miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages

Eduardo Milton Ramos-Sanchez; Luiza Campos Reis; Marina de Assis Souza; Sandra Márcia Muxel; Kamila Reis Santos; Dimitris Lagos; Valéria Rêgo Alves Pereira; Maria Edileuza Felinto de Brito; Paul Martin Kaye; Lucile Maria Floeter-Winter; Hiro Goto

doi:10.3389/fcimb.2022.826039

miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages

Eduardo Milton Ramos-Sanchez, Luiza Campos Reis, Marina de Assis Souza, Sandra Márcia Muxel, Kamila Reis Santos, Dimitris Lagos, Valéria Rêgo Alves Pereira, Maria Edileuza Felinto de Brito, Paul Martin Kaye, Lucile Maria Floeter-Winter, Hiro Goto^*

^*Corresponding author for this work

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

Visceral leishmaniasis caused by Leishmania (Leishmania) infantum in Latin America progress with hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, and weight loss and maybe lethal mainly in untreated cases. miRNAs are important regulators of immune and inflammatory gene expression, but their mechanisms of action and their relationship to pathogenesis in leishmaniasis are not well understood. In the present study, we sought to quantify changes in miRNAs associated with immune and inflammatory pathways using the L. (L.) infantum promastigote infected- human monocytic THP-1 cell model and plasma from patients with visceral leishmaniasis. We identified differentially expressed miRNAs in infected THP-1 cells compared with non-infected cells using qPCR arrays. These miRNAs were submitted to in silico analysis, revealing targets within functional pathways associated with TGF-β, chemokines, glucose metabolism, inflammation, apoptosis, and cell signaling. In parallel, we identified differentially expressed miRNAs in active visceral leishmaniasis patient plasma compared with endemic healthy controls. In silico analysis of these data indicated different predicted targets within the TGF-β, TLR4, IGF-I, chemokine, and HIF1α pathways. Only a small number of miRNAs were commonly identified in these two datasets, notably with miR-548d-3p being up-regulated in both conditions. To evaluate the potential biological role of miR-548d-3p, we transiently transfected a miR-548d-3p inhibitor into L. (L.) infantum infected-THP-1 cells, finding that inhibition of miR-548d-3p enhanced parasite growth, likely mediated through reduced levels of MCP-1/CCL2 and nitric oxide production. Further work will be required to determine how miR-548d-3p plays a role in vivo and whether it serves as a potential biomarker of progressive leishmaniasis.

Original language	English
Article number	826039
Number of pages	14
Journal	Frontiers in cellular and infection microbiology
Volume	12
DOIs	https://doi.org/10.3389/fcimb.2022.826039 https://doi.org/10.3389/fcimb.2022.876035
Publication status	Published - 10 Feb 2022

Bibliographical note

Keywords

Animals
Humans
Leishmania infantum/genetics
Leishmaniasis, Visceral
Macrophages
MicroRNAs/genetics
Parasites/genetics

Access to Document

10.3389/fcimb.2022.826039Licence: CC BY
10.3389/fcimb.2022.876035Licence: CC BY

Corrigendum: miR-548d-3p Is Up-regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages
© 2022 Ramos-Sanchez, Reis, Souza, Muxel, Santos, Lagos, Pereira, de Brito, Kaye, Floeter-Winter and Goto
Final published version, 192 KBLicence: CC BY
miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages
© 2022 Ramos-Sanchez, Reis, Souza, Muxel, Santos, Lagos, Pereira, Brito, Kaye, Floeter-Winter and Goto.
Final published version, 5.53 MBLicence: CC BY
miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages
© 2022 Author(s)
Final published version, 5.53 MBLicence: CC BY

Cite this

Ramos-Sanchez, E. M., Reis, L. C., Souza, M. D. A., Muxel, S. M., Santos, K. R., Lagos, D., Pereira, V. R. A., de Brito, M. E. F., Kaye, P. M., Floeter-Winter, L. M., & Goto, H. (2022). miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages. Frontiers in cellular and infection microbiology, 12, Article 826039. https://doi.org/10.3389/fcimb.2022.826039, https://doi.org/10.3389/fcimb.2022.876035

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abstract = "Visceral leishmaniasis caused by Leishmania (Leishmania) infantum in Latin America progress with hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, and weight loss and maybe lethal mainly in untreated cases. miRNAs are important regulators of immune and inflammatory gene expression, but their mechanisms of action and their relationship to pathogenesis in leishmaniasis are not well understood. In the present study, we sought to quantify changes in miRNAs associated with immune and inflammatory pathways using the L. (L.) infantum promastigote infected- human monocytic THP-1 cell model and plasma from patients with visceral leishmaniasis. We identified differentially expressed miRNAs in infected THP-1 cells compared with non-infected cells using qPCR arrays. These miRNAs were submitted to in silico analysis, revealing targets within functional pathways associated with TGF-β, chemokines, glucose metabolism, inflammation, apoptosis, and cell signaling. In parallel, we identified differentially expressed miRNAs in active visceral leishmaniasis patient plasma compared with endemic healthy controls. In silico analysis of these data indicated different predicted targets within the TGF-β, TLR4, IGF-I, chemokine, and HIF1α pathways. Only a small number of miRNAs were commonly identified in these two datasets, notably with miR-548d-3p being up-regulated in both conditions. To evaluate the potential biological role of miR-548d-3p, we transiently transfected a miR-548d-3p inhibitor into L. (L.) infantum infected-THP-1 cells, finding that inhibition of miR-548d-3p enhanced parasite growth, likely mediated through reduced levels of MCP-1/CCL2 and nitric oxide production. Further work will be required to determine how miR-548d-3p plays a role in vivo and whether it serves as a potential biomarker of progressive leishmaniasis.",

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Ramos-Sanchez, EM, Reis, LC, Souza, MDA, Muxel, SM, Santos, KR, Lagos, D, Pereira, VRA, de Brito, MEF, Kaye, PM, Floeter-Winter, LM & Goto, H 2022, 'miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages', Frontiers in cellular and infection microbiology, vol. 12, 826039. https://doi.org/10.3389/fcimb.2022.826039, https://doi.org/10.3389/fcimb.2022.876035

TY - JOUR

T1 - miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages

AU - Ramos-Sanchez, Eduardo Milton

AU - Reis, Luiza Campos

AU - Souza, Marina de Assis

AU - Muxel, Sandra Márcia

AU - Santos, Kamila Reis

AU - Lagos, Dimitris

AU - Pereira, Valéria Rêgo Alves

AU - de Brito, Maria Edileuza Felinto

AU - Kaye, Paul Martin

AU - Floeter-Winter, Lucile Maria

AU - Goto, Hiro

PY - 2022/2/10

Y1 - 2022/2/10

N2 - Visceral leishmaniasis caused by Leishmania (Leishmania) infantum in Latin America progress with hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, and weight loss and maybe lethal mainly in untreated cases. miRNAs are important regulators of immune and inflammatory gene expression, but their mechanisms of action and their relationship to pathogenesis in leishmaniasis are not well understood. In the present study, we sought to quantify changes in miRNAs associated with immune and inflammatory pathways using the L. (L.) infantum promastigote infected- human monocytic THP-1 cell model and plasma from patients with visceral leishmaniasis. We identified differentially expressed miRNAs in infected THP-1 cells compared with non-infected cells using qPCR arrays. These miRNAs were submitted to in silico analysis, revealing targets within functional pathways associated with TGF-β, chemokines, glucose metabolism, inflammation, apoptosis, and cell signaling. In parallel, we identified differentially expressed miRNAs in active visceral leishmaniasis patient plasma compared with endemic healthy controls. In silico analysis of these data indicated different predicted targets within the TGF-β, TLR4, IGF-I, chemokine, and HIF1α pathways. Only a small number of miRNAs were commonly identified in these two datasets, notably with miR-548d-3p being up-regulated in both conditions. To evaluate the potential biological role of miR-548d-3p, we transiently transfected a miR-548d-3p inhibitor into L. (L.) infantum infected-THP-1 cells, finding that inhibition of miR-548d-3p enhanced parasite growth, likely mediated through reduced levels of MCP-1/CCL2 and nitric oxide production. Further work will be required to determine how miR-548d-3p plays a role in vivo and whether it serves as a potential biomarker of progressive leishmaniasis.

AB - Visceral leishmaniasis caused by Leishmania (Leishmania) infantum in Latin America progress with hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, and weight loss and maybe lethal mainly in untreated cases. miRNAs are important regulators of immune and inflammatory gene expression, but their mechanisms of action and their relationship to pathogenesis in leishmaniasis are not well understood. In the present study, we sought to quantify changes in miRNAs associated with immune and inflammatory pathways using the L. (L.) infantum promastigote infected- human monocytic THP-1 cell model and plasma from patients with visceral leishmaniasis. We identified differentially expressed miRNAs in infected THP-1 cells compared with non-infected cells using qPCR arrays. These miRNAs were submitted to in silico analysis, revealing targets within functional pathways associated with TGF-β, chemokines, glucose metabolism, inflammation, apoptosis, and cell signaling. In parallel, we identified differentially expressed miRNAs in active visceral leishmaniasis patient plasma compared with endemic healthy controls. In silico analysis of these data indicated different predicted targets within the TGF-β, TLR4, IGF-I, chemokine, and HIF1α pathways. Only a small number of miRNAs were commonly identified in these two datasets, notably with miR-548d-3p being up-regulated in both conditions. To evaluate the potential biological role of miR-548d-3p, we transiently transfected a miR-548d-3p inhibitor into L. (L.) infantum infected-THP-1 cells, finding that inhibition of miR-548d-3p enhanced parasite growth, likely mediated through reduced levels of MCP-1/CCL2 and nitric oxide production. Further work will be required to determine how miR-548d-3p plays a role in vivo and whether it serves as a potential biomarker of progressive leishmaniasis.

KW - Animals

KW - Humans

KW - Leishmania infantum/genetics

KW - Leishmaniasis, Visceral

KW - Macrophages

KW - MicroRNAs/genetics

KW - Parasites/genetics

U2 - 10.3389/fcimb.2022.826039

DO - 10.3389/fcimb.2022.826039

M3 - Article

C2 - 35372119

SN - 2235-2988

VL - 12

JO - Frontiers in cellular and infection microbiology

JF - Frontiers in cellular and infection microbiology

M1 - 826039

ER -