Differential immune response modulation in early Leishmania amazonensis infection of BALB/c and C57BL/6 macrophages based on transcriptome profiles

Aoki, Juliana Ide; Muxel, Sandra Márcia; Zampieri, Ricardo Andrade; Müller, Karl Erik; Nerland, Audun Helge; Flöeter-Winter, Lucile Maria

doi:10.1038/s41598-019-56305-1

Cited by 33 publications

(39 citation statements)

References 98 publications

(127 reference statements)

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“…However, the parasite can subvert the activation of macrophages to establish infection [36]. The genomic and transcriptomic networks during Leishmania infection have been providing interesting data regarding how Leishmania can to modulate the gene organization and gene expression of its host [37][38][39][40]. Additionally, we have observed differentially expressed genes profile during the different phases of parasite growth [37,38,41].…”

Section: Discussionmentioning

confidence: 82%

Metabolomic Profile of BALB/c Macrophages Infected with Leishmania amazonensis: Deciphering L-Arginine Metabolism

Muxel

Mamani-Huanca

Aoki

et al. 2019

IJMS

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Background: Leishmaniases are neglected tropical diseases that are caused by Leishmania, being endemic worldwide. L-arginine is an essential amino acid that is required for polyamines production on mammal cells. During Leishmania infection of macrophages, L-arginine is used by host and parasite arginase to produce polyamines, leading to parasite survival; or, by nitric oxide synthase 2 to produce nitric oxide leading to parasite killing. Here, we determined the metabolomic profile of BALB/c macrophages that were infected with L. amazonensis wild type or with L. amazonensis arginase knockout, correlating the regulation of L-arginine metabolism from both host and parasite. Methods: The metabolites of infected macrophages were analyzed by capillary electrophoresis coupled with mass spectrometry (CE-MS). The metabolic fingerprints analysis provided the dual profile from the host and parasite. Results: We observed increased levels of proline, glutamic acid, glutamine, L-arginine, ornithine, and putrescine in infected-L. amazonensis wild type macrophages, which indicated that this infection induces the polyamine production. Despite this, we observed reduced levels of ornithine, proline, and trypanothione in infected-L. amazonensis arginase knockout macrophages, indicating that this infection reduces the polyamine production. Conclusions: The metabolome fingerprint indicated that Leishmania infection alters the L-arginine/polyamines/trypanothione metabolism inside the host cell and the parasite arginase impacts on L-arginine metabolism and polyamine production, defining the infection fate.Int. J. Mol. Sci. 2019, 20, 6248 2 of 20 forms found in the proboscis of the phlebotomine sand fly host, to amastigote forms in the interior of macrophage phagolysosomes in the mammalian host [3]. Leishmania infection results in the regulation of pathways that are involved in the inflammatory response and leishmanicidal mechanisms, such as nitric oxide (NO) production via nitric oxide synthase 2 (NOS2), which is induced by Th1-cytokines [4][5][6][7][8][9]. However, Leishmania can subvert these mechanisms, which impacts on Th1/Th2 cytokine balance and induces macrophage arginase 1 (ARG1) activity to produce polyamines, putrescine, spermidine, and spermine, leading to Leishmania survival [6,[10][11][12].L-arginine is an essential amino acid and a precursor in the synthesis of proteins, urea, ornithine, citrulline, NO, creatinine, agmatine, glutamate, proline, putrescine, spermidine, and spermine, supporting the proline, glutamate, and polyamine metabolism at the whole organism level or cellular level in mammals. Its availability and metabolization can modulate inflammation and immune response regulation during infections and also recover the physiological steady-state [13,14].In mammalian cells, the endogenous synthesis of L-arginine from proline or glutamate via ornithine is not sufficient for supplying several pathways that need this amino acid as a precursor. L-arginine uptakes occur via cationic amino acid transporters (CAT1, CAT2A, ...

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Section: Discussionmentioning

confidence: 82%

Metabolomic Profile of BALB/c Macrophages Infected with Leishmania amazonensis: Deciphering L-Arginine Metabolism

Muxel

Mamani-Huanca

Aoki

et al. 2019

IJMS

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“…Some of the miRNAs modulated during infection have been implicated in macrophage polarization, as shown for the M1 phenotype (miRNA-146 and miRNA-210) and for M2 phenotype (miRNA-130a, miRNA-130b, miRNA-155, miRNA-21, miRNA-19a, miRNA-23a, miRNA-125a, miRNA-125b, miRNA-26a, miRNA-26b, and miRNA-720) [73]. In this way, the transcription profile of murine macrophages indicates a mix of M1/M2 phenotypes in murine macrophages infected with L. amazonensis, whereas in BALB/c macrophages, differential downregulation of Il1b is observed once C57BL/6 macrophages upregulate Il1b, a molecule that mediates nitric oxide (NO) production and confers resistance against Leishmania infection [74,75].…”

Section: Leishmania-host Interactionsmentioning

confidence: 99%

MicroRNAs: Biological Regulators in Pathogen–Host Interactions

Acuña

Flöeter-Winter

Muxel

2020

Cells

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An inflammatory response is essential for combating invading pathogens. Several effector components, as well as immune cell populations, are involved in mounting an immune response, thereby destroying pathogenic organisms such as bacteria, fungi, viruses, and parasites. In the past decade, microRNAs (miRNAs), a group of noncoding small RNAs, have emerged as functionally significant regulatory molecules with the significant capability of fine-tuning biological processes. The important role of miRNAs in inflammation and immune responses is highlighted by studies in which the regulation of miRNAs in the host was shown to be related to infectious diseases and associated with the eradication or susceptibility of the infection. Here, we review the biological aspects of microRNAs, focusing on their roles as regulators of gene expression during pathogen–host interactions and their implications in the immune response against Leishmania, Trypanosoma, Toxoplasma, and Plasmodium infectious diseases.

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“…The parasite is able to subvert the host response at multiple levels including modification of cytokines, chemokines, and their receptor expression, preventing antigen presentation by major histocompatibility complex (MHC) class II molecules and killing mechanisms through reduction of NO production. This impairment of immune response, early in infection, favors parasite establishment and development of chronic disease ( Ji et al, 2003 ; Aoki et al, 2019 ). Several studies showed that L. amazonensis induces TGF-β production early in infection.…”

Section: Discussionmentioning

confidence: 99%

“…infection. BALB/c and C57BL/6 non-infected macrophages present over 500 genes differentially expressed, which probably influences host response in the event of an infection ( Aoki et al, 2019 ). Similarly, Probst et al (2012) showed significant differences between C57BL/6 and CBA macrophages baseline gene expression profiles, suggesting that the higher capacity to control L. amazonensis infection by C57BL/6 macrophages is due to the baseline transcriptional signature of these cells.…”

Section: Introductionmentioning

confidence: 99%

“…M1 macrophages have increased nitric oxide synthase 2 (NOS2) expression and nitric oxide (NO) levels, which leads to parasite control. On the other hand, disease progression is related to macrophages polarization to an anti-inflammatory M2 phenotype with Th2 cell-mediated production of IL-4, IL-13, IL-10, TGF-β, and macrophage colony-stimulating factor (M-CSF), which increase arginase 1 activity and polyamine production, resulting in parasite replication ( Mantovani et al, 2004 ; Gordon and Taylor, 2005 ; Lawrence and Natoli, 2011 ; Wang et al, 2014 ; Muxel et al, 2018 ; Aoki et al, 2019 ;). It is, however, known that cytokines are not exclusive from one or other profile.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of Cytokines and Extracellular Matrix Proteins Expression by Leishmania amazonensis in Susceptible and Resistant Mice

et al. 2020

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Leishmaniases are a complex of diseases with a broad spectrum of clinical forms, which depend on the parasite species, immunological status, and genetic background of the host. In the Leishmania major model, susceptibility is associated with the Th2 pattern of cytokines production, while resistance is associated with Th1 response. However, the same dichotomy does not occur in L. amazonensis -infected mice. Cytokines are key players in these diseases progression, while the extracellular matrix (ECM) components participate in the process of parasite invasion as well as lesion healing. In this article, we analyzed the influence of host genetics on the expression of cytokines, inducible nitric oxide synthase (iNOS), and ECM proteins, as well as the parasite load in mice with different genetic backgrounds infected by L. amazonensis . C57BL/10 and C3H/He mice were subcutaneously infected with 10 6 L. amazonensis promastigotes. Lesion kinetics, parasite load, cytokines, iNOS, and ECM proteins expression were measured by quantitative PCR (qPCR) in the footpad, draining lymph nodes, liver, and spleen at early (24 h and 30 days) and late phase (120 and 180 days) of infection. Analysis of lesion kinetics showed that C57BL/10 mice developed ulcerative lesions at the inoculation site after L. amazonensis infection, while C3H/He showed slight swelling in the footpad 180 days after infection. C57BL/10 showed progressive enhancement of parasite load in all analyzed organs, while C3H/He mice showed extremely low parasite loads. Susceptible C57BL/10 mice showed high levels of TGF-β mRNA in the footpad early in infection and high levels of proinflammatory cytokines mRNA (IL-12, TNF-α, and IFN-γ) and iNOS in the late phase of the infection. There is an association between increased expression of fibronectin, laminin, collagen III and IV, and TGF-β. On the other hand, resistant C3H/He mice presented a lower repertory of cytokines mRNA expression when compared with susceptible C57BL/10 mice, basically producing TNF-α, collagen IV, and laminin early in infection. The findings of our study indicate that L. amazonensis infection induces different cytokine expression in resistant and susceptible mice but not like the L. major model. An organ-compartmentalized cytokine response was observed in our model. Host genetics determine this response, which modulates ECM proteins expression.

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Differential immune response modulation in early Leishmania amazonensis infection of BALB/c and C57BL/6 macrophages based on transcriptome profiles

Cited by 33 publications

References 98 publications

Metabolomic Profile of BALB/c Macrophages Infected with Leishmania amazonensis: Deciphering L-Arginine Metabolism

Metabolomic Profile of BALB/c Macrophages Infected with Leishmania amazonensis: Deciphering L-Arginine Metabolism

MicroRNAs: Biological Regulators in Pathogen–Host Interactions

Modulation of Cytokines and Extracellular Matrix Proteins Expression by Leishmania amazonensis in Susceptible and Resistant Mice

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