Abstract
There is an urgent need to treat tuberculosis (TB) quickly, effectively and without side effects. Mycobacterium tuberculosis (Mtb), the causative organism of TB, can survive for long periods of time within macrophages and dendritic cells and these intracellular bacilli are difficult to eliminate with current drug regimens. It is well established that Mtb responds differentially to drug treatment depending on its extracellular and intracellular location and replicative state. In this study, we isolated and cultured lung derived dendritic cells to be used as a screening system for drug efficacy against intracellular mycobacteria. Using mono- or combination drug treatments, we studied the action of spectinamide-1599 and pyrazinamide (antibiotics targeting slow-growing bacilli) in killing bacilli located within lung derived dendritic cells. Furthermore, because IFN-γ is an essential cytokine produced in response to Mtb infection and present during TB chemotherapy, we also assessed the efficacy of these drugs in the presence and absence of IFN-γ. Our results demonstrated that monotherapy with either spectinamide-1599 or pyrazinamide can reduce the intracellular bacterial burden by more than 99.9%. Even more impressive is that when TB infected lung derived dendritic cells are treated with spectinamide-1599 and pyrazinamide in combination with IFN-γ a strong synergistic effect was observed, which reduced the intracellular burden below the limit of detection. We concluded that IFN-γ activation of lung derived dendritic cells is essential for synergy between spectinamide-1599 and pyrazinamide.
Highlights
Tuberculosis (TB), one of the world’s oldest and deadliest pandemic diseases, is the cause of enormous suffering to humans and animals around the globe
We demonstrated that cultures of lung derived Dendritic cells (DCs) can sustain long-term intracellular infection with Mycobacterium tuberculosis (Mtb) (H37Ra strain)
Cell suspensions of lung CD11c positive cells were cultured in the presence of complete RPMI medium (cRPMI) containing 20 ng/mL of recombinant murine GM-Colony-stimulating factors- (CSF) during 1, 7, 15, and 30 days
Summary
Tuberculosis (TB), one of the world’s oldest and deadliest pandemic diseases, is the cause of enormous suffering to humans and animals around the globe. TB adversely impacts the lives of patients, their families and communities (WHO, 2015). There are complex and long multidrug regimen treatments available that can cure TB, the length, complexity and toxicity of these treatments often lead to poor patient adherence or withdrawal (WHO, 2015, 2017). The latter has contributed to the emergence and spread of multidrug resistant strains of Mycobacterium tuberculosis (Mtb) (WHO, 2015, 2017). New, efficacious drugs allowing for shorter multidrug regimens are needed to eliminate the global menace of TB. One impediment in achieving this goal is our limited understanding of drug efficacy against intracellular bacilli
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