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

Christoph Hölscher,Alexandra Hölscher,Stephan C Schäfer,Annie Linnea Müller,Jessica Gräb,Jan Rybniker

doi:10.1038/s41598-020-70184-x

Christoph Hölscher, Alexandra Hölscher + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-70184-x

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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.

Highlights

Host-modulating therapies have become an important focus in the development of novel concepts for improved management of tuberculosis (TB)
We have recently shown that genetic or chemical inhibition of p38 mitogen-activated protein kinase (MAPK) in vitro results in abrogation of Mycobacterium tuberculosis (Mtb)-induced host cell death and decreased release of inflammatory alarmins such as High-Mobility-GroupProtein B1 (HMGB1) ex vivo7. 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 d isease[8]
We here analyzed the outcome of experimental TB in vivo under p38 MAPK inhibition with and without antibiotic treatment during acute and chronic infection of C57BL/6 mice

Summary

Introduction

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. 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. 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 d isease[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. We here analyzed the outcome of experimental TB in vivo under p38 MAPK inhibition with and without antibiotic treatment during acute and chronic infection of C57BL/6 mice

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