S100A12 Is Part of the Antimicrobial Network against Mycobacterium leprae in Human Macrophages.

Susan Realegeno,Matteo Pellegrini,Robert L Modlin,Ernest Y Lee,Thomas H Rea,Philip T Liu,Maria T Ochoa,Gerard C L Wong,Rosane Teles,Kindra M Kelly-Scumpia,Nathan W Schmidt,Jing Lu,Angeline Tilly Dang,Euzenir N Sarno,Mirjam Schenk

doi:10.1371/journal.ppat.1005705

Susan Realegeno, Matteo Pellegrini + Show 13 more

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https://doi.org/10.1371/journal.ppat.1005705

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Abstract

Triggering antimicrobial mechanisms in macrophages infected with intracellular pathogens, such as mycobacteria, is critical to host defense against the infection. To uncover the unique and shared antimicrobial networks induced by the innate and adaptive immune systems, gene expression profiles generated by RNA sequencing (RNAseq) from human monocyte-derived macrophages (MDMs) activated with TLR2/1 ligand (TLR2/1L) or IFN-γ were analyzed. Weighed gene correlation network analysis identified modules of genes strongly correlated with TLR2/1L or IFN-γ that were linked by the “defense response” gene ontology term. The common TLR2/1L and IFN-γ inducible human macrophage host defense network contained 16 antimicrobial response genes, including S100A12, which was one of the most highly induced genes by TLR2/1L. There is limited information on the role of S100A12 in infectious disease, leading us to test the hypothesis that S100A12 contributes to host defense against mycobacterial infection in humans. We show that S100A12 is sufficient to directly kill Mycobacterium tuberculosis and Mycobacterium leprae. We also demonstrate that S100A12 is required for TLR2/1L and IFN-γ induced antimicrobial activity against M. leprae in infected macrophages. At the site of disease in leprosy, we found that S100A12 was more strongly expressed in skin lesions from tuberculoid leprosy (T-lep), the self-limiting form of the disease, compared to lepromatous leprosy (L-lep), the progressive form of the disease. These data suggest that S100A12 is part of an innate and adaptive inducible antimicrobial network that contributes to host defense against mycobacteria in infected macrophages.

Highlights

Intracellular pathogens reside in macrophages, exploiting host metabolic processes, while at the same time inhibiting host defense mechanisms
We demonstrate that S100A12 is required for TLR2/1 ligand (TLR2/1L) and IFN-γ induced antimicrobial activity against M. leprae in infected macrophages
Macrophage antimicrobial activity induced by innate and adaptive immune stimuli is crucial for controlling infection against intracellular pathogens

Summary

Introduction

Intracellular pathogens reside in macrophages, exploiting host metabolic processes, while at the same time inhibiting host defense mechanisms. Activation of these infected macrophages via the innate and adaptive immune system triggers antimicrobial responses that overcome microbial escape strategies. TLR2/1L and IFN-γ trigger distinct signaling pathways in human macrophages, but converge on a common host defense pathway, involving the vitamin D-dependent induction of antimicrobial peptides [5,6,7]. The identification of the host defense network by which the innate and adaptive immune systems induce antimicrobial activity in human macrophages is important for understanding mechanisms of resistance versus susceptibility to intracellular bacteria

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