL and 6.25 to 12.5 μg/mL reduced intracellular M. tuberculosis H37Rv and extensively drug-resistant tuberculosis (XDR-TB) 72 h post-infection in RAW 264.7 cells. TQ treatment also produced a concentration-dependent reduction in nitric oxide production in both H37Rv and XDR-TB infected RAW 264.7 cells. Furthermore, TQ reduced the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory molecules such as tumor necrosis factor-alpha (TNF-α) and interlukin-6 (IL-6) in H37Rv-infected cells and eventually reduced pathogen-derived stress in host cells.ConclusionsTQ inhibits intracellular H37Rv and XDR-TB replication and MTB-induced production of NO and pro-inflammatory molecules. Therefore, along with its anti-inflammatory effects, TQ represents a prospective treatment option to combat Mycobacterium tuberculosis infection.
Highlights
Human tuberculosis, which is caused by the pathogen Mycobacterium tuberculosis, remains a major public health concern
Our results show that TQ (i) inhibits the replication of intracellular H37Rv and XDR-TB M. tuberculosis in mouse macrophage RAW 264.7 cells and (ii) reduces the production of Mycobacterium tuberculosis (MTB)-induced pro-inflammatory cytokines (IL-6 and Tumor necrosis factor-alpha (TNF-α)) and nitric oxide (NO) in human type II alveolar epithelial cells (A549) and PMA-induced human macrophage THP-1 cells in vitro
Influence of TQ on M. tuberculosis replication in raw 264.7 cells Colony-forming unit (CFU) assay To investigate the effects of TQ on M. tuberculosis replication in Raw 264.7 cells, confluent cell layers grown overnight in 96-well plates were infected with H37Rv and XDR-TB at an multiplicity of infection (MOI) of 1:1 and treated with TQ at concentrations ranging from 3.13 to 25 μg/mL with the first-line drug isoniazid (INH) in different concentrations
Summary
Human tuberculosis, which is caused by the pathogen Mycobacterium tuberculosis, remains a major public health concern. Tuberculosis (TB) still accounts for millions of cases of active disease and deaths worldwide and remains a global health emergency. In 2015, the World Health Organization estimated that there were 10.4 million new (incident) TB cases worldwide, of which people with HIV accounted for 1.2 million (11%) [1]. Mycobacterium tuberculosis can enhance the production of nitric oxide (NO) in infected cells [4]. Nitric oxide a small reactive nitrogen intermediate (RNI) that is produced from arginine by an enzymatic reaction. The production of RNI in host cells is considered an antimicrobial agent against intracellular microorganisms [6]. There is a point of controversy: host-derived stress such as that originating from reactive oxygen species (ROS) and RNI induces drug tolerance in Mycobacterium tuberculosis [7]. Excessive production of NO has cytotoxic effects and leads to nuclear DNA damage, which could bring about cell death [5]
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