Cyclooxygenase inhibitors impair CD4 T cell immunity and exacerbate Mycobacterium tuberculosis infection in aerosol-challenged mice

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.

Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients

“…Of particular note is that the time interval for the development of a substantial adaptive immune response, approximately 7 days after development of symptomatic disease, is consistent with the time course of COVID-19 mortality [10,31]. The reported potential role of ibuprofen in worsening COVID-19 treatment [95] might also be partially explained by its suppression of innate immunity [96,97] which may lead to a higher viral load and consequent overactivation of the adaptive immune system which again may become fatal in elderly patients [98,99]. Even moderate lung damage due to a weak cytokine storm could lead to hypoxemia that in turn results in mortality due to underlying conditions.…”

Monocytic myeloid-derived suppressor cells reflect tuberculosis severity and are influenced by cyclooxygenase-2 inhibitors

“…14 Although there are conflicting reports about the effect of adjunctive COX-2i in murine TB, 31 acute TB infection in animal models suggests a beneficial role under high inflammatory conditions. 31,33,46,47 In human studies, aspirin treatment in TB meningitis reduced new brain infarcts and related deaths, possibly through thromboxane A2. 48 COX-2-specific inhibitors are currently under investigation as treatment to prevent immune reconstitution inflammatory syndrome (TB-IRIS) (NCT02060006).…”

“…28 There are conflicting data on the role of COX-2 and PGE 2 in TB. [29][30][31][32] Although COX-i seems to increase bacterial load in the murine aerosol infection model, it appears that COX-i treatment improves the outcome after intravenous infection in highly susceptible mice. 31,33 We present data from the first-in-man phase I clinical trial of the in vivo effects of COX-2i on M-MDSCs in peripheral blood from TB patients.…”

Empirical Treatment and Prevention of COVID-19

“…However, use of NSAIDs can result in hypersensitivity [ 11 ] and acute thromboembolic events [ 12 ]. There were a few reports regarding concerns that NSAIDs can weaken the immune system if applied a week or longer [ 10 13 ]. Prednisolone is safer and more efficacious, considering that it can overcome the overall inflammatory process in a cell by suppressing the diverse kind of cytokines including interleukins and tumor necrosis factor-α [ 14 ].…”