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

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.

Author Summary

Macrophage antimicrobial activity induced by innate and adaptive immune stimuli is crucial for controlling infection against intracellular pathogens. In order to characterize host defense pathways, we activated human macrophages with innate and adaptive immune stimuli known to induce antimicrobial activity against mycobacteria, identifying a set of 16 antimicrobial response genes. One of these, S100A12, is present in humans, but not mice, has limited studies in infectious disease. By studying leprosy as a model, we found that expression of S100A12 was greater in skin lesions from patients with the self-limiting versus the progressive form of the disease. Furthermore, we show that S100A12 is sufficient to kill mycobacteria and is required for decreasing the relative viability of M. leprae in infected macrophages.