Article
Large-Scale Gene Expression Signatures Reveal a Microbicidal Pattern of Activation in Mycobacterium leprae-Infected Monocyte-Derived Macrophages With Low Multiplicity of Infection
Registro en:
LEAL-CALVO, Thyago et al. Large-Scale Gene Expression Signatures Reveal a Microbicidal Pattern of Activation in Mycobacterium leprae-Infected Monocyte-Derived Macrophages With Low Multiplicity of Infection. Frontiers in Immunology, v. 12, Article 647832, p. 1 - 12, Apr. 2021.
1664-3224
10.3389/fimmu.2021.647832
Autor
Leal-Calvo, Thyago
Martins, Bruna Leticia
Bertoluci, Daniele Ferreira
Rosa, Patricia Sammarco
Camargo, Rodrigo Mendes de
Germano, Giovanna Vale
Souza, Vania Nieto Brito de
Latini, Ana Carla Pereira
Moraes, Milton Ozório
Resumen
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.