Abstract

The effect of corticosteroids on human physiology is complex and their use in tuberculosis patients remains controversial. In a high-throughput screening approach designed to discover virulence inhibitors, several corticosteroids were found to prevent cytolysis of fibroblasts infected with mycobacteria. Further experiments with Mycobacterium tuberculosis showed anti-cytolytic activity in the 10 nM range, but no effect on bacterial growth or survival in the absence of host cells at 20 μM. The results from a panel of corticosteroids with various affinities to the glucocorticoid- and mineralocorticoid receptors indicate that the inhibition of cytolysis most likely is mediated through the glucocorticoid receptor. Using live-imaging of M. tuberculosis-infected human monocyte-derived macrophages, we also show that corticosteroids to some extent control intracellular bacteria. In vitro systems with reduced complexity are to further study and understand the interactions between bacterial infection, immune defense and cell signaling.

Highlights

  • Tuberculosis (TB) is the leading cause of death from a single infectious agent and one of the top 10 causes of death worldwide

  • We show that corticosteroids prevent cytolysis of mycobacteria-infected lung fibroblast cells, and reduce intracellular bacterial growth in human monocyte-derived macrophages even though they have no effect on bacterial growth or survival in the absence of host cells

  • The human monocyte-derived macrophages (hMDMs) were seeded in a 384-well plate (8000 cells/well) and infected with M. tuberculosis H37Rv:pCherry3 reporter strain at a multiplicity of infection (MOI) of 1:1 in the presence of 0.5 mM of corticosteroid

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Summary

Introduction

Tuberculosis (TB) is the leading cause of death from a single infectious agent and one of the top 10 causes of death worldwide. Corticosteroids are the major hormones of the hypothalamicpituitary-adrenal axis They are best known for their strong antiinflammatory and immune modulatory activity, but they are important in fetal development, metabolism, body fluid homeostasis and many other physiological processes. The target glucocorticoid receptor (GR) is a versatile transcription factor expressed in most cells in the body. It is expressed in several splice variants and can act on DNA both by transactivation and transrepression. Glucocorticoids have immunostimulatory effects [9], and act as a potent anti-apoptotic in primary human fibroblasts whereas it is proapoptotic in hematopoietic cells. Corticosteroids have a systemic and complex impact on human physiology, the in vitro experiments presented can help us understand the host response to mycobacterial infection on a cellular level

Cell culture
Compounds
Infection of hMDMs monitored by IncuCyte live cell microscopy
Results and discussion
Full Text
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