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Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature

Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-γ within lesions. Phagocytic cells recruited to lesions, such as monocytes, are then exposed to IFN-γ which triggers their ability to kill the intracellular parasites. Consistent with this, transcriptional a...

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Autores principales: Farias Amorim, Camila, O. Novais, Fernanda, Nguyen, Ba T., Nascimento, Mauricio T., Lago, Jamile, Lago, Alexsandro S., Carvalho, Lucas P., Beiting, Daniel P., Scott, Phillip
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043375/
https://www.ncbi.nlm.nih.gov/pubmed/33793565
http://dx.doi.org/10.1371/journal.pntd.0009321
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author Farias Amorim, Camila
O. Novais, Fernanda
Nguyen, Ba T.
Nascimento, Mauricio T.
Lago, Jamile
Lago, Alexsandro S.
Carvalho, Lucas P.
Beiting, Daniel P.
Scott, Phillip
author_facet Farias Amorim, Camila
O. Novais, Fernanda
Nguyen, Ba T.
Nascimento, Mauricio T.
Lago, Jamile
Lago, Alexsandro S.
Carvalho, Lucas P.
Beiting, Daniel P.
Scott, Phillip
author_sort Farias Amorim, Camila
collection PubMed
description Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-γ within lesions. Phagocytic cells recruited to lesions, such as monocytes, are then exposed to IFN-γ which triggers their ability to kill the intracellular parasites. Consistent with this, transcriptional analysis of patient lesions identified an interferon stimulated gene (ISG) signature. To determine whether localized L. braziliensis infection triggers a systemic immune response that may influence the disease, we performed RNA sequencing (RNA-seq) on the blood of L. braziliensis-infected patients and healthy controls. Functional enrichment analysis identified an ISG signature as the dominant transcriptional response in the blood of patients. This ISG signature was associated with an increase in monocyte- and macrophage-specific marker genes in the blood and elevated serum levels IFN-γ. A cytotoxicity signature, which is a dominant feature in the lesions, was also observed in the blood and correlated with an increased abundance of cytolytic cells. Thus, two transcriptional signatures present in lesions were found systemically, although with a substantially reduced number of differentially expressed genes (DEGs). Finally, we found that the number of DEGs and ISGs in leishmaniasis was similar to tuberculosis–another localized infection–but significantly less than observed in malaria. In contrast, the cytolytic signature and increased cytolytic cell abundance was not found in tuberculosis or malaria. Our results indicate that systemic signatures can reflect what is occurring in leishmanial lesions. Furthermore, the presence of an ISG signature in blood monocytes and macrophages suggests a mechanism to limit systemic spread of the parasite, as well as enhance parasite control by pre-activating cells prior to lesion entry.
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spelling pubmed-80433752021-04-20 Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature Farias Amorim, Camila O. Novais, Fernanda Nguyen, Ba T. Nascimento, Mauricio T. Lago, Jamile Lago, Alexsandro S. Carvalho, Lucas P. Beiting, Daniel P. Scott, Phillip PLoS Negl Trop Dis Research Article Cutaneous leishmaniasis is a localized infection controlled by CD4+ T cells that produce IFN-γ within lesions. Phagocytic cells recruited to lesions, such as monocytes, are then exposed to IFN-γ which triggers their ability to kill the intracellular parasites. Consistent with this, transcriptional analysis of patient lesions identified an interferon stimulated gene (ISG) signature. To determine whether localized L. braziliensis infection triggers a systemic immune response that may influence the disease, we performed RNA sequencing (RNA-seq) on the blood of L. braziliensis-infected patients and healthy controls. Functional enrichment analysis identified an ISG signature as the dominant transcriptional response in the blood of patients. This ISG signature was associated with an increase in monocyte- and macrophage-specific marker genes in the blood and elevated serum levels IFN-γ. A cytotoxicity signature, which is a dominant feature in the lesions, was also observed in the blood and correlated with an increased abundance of cytolytic cells. Thus, two transcriptional signatures present in lesions were found systemically, although with a substantially reduced number of differentially expressed genes (DEGs). Finally, we found that the number of DEGs and ISGs in leishmaniasis was similar to tuberculosis–another localized infection–but significantly less than observed in malaria. In contrast, the cytolytic signature and increased cytolytic cell abundance was not found in tuberculosis or malaria. Our results indicate that systemic signatures can reflect what is occurring in leishmanial lesions. Furthermore, the presence of an ISG signature in blood monocytes and macrophages suggests a mechanism to limit systemic spread of the parasite, as well as enhance parasite control by pre-activating cells prior to lesion entry. Public Library of Science 2021-04-01 /pmc/articles/PMC8043375/ /pubmed/33793565 http://dx.doi.org/10.1371/journal.pntd.0009321 Text en © 2021 Farias Amorim et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Farias Amorim, Camila
O. Novais, Fernanda
Nguyen, Ba T.
Nascimento, Mauricio T.
Lago, Jamile
Lago, Alexsandro S.
Carvalho, Lucas P.
Beiting, Daniel P.
Scott, Phillip
Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature
title Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature
title_full Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature
title_fullStr Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature
title_full_unstemmed Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature
title_short Localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic IFN-γ signature
title_sort localized skin inflammation during cutaneous leishmaniasis drives a chronic, systemic ifn-γ signature
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043375/
https://www.ncbi.nlm.nih.gov/pubmed/33793565
http://dx.doi.org/10.1371/journal.pntd.0009321
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