Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism

Sandra Marcia Muxel; Maria Fernanda Laranjeira-Silva; Ricardo Andrade Zampieri; Lucile Maria Floeter-Winter

doi:10.1038/srep44141

journal article Open Access Mar 09, 2017

Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism

Sandra Marcia Muxel Maria Fernanda Laranjeira-Silva Ricardo Andrade Zampieri Lucile Maria Floeter-Winter

Scientific Reports Vol. 7 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/srep44141

Abstract

AbstractLeishmania (Leishmania)amazonensisis an intracellular protozoan parasite responsible for the cutaneous leishmaniasis. The parasite replicates inside mammalian macrophage to establish infection. Host-pathogen interactions result in microRNA-mediated post-transcriptional regulation of host genes involved in inflammatory immune response. We analyzed macrophage miRNA profiles duringL. (L.)amazonensisinfection. The regulation of macrophage miRNA expression by the parasite correlates with/depends on parasite arginase activity during infection.L. (L.)amazonensis (La-WT) presented significant miRNA profile alteration (27%) compared toL. (L.)amazonensisarginase knockout (La-arg−) (~40%) in relation to uninfected-macrophages. We observed that 78% of the altered miRNAs were up-regulated inLa-WT infection, while only 32% were up-regulated inLa-arg−-infected macrophages. In contrast toLa-WT, the lack ofL. (L.)amazonensisarginase led to the inhibition of miR-294 and miR-721 expression. The expression of miR-294 and miR-721 was recovered to levels similar toLa-WT inLa-arg−addback mutant. The inhibition of miR-294/Nos2 and miR721/Nos2interactions increased NOS2 expression and NO production, and reducedL. (L.)amazonensisinfectivity, confirmingNos2as target of these miRNAs. The role of miR-294 and miR-721 in the regulation of NOS2 expression duringLeishmaniareplication in infected macrophages pointing these miRNAs as potential new targets for drug development.

Topics

No keywords indexed for this article. Browse by subject →

References

53

[1]

Bogdan, C. Mechanisms and consequences of persistence of intracellular pathogens: leishmaniasis as an example. Cellular microbiology 10, 1221–1234, doi: 10.1111/j.1462-5822.2008.01146.x (2008). 10.1111/j.1462-5822.2008.01146.x

[2]

Liese, J., Schleicher, U. & Bogdan, C. The innate immune response against Leishmania parasites. Immunobiology 213, 377–387, doi: 10.1016/j.imbio.2007.12.005 (2008). 10.1016/j.imbio.2007.12.005

[3]

Nathan, C. & Shiloh, M. U. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci USA 97, 8841–8848 (2000). 10.1073/pnas.97.16.8841

[4]

Gregory, D. J. & Olivier, M. Subversion of host cell signalling by the protozoan parasite Leishmania. Parasitology 130 Suppl, S27–35, doi: 10.1017/S0031182005008139 (2005). 10.1017/s0031182005008139

[5]

Green, S. J., Crawford, R. M., Hockmeyer, J. T., Meltzer, M. S. & Nacy, C. A. Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha. J Immunol 145, 4290–4297 (1990). 10.4049/jimmunol.145.12.4290

[6]

Green, S. J., Meltzer, M. S., Hibbs, J. B. Jr. & Nacy, C. A. Activated macrophages destroy intracellular Leishmania major amastigotes by an L-arginine-dependent killing mechanism. J Immunol 144, 278–283 (1990). 10.4049/jimmunol.144.1.278

[7]

Liew, F. Y. et al. Resistance to Leishmania major infection correlates with the induction of nitric oxide synthase in murine macrophages. European journal of immunology 21, 3009–3014, doi: 10.1002/eji.1830211216 (1991). 10.1002/eji.1830211216

[8]

Wanasen, N., MacLeod, C. L., Ellies, L. G. & Soong, L. L-arginine and cationic amino acid transporter 2B regulate growth and survival of Leishmania amazonensis amastigotes in macrophages. Infection and immunity 75, 2802–2810, doi: 10.1128/IAI.00026-07 (2007). 10.1128/iai.00026-07

[9]

Iniesta, V. et al. Arginase I induction in macrophages, triggered by Th2-type cytokines, supports the growth of intracellular Leishmania parasites. Parasite immunology 24, 113–118 (2002). 10.1046/j.1365-3024.2002.00444.x

[10]

da Silva, E. R., Castilho, T. M., Pioker, F. C., Tomich de Paula Silva, C. H. & Floeter-Winter, L. M. Genomic organisation and transcription characterisation of the gene encoding Leishmania (Leishmania) amazonensis arginase and its protein structure prediction. International journal for parasitology 32, 727–737 (2002). 10.1016/s0020-7519(02)00002-4

[11]

da Silva, M. F., Zampieri, R. A., Muxel, S. M., Beverley, S. M. & Floeter-Winter, L. M. Leishmania amazonensis arginase compartmentalization in the glycosome is important for parasite infectivity. PLoS One 7, e34022, doi: 10.1371/journal.pone.0034022 (2012). 10.1371/journal.pone.0034022

[12]

Dixit, V. & Mak, T. W. NF-kappaB signaling. Many roads lead to madrid. Cell 111, 615–619 (2002). 10.1016/s0092-8674(02)01166-2

[13]

Castilho-Martins, E. A., Laranjeira da Silva, M. F., dos Santos, M. G., Muxel, S. M. & Floeter-Winter, L. M. Axenic Leishmania amazonensis promastigotes sense both the external and internal arginine pool distinctly regulating the two transporter-coding genes. PLoS One 6, e27818, doi: 10.1371/journal.pone.0027818 (2011). 10.1371/journal.pone.0027818

[14]

Baltimore, D., Boldin, M. P., O’Connell, R. M., Rao, D. S. & Taganov, K. D. MicroRNAs: new regulators of immune cell development and function. Nature immunology 9, 839–845, doi: 10.1038/ni.f.209 (2008). 10.1038/ni.f.209

[15]

O’Neill, L. A., Sheedy, F. J. & McCoy, C. E. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol 11, 163–175, doi: 10.1038/nri2957 (2011). 10.1038/nri2957

[16]

Bagga, S. et al. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122, 553–563, doi: 10.1016/j.cell.2005.07.031 (2005). 10.1016/j.cell.2005.07.031

[17]

Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773, doi: 10.1038/nature03315 (2005). 10.1038/nature03315

[18]

Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004). 10.1016/s0092-8674(04)00045-5

[19]

The nuclear RNase III Drosha initiates microRNA processing

Yoontae Lee, Chiyoung Ahn, Jinju Han et al.

Nature 2003 10.1038/nature01957

[20]

Bernstein, E., Caudy, A. A., Hammond, S. M. & Hannon, G. J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363–366, doi: 10.1038/35053110 (2001). 10.1038/35053110

[21]

Hutvagner, G. et al. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293, 834–838, doi: 10.1126/science.1062961 (2001). 10.1126/science.1062961

[22]

Schwarz, D. S. et al. Asymmetry in the assembly of the RNAi enzyme complex. Cell 115, 199–208 (2003). 10.1016/s0092-8674(03)00759-1

[23]

Wang, B. et al. Distinct passenger strand and mRNA cleavage activities of human Argonaute proteins. Nature structural & molecular biology 16, 1259–1266, doi: 10.1038/nsmb.1712 (2009). 10.1038/nsmb.1712

[24]

Vaucheret, H., Vazquez, F., Crete, P. & Bartel, D. P. The action of ARGONAUTE1 in the miRNA pathway and its regulation by the miRNA pathway are crucial for plant development. Genes Dev 18, 1187–1197, doi: 10.1101/gad.1201404 (2004). 10.1101/gad.1201404

[25]

Frank, B. et al. Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR-210. Parasites & vectors 8, 404, doi: 10.1186/s13071-015-0974-3 (2015). 10.1186/s13071-015-0974-3

[26]

Mukherjee, B. et al. Antimony-Resistant Leishmania donovani Exploits miR-466i To Deactivate Host MyD88 for Regulating IL-10/IL-12 Levels during Early Hours of Infection. J Immunol 195, 2731–2742, doi: 10.4049/jimmunol.1402585 (2015). 10.4049/jimmunol.1402585

[27]

Lemaire, J. et al. MicroRNA expression profile in human macrophages in response to Leishmania major infection. PLoS neglected tropical diseases 7, e2478, doi: 10.1371/journal.pntd.0002478 (2013). 10.1371/journal.pntd.0002478

[28]

Ghosh, J., Bose, M., Roy, S. & Bhattacharyya, S. N. Leishmania donovani targets Dicer1 to downregulate miR-122, lower serum cholesterol, and facilitate murine liver infection. Cell host & microbe 13, 277–288, doi: 10.1016/j.chom.2013.02.005 (2013). 10.1016/j.chom.2013.02.005

[29]

Geraci, N. S., Tan, J. C. & McDowell, M. A. Characterization of microRNA expression profiles in Leishmania-infected human phagocytes. Parasite immunology 37, 43–51, doi: 10.1111/pim.12156 (2015). 10.1111/pim.12156

[30]

Houbaviy, H. B., Murray, M. F. & Sharp, P. A. Embryonic stem cell-specific MicroRNAs. Developmental cell 5, 351–358 (2003). 10.1016/s1534-5807(03)00227-2

[31]

Zheng, G. X. et al. A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells. PLoS genetics 7, e1002054, doi: 10.1371/journal.pgen.1002054 (2011). 10.1371/journal.pgen.1002054

[32]

Wang, Y., Liang, Y. & Lu, Q. MicroRNA epigenetic alterations: predicting biomarkers and therapeutic targets in human diseases. Clinical genetics 74, 307–315, doi: 10.1111/j.1399-0004.2008.01075.x (2008). 10.1111/j.1399-0004.2008.01075.x

[33]

Wong, C. C. et al. Inactivating CUX1 mutations promote tumorigenesis. Nature genetics 46, 33–38, doi: 10.1038/ng.2846 (2014). 10.1038/ng.2846

[34]

Wheeler, G., Ntounia-Fousara, S., Granda, B., Rathjen, T. & Dalmay, T. Identification of new central nervous system specific mouse microRNAs. FEBS letters 580, 2195–2200, doi: 10.1016/j.febslet.2006.03.019 (2006). 10.1016/j.febslet.2006.03.019

[35]

Laranjeira-Silva, M. F., Zampieri, R. A., Muxel, S. M., Beverley, S. M. & Floeter-Winter, L. M. Leishmania amazonensis arginase compartmentalization in the glycosome is important for parasite infectivity. PLoS One 7, e34022, doi: 10.1371/journal.pone.0034022 (2012). 10.1371/journal.pone.0034022

[36]

Wanasen, N. & Soong, L. L-arginine metabolism and its impact on host immunity against Leishmania infection. Immunologic research 41, 15–25, doi: 10.1007/s12026-007-8012-y (2008). 10.1007/s12026-007-8012-y

[37]

Laranjeira-Silva, M. F. & Floeter-Winter, L. M. In Proteins and Proteomics of Leishmania and Trypanossoma Vol. 67 Subcellular Biochemistry(ed. Marta H. Branquinha, Andre L. S. Santos, Claudia M. d’Avila-Levy, Lucimar F. Kneipp & Catia L. Sodre ) Ch. 4, 103–118 (Springer, 2014).

[38]

Roberts, S. C. et al. Arginase plays a pivotal role in polyamine precursor metabolism in Leishmania. Characterization of gene deletion mutants. J Biol Chem 279, 23668–23678, doi: 10.1074/jbc.M402042200 (2004). 10.1074/jbc.m402042200

[39]

Lima-Junior, D. S. et al. Inflammasome-derived IL-1beta production induces nitric oxide-mediated resistance to Leishmania. Nature medicine 19, 909–915, doi: 10.1038/nm.3221 (2013). 10.1038/nm.3221

[40]

Darlyuk, I. et al. Arginine homeostasis and transport in the human pathogen Leishmania donovani. J Biol Chem 284, 19800–19807, doi: 10.1074/jbc.M901066200 (2009). 10.1074/jbc.m901066200

[41]

Shaked-Mishan, P. et al. A novel high-affinity arginine transporter from the human parasitic protozoan Leishmania donovani. Molecular microbiology 60, 30–38, doi: 10.1111/j.1365-2958.2006.05060.x (2006). 10.1111/j.1365-2958.2006.05060.x

[42]

Goldman-Pinkovich, A. et al. An Arginine Deprivation Response Pathway Is Induced in Leishmania during Macrophage Invasion. PLoS pathogens 12, e1005494, doi: 10.1371/journal.ppat.1005494 (2016). 10.1371/journal.ppat.1005494

[43]

Bhattacharyya, S. N., Habermacher, R., Martine, U., Closs, E. I. & Filipowicz, W. Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125, 1111–1124, doi: 10.1016/j.cell.2006.04.031 (2006). 10.1016/j.cell.2006.04.031

[44]

Laranjeira-Silva, M. F., Zampieri, R. A., Muxel, S. M., Floeter-Winter, L. M. & Markus, R. P. Melatonin attenuates Leishmania (L.) amazonensis infection by modulating arginine metabolism. J Pineal Res 59, 478–487, doi: 10.1111/jpi.12279 (2015). 10.1111/jpi.12279

[45]

Castilho-Martins, E. A. et al. Capillary electrophoresis reveals polyamine metabolism modulation in Leishmania (Leishmania) amazonensis wild type and arginase knockout mutants under arginine starvation. Electrophoresis, doi: 10.1002/elps.201500114 (2015). 10.1002/elps.201500114

[46]

Gaur, U. et al. An effect of parasite-encoded arginase on the outcome of murine cutaneous leishmaniasis. J Immunol 179, 8446–8453 (2007). 10.4049/jimmunol.179.12.8446

[47]

Mahnke, A. et al. Hypoxia in Leishmania major skin lesions impairs the NO-dependent leishmanicidal activity of macrophages. The Journal of investigative dermatology 134, 2339–2346, doi: 10.1038/jid.2014.121 (2014). 10.1038/jid.2014.121

[48]

Beck, K. F. & Sterzel, R. B. Cloning and sequencing of the proximal promoter of the rat iNOS gene: activation of NFkappaB is not sufficient for transcription of the iNOS gene in rat mesangial cells. FEBS letters 394, 263–267 (1996). 10.1016/0014-5793(96)00966-0

[49]

Reveneau, S. et al. Oct-1 cooperates with the TATA binding initiation complex to control rapid transcription of human iNOS. Cell Mol Life Sci 69, 2609–2619, doi: 10.1007/s00018-012-0939-z (2012). 10.1007/s00018-012-0939-z

[50]

Yu, Z., Zhang, W. & Kone, B. C. Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB. The Biochemical journal 367, 97–105, doi: 10.1042/BJ20020588 (2002). 10.1042/bj20020588

Showing 50 of 53 references

Cited By

87

Recent advances in the development and clinical application of miRNAs in infectious diseases

Sara Nunes, Rana Bastos · 2025

Non-coding RNA Research

Bidirectional cytokine-microRNA control: A novel immunoregulatory framework in leishmaniasis

Abdollah Jafarzadeh, Maryam Nemati · 2022

PLOS Pathogens

Non-Coding RNAs in the Etiology and Control of Major and Neglected Human Tropical Diseases

Ousman Tamgue, Cybelle Fodieu Mezajou · 2021

Frontiers in Immunology

Th1-Th2 Cross-Regulation Controls Early Leishmania Infection in the Skin by Modulating the Size of the Permissive Monocytic Host Cell Reservoir

Matheus Batista Carneiro, Mateus Eustáquio Lopes · 2020

Cell Host & Microbe

c-Myc is a novel Leishmania virulence factor by proxy that targets the host miRNA system and is essential for survival in human macrophages

Lucie Colineau, Ulrike Lambertz · 2018

Journal of Biological Chemistry

Behavior of two Leishmania infantum strains—evaluation of susceptibility to antimonials and expression of microRNAs in experimentally infected J774 macrophages and in BALB/c mice

Stella Costa Silva, Débora Faria Silva · 2018

Parasitology Research

Metrics

87

Citations

53

References

Details

Published: Mar 09, 2017
Vol/Issue: 7(1)
License: View

Authors

S

Sandra Marcia Muxel

M

Maria Fernanda Laranjeira-Silva

R

Ricardo Andrade Zampieri

L

Lucile Maria Floeter-Winter

Cite This Article

Sandra Marcia Muxel, Maria Fernanda Laranjeira-Silva, Ricardo Andrade Zampieri, et al. (2017). Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism. Scientific Reports, 7(1). https://doi.org/10.1038/srep44141

Leishmania (Leishmania) amazonensis induces macrophage miR-294 and miR-721 expression and modulates infection by targeting NOS2 and L-arginine metabolism

You May Also Like