Abstract
Tuberculosis, caused by infection with Mycobacterium tuberculosis (Mtb), kills over 1.6 million people each year despite availability of antibiotics. The increase in drug resistant Mtb strains is a major public health emergency and host-directed therapy as adjunct to antibiotic treatment has gained increased interest. Cyclooxygenase inhibitors (COXi) are frequently used drugs to alleviate tuberculosis related symptoms. Mouse studies of acute intravenous Mtb infection have suggested a potential benefit of COXi for host-directed therapy. Here we show that COXi treatment (ibuprofen and celecoxib) is detrimental to Mtb control in different mouse models of respiratory infection. This effect links to impairments of the Type-1 helper (Th1) T-cell response as CD4 T-cells in COXi-treated animals have significantly decreased Th1 differentiation, reduced IFNγ expression and decreased protective capacity upon adoptive transfer. If confirmed in clinical trials, these findings could have major impact on global health and question the use of COXi for host-directed therapy.
Highlights
Tuberculosis, caused by infection with Mycobacterium tuberculosis (Mtb), kills over 1.6 million people each year despite availability of antibiotics
We found that celecoxib-treated mice had higher bacillary burdens in lungs and spleen after both 2 and 8 weeks of treatment, corresponding to week 6 and 12 of the infection, respectively (Fig. 1a)
Cyclooxygenase inhibitors (COXi) reduced inflammation and neutrophilic infiltration[12,13,14], but we found no difference in the number of neutrophils, inflammatory monocytes, macrophages/monocytes or alveolar macrophages/dendritic cells (DCs) in the lungs (Fig. 1c, d and Supplementary Fig. 1)
Summary
Tuberculosis, caused by infection with Mycobacterium tuberculosis (Mtb), kills over 1.6 million people each year despite availability of antibiotics. We show that COXi treatment (ibuprofen and celecoxib) is detrimental to Mtb control in different mouse models of respiratory infection This effect links to impairments of the Type-1 helper (Th1) T-cell response as CD4 T-cells in COXi-treated animals have significantly decreased Th1 differentiation, reduced IFNγ expression and decreased protective capacity upon adoptive transfer. Among the already approved medicines, non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase inhibitors (COXi), have been proposed as candidates for host-directed therapy due to their potential to reduce inflammation and hereby resolve host-meditated immune pathology[2,3,4]. More recent studies have convincingly shown that treatment with ibuprofen or aspirin alone reduces the bacterial burden and prolongs survival after intravenous (i.v.) infection of highly TB-susceptible C3HeB/FeJ mice[12,13,14] In this model, mice rapidly developed severe lung pathology and inflammation, which was reduced by COXi13. If COXi pose a risk of TB progression in Mtb infected subjects, it could have major impact on the global TB epidemic and question the relevance of these drugs as candidates for host-directed therapy
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