The Eicosanoid system – effects on pathogenesis and potential as targets for Host Directed Therapy in Tuberculosis

Abstract

Tuberculosis (TB) is a major global health challenge and one of the top 10 causes of death worldwide. Current treatment strategies involve long-lasting drug regimens with risk of side effects and reduced compliance, leading to the development of antibiotic resistance. Host-Directed Therapy (HDT) aims to modulate the host response and improve treatment outcomes by augmenting favorable responses or inhibiting dysfunctional mechanisms. Lipid mediators known as eicosanoids play a crucial role in modulating the immune system during TB infection. The PhD project “The Eicosanoid system – effects on pathogenesis and potential as targets for Host Directed Therapy in Tuberculosis” explores the effects of eicosanoids on immunity in TB and their potential as HDT targets. TB patients included in a prospective observational cohort and patients included in a phase I/II randomized clinical trial with a Cyclooxygenase-2 inhibitor (COX-2i) as intervention, were included. To determine levels of inflammatory mediators, including eicosanoids, methods such as ELISA, multiplex and LC-MS were applied. Cells and proteins related to eicosanoid function were isolated from blood and investigated using flow cytometry, while mycobacterial killing capacity of immune cells was determined by using an in vitro killing assay. We show that anti-inflammatory eicosanoids are associated with severity of TB disease and reduced during TB treatment, while both innate and adaptive immune cells make important contributions to eicosanoid mediator production. We report that selective targeting of eicosanoid pathways with COX-2i`s as HDT adjunctive to standard TB treatment impair macrophage potential to control mycobacterial growth, an effect possibly caused by an overall lowered pro-inflammatory function. Our studies provide knowledge about dynamics of eicosanoids in different stages of TB infection, and give new insight on the potential effects of HDT targeting host eicosanoid biosynthesis in TB disease.