Large-Scale Gene Expression Signatures Reveal a Microbicidal Pattern of Activation in Mycobacterium leprae-Infected Monocyte-Derived Macrophages With Low Multiplicity of Infection

Abstract

Leprosy is a disease with a clinical spectrum of presentations that is also manifested in diverse histological features. At one pole, lepromatous lesions (L-pole) have phagocytic foamy macrophages heavily parasitized with freely multiplying intracellular Mycobacterium leprae. At the other pole, the presence of epithelioid giant cells and granulomatous formation in tuberculoid lesions (T-pole) lead to the control of M. leprae replication and the containment of its spread. The mechanism that triggers this polarization is unknown, but macrophages are central in this process. Over the past few years, leprosy has been studied using large scale techniques to shed light on the basic pathways that, upon infection, rewire the host cellular metabolism and gene expression. M. leprae is particularly peculiar as it invades Schwann cells in the nerves, reprogramming their gene expression leading to a stem-like cell phenotype. This modulatory behavior exerted by M. leprae is also observed in skin macrophages. Here, we used live M. leprae to infect (10:1 multiplicity of infection) monocyte-derived macrophages (MDMs) for 48 h and analyzed the whole gene expression profile using microarrays. In this model, we observe an intense upregulation of genes consistent with a cellular immune response, with enriched pathways including peptide and protein secretion, leukocyte activation, inflammation, and cellular divalent inorganic cation homeostasis. Among the most differentially expressed genes (DEGs) are CCL5/RANTES and CYP27B1, and several members of the metallothionein and metalloproteinase families. This is consistent with a proinflammatory state that would resemble macrophage rewiring toward granulomatous formation observed at the T-pole. Furthermore, a comparison with a dataset retrieved from the Gene Expression Omnibus of M. leprae-infected Schwann cells (MOI 100:1) showed that the patterns among the DEGs are highly distinct, as the Schwann cells under these conditions had a scavenging and phagocytic gene profile similar to M2-like macrophages, with enriched pathways rearrangements in the cytoskeleton, lipid and cholesterol metabolism and upregulated genes including MVK, MSMO1, and LACC1/FAMIN. In summary, macrophages may have a central role in defining the paradigmatic cellular (T-pole) vs. humoral (L-pole) responses and it is likely that the multiplicity of infection and genetic polymorphisms in key genes are gearing this polarization.

Asymptomatic Hyperuricemia Promotes Recovery from Ischemic Organ Injury by Modulating the Phenotype of Macrophages

“…To investigate whether this is also the case in macrophages, we searched online databases for urate transporters expressed by macrophages. Microarray data of human blood monocyte-differentiated macrophages [ 38 ] ( Figure 2 F) and mouse bone marrow-derived macrophages [ 39 ] ( Figure 2 G) from the public domain suggested that these cells highly expressed the urate transporter solute carrier family 2 member ( SLC2A9/Glut9 ). RT-qPCR confirmed the expression of SLC2A9/Glut9 in mouse bone marrow-derived macrophages ( Figure 2 H).…”

“…We analyzed expression patterns of urate reabsorption transporters Slc2a9 , Slc22a11 , Slc22a12 , and Slc22a13 and urate excretion transporters Slc2a6 , Slc2a7 , Abcc4 , Slc17a1 , and Slc17a3 as previously described of either human blood monocyte-differentiated macrophages ( n = 3 controls) [ 38 ] and mouse bone marrow-derived macrophages ( n = 3 unstimulated controls) [ 39 ]. All data were downloaded as a processed expression matrix without quality control, which means that the reliability of the Affymetrix GeneChip microarray is unknown.…”

“…All data were downloaded as a processed expression matrix without quality control, which means that the reliability of the Affymetrix GeneChip microarray is unknown. Microarray of human macrophages (GSE162416) used the platform Illumina HumanHT-12 V4.0 expression beadchip [ 38 ] and that of mouse macrophages (GSE100059) used Affymetrix Mouse Exon 1.0 ST Array (Mm_ENTREZG_v18) [ 39 ]. Heat maps were generated using GraphPad Prism 7 software.…”

Progress of the Art of Macrophage Polarization and Different Subtypes in Mycobacterial Infection

“…At one pole of leprosy, the presence of MGCs and granuloma configuration in tuberculoid leprosy (TT) contributes to the containment of M. leprae proliferation and transmission (Figure 1A). At the other pole, lepromatous leprosy (LL) has phagocytic FCs heavily parasitized with freely multiplying intracellular M. leprae (Figure 1B) (12). Ma et al have constructed a map via integrating single-cell RNA sequencing with spatial sequencing to identify that the primary cell types, consisting of T cells, Mjs, keratinocytes, endothelial cells, and fibroblasts, were described to research the cellular composition and status discrepancies between reversal reactions and LL, and LGCs are more frequent in both lesions.…”

“…At one pole of leprosy, the presence of MGCs and granuloma configuration in tuberculoid leprosy (TT) contributes to the containment of M. leprae proliferation and transmission ( Figure 1A ). At the other pole, lepromatous leprosy (LL) has phagocytic FCs heavily parasitized with freely multiplying intracellular M. leprae ( Figure 1B ) ( 12 ). Ma et al.…”