Corticosteroids against Mycobacterium tubercolosis

What is it about?

Corticosteroids are host-directed drugs with proven beneficial effect on survival of tuberculosis (TB) patients, but their precise mechanisms of action in this disease remain largely unknown. Here we show that corticosteroids such as dexamethasone inhibit necrotic cell death of cells infected with Mycobacterium tuberculosis (Mtb) by facilitating mitogen-activated protein kinase phosphatase 1 (MKP-1)-dependent dephosphorylation of p38 MAPK. Characterization of infected mixed lineage kinase domain-like (MLKL) and tumor necrosis factor receptor 1 (TNFR1) knockout cells show that the underlying mechanism is independent from TNFα-signaling and necroptosis. Our results link corticosteroid function and p38 MAPK inhibition to abrogation of necrotic cell death mediated by mitochondrial membrane permeability transition, and open new avenues for research on novel host-directed therapies (HDT).

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Why is it important?

This key finding here provides an excellent opportunity to gain fundamental insight into mechanisms of Mtb-induced host cell death and its impact on a clinically approved therapeutic intervention. Using corticosteroids as a starting point, we systematically investigated cellular machineries executing apoptosis, necroptosis, and alternative forms of regulated necrosis. Our mechanistic studies identified the mitochondrial permeability transition pore (mPTP) to be involved in necrotic cell death upon Mtb infection. The data obtained suggest that Mtb controls necrosis by manipulating mitochondrial membrane integrity and successful therapeutic interventions ultimately target mitochondria and interfere with TB pathogenesis.