Abstract
Eicosanoids modulate both innate and adaptive immune responses in Mycobacterium tuberculosis (Mtb) infection and have been suggested as possible Host Directed Therapy (HDT) targets, but more knowledge of eicosanoid dynamics in Mtb infection is required. We investigated the levels and ratios of eicosanoid mediators and their cellular sources, monocyte subsets and CD4 T cells in Tuberculosis (TB) patients with various clinical states of Mtb infection. Patients consenting to prospective enrolment in a TB quality registry and biorepository, 16 with pulmonary TB (before and at-end-of treatment), 14 with extrapulmonary TB and 17 latently infected (LTBI) were included. Plasma levels of Prostaglandin E2 (PGE2), Lipoxin A4 (LXA4), and Leukotriene B4 (LTB4) were measured by enzyme-linked immunosorbent assay. Monocyte subsets and CD4 T cells and their expression of Cyclooxygenase-2 (COX-2), Prostaglandin receptor EP2 (EP2), and 5-Lipoxygenase (5-LOX) were analyzed by flow cytometry with and without Purified Protein Derivate (PPD)-stimulation. Pulmonary TB patients had elevated levels of the anti-inflammatory mediator LXA4 at diagnosis compared to LTBI (p < 0.01), while levels of PGE2 and LTB4 showed no difference between clinical states of Mtb infection. LTB4 was the only mediator to be reduced upon treatment (p < 0.05), along with the ratio LTB4/LXA4 (p < 0.01). Pulmonary TB patients had higher levels of total monocytes at diagnosis compared to end-of-treatment and LTBI (both p < 0.05), and a relative increase in the classical monocyte subset. All monocyte subsets had low basal expression of COX-2 and 5-LOX, which were markedly increased upon PPD stimulation. By contrast, the expression of EP2 was reduced upon stimulation. CD4 T cells expressed low basal COX-2 activity that increased modestly upon stimulation, whereas their basal expression of 5-LOX was considerable. In conclusion, the level of eicosanoids in plasma seem to vary between clinical states of Mtb infection. Mediators in the eicosanoid system are present in monocytes and CD4 T cells. The expression of eicosanoids in monocytes are responsive to mycobacterial stimulation independent of Mtb disease state, but subsets are heterogeneous with regard to eicosanoid-mediator expression. Further exploration of eicosanoid mediators as targets for HDT in TB are warranted.
Highlights
Nearly 10 million new cases of tuberculosis (TB) resulting in 1.3 million deaths, are reported annually despite intensive global strategies to fight the TB epidemic [1, 2]
Plasma levels of Prostaglandin E2 (PGE2), Lipoxin A4 (LXA4), and Leukotriene B4 (LTB4) were analyzed at diagnosis of TB disease (PTB and extrapulmonary TB (EPTB)) and compared to latent TB infection (LTBI)
As expression of eicosanoid enzymes may be unevenly distributed in different monocyte subsets, we further explored the eicosanoid expression between the classical monocytes (CM), intermediate monocytes (IM), Non-classical monocytes (NCM) monocyte subsets in the different stages of Mycobacterium Tuberculosis (Mtb) infection
Summary
Nearly 10 million new cases of tuberculosis (TB) resulting in 1.3 million deaths, are reported annually despite intensive global strategies to fight the TB epidemic [1, 2]. In Mtb infection, the dynamics between eicosanoids may impact on protective host immune responses important for containment or progression of TB disease [6, 14, 20]. Disease severity in TB has been reported to be associated with increased ratio of LXA4/LTB4 and/or reduced ratio of PGE2/LXA4, rather than changes in absolute levels of specific metabolites [21, 22]. Still, it is unclear whether eicosanoids can act as biomarkers, separating latent from active TB cases or reflecting responses to TB therapy [22]
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