Chemical p38 MAP kinase inhibition constrains tissue inflammation and improves antibiotic activity in Mycobacterium tuberculosis-infected mice

Abstract

Host-modulating therapies have become an important focus in the development of novel concepts for improved management of tuberculosis (TB). Previous in vitro studies revealed that the p38 MAP kinase signaling pathway coordinates several inflammatory and stress responses in Mycobacterium tuberculosis (Mtb)-infected host cells. Here we extend these findings and show that in vivo treatment of Mtb-infected C57BL/6 mice with doramapimod, a p38 MAP-kinase inhibitor, results in reduced inflammation, granuloma formation and lung pathology. Moreover, doramapimod, together with standard antibiotic treatment, significantly reduced lung and spleen mycobacterial loads compared to antibiotic treatment alone. Our in vivo data suggest the opportunity to repurpose p38 MAPK inhibitors for adjunct host directed therapies. We also provide first data on safety of p38 MAPK inhibition which is of relevance for future application of these substances in inflammatory diseases and concomitant TB. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the major killer among infectious agents which led to 1.5 million deaths in 2018 1. Treatment of TB requires combinations of antibiotics for several months, a strategy which becomes increasingly complicated in times of rising numbers of multi-drug resistant Mtb-isolates 1. Adjunctive host directed therapy (HDT) might improve and accelerate treatment by modifying host pathways targeted by Mtb 2-6. In HDT, one promising approach is to manipulate signaling pathways that contribute to immunopathology by causing hyperinflammation, necrosis and tissue damage. We have recently shown that genetic or chemical inhibition of p38 mitogen-activated protein kinase (MAPK) in vitro results in abrogation of Mtb-induced host cell death and decreased release of inflammatory alarmins such as High-Mobility-Group-Protein B1 (HMGB1) ex vivo 7. p38 MAPK is a validated target in autoimmune and inflammatory diseases and several small molecule inhibitors have been tested in clinical trials mainly against rheumatoid arthritis, psoriasis and Crohn's disease 8. This provides an opportunity to repurpose these substances with excellent safety profiles as adjunct therapeutics in combination with anti-mycobacterial drugs against active TB. As a serine/threonine protein kinase, p38 MAPK plays an important role in orchestrating the immune response of the host by coordinating the release of proinflammatory cytokines such as interleukin (IL-) 1-beta (β) or tumor necrosis factor (TNF) upon infection 8. Clinical application of p38 MAPK inhibitors theoretically

Stress signaler p38 mitogen-activated kinase activation: a cause for concern?

“…The sustained overexpression of the p38 is a characteristic of chronic inflammation in aging tissues and promotes multiple human diseases. Therefore, p38 can be an ideal therapeutic target for reducing deleterious changes to the cell and its inflammatory environment [ 78 , 79 ]. Several therapeutic approaches have been designed to reduce the activation of upstream mediators and downstream effectors of p38 pathways [ 80 , 81 ].…”

Crosstalk between p38 MAPK and GR Signaling

“…Early inhibitors like SB203580 and SB202190 act on the ATP binding site, while newer ones like BIRB 796/Doramapimod interfere indirectly with ATP binding, preventing p38’s catalytic activity. Nowadays, these tools are widely used for in vitro and in vivo studies, as well as being investigated in pre-clinical trials and offering new host-modulating therapy forms for various diseases including rheumatoid arthritis, Crohn’s disease, tuberculosis, and cancer [ 8 , 9 ].…”

microRNAs associated with the pathogenesis and their role in regulating various signaling pathways during Mycobacterium tuberculosis infection

“…Signaling via ERK1/2 and p38 inhibits a well-known mycobacterial TLR2 agonist. Thus, the p38 MAPK and ERK1/2 pathways regulate macrophage antimicrobial function and antigen presentation by infected macrophages, potentially contributing to host immune evasion ( Liu P et al., 2016 ; Liu P et al, 2016; Hölscher et al., 2020 ). TNF mRNA is stabilized by activated MK2 ( Campbell et al., 2014 ).…”