Abstract

Following infection, virulent mycobacteria persist and grow within the macrophage, suggesting that the intrinsic activation of an innate antimicrobial response is subverted by the intracellular pathogen. For Mycobacterium leprae, the intracellular bacterium that causes leprosy, the addition of exogenous innate or adaptive immune ligands to the infected monocytes/macrophages was required to detect a vitamin D-dependent antimicrobial activity. We investigated whether there is an intrinsic immune response to M. leprae in macrophages that is inhibited by the pathogen. Upon infection of monocytes with M. leprae, there was no upregulation of CYP27B1 nor its enzymatic activity converting the inactive prohormone form of vitamin D (25-hydroxyvitamin D) to the bioactive form (1,25α-dihydroxyvitamin D). Given that M. leprae-induced type I interferon (IFN) inhibited monocyte activation, we blocked the type I IFN receptor (IFNAR), revealing the intrinsic capacity of monocytes to recognize M. leprae and upregulate CYP27B1. Consistent with these in vitro studies, an inverse relationship between expression of CYP27B1 vs. type I IFN downstream gene OAS1 was detected in leprosy patient lesions, leading us to study cytokine-derived macrophages (MΦ) to model cellular responses at the site of disease. Infection of IL-15-derived MΦ, similar to MΦ in lesions from the self-limited form of leprosy, with M. leprae did not inhibit induction of the vitamin D antimicrobial pathway. In contrast, infection of IL-10-derived MΦ, similar to MΦ in lesions from patients with the progressive form of leprosy, resulted in induction of type I IFN and suppression of the vitamin D directed pathway. Importantly, blockade of the type I IFN response in infected IL-10 MΦ decreased M. leprae viability. These results indicate that M. leprae evades the intrinsic capacity of human monocytes/MΦ to activate the vitamin D-mediated antimicrobial pathway via the induction of type I IFN.

Highlights

  • The ability of macrophages (MF) to kill intracellular pathogens is critical to the outcome of infection

  • Our macrophages are equipped with the ability to detect and kill invading pathogens, and yet, these cells of the innate immune system are still subject to infection by intracellular bacterium

  • By studying Mycobacterium leprae, the etiological agent of leprosy, we describe an immune evasion mechanism whereby this bacterial pathogen utilizes our own antiviral immune response against the macrophage

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Summary

Introduction

The ability of macrophages (MF) to kill intracellular pathogens is critical to the outcome of infection. In the absence of these exogenous stimuli, there is evidence for intrinsic antimicrobial mechanisms, these are not clearly defined nor sustained [3]. In this regard, microbial pathogens have evolved mechanisms to evade these host defense pathways, establishing infection that results in clinical disease. We investigated whether in the absence of exogenous triggers such as TLR2L or IFN-γ, there is intrinsic activation of a vitamin D-dependent antimicrobial pathway in infected human MF, as well as the presence of bacterial mechanisms of escape, by studying leprosy as a disease model. Gene expression profiling of skin lesions from patients with the different forms of leprosy suggested a correlation between activation of the vitamin D pathway and favorable disease outcomes [5]

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