Publications by authors named "Valéria M Borges"

61 Publications

Defective in Lipophosphoglycan Biosynthesis Interferes With Activation of Human Neutrophils.

Front Cell Infect Microbiol 2022 6;12:788196. Epub 2022 Apr 6.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.

Visceral leishmaniasis (VL) is often associated with hematologic manifestations that may interfere with neutrophil response. Lipophosphoglycan (LPG) is a major molecule on the surface of promastigotes, which has been associated with several aspects of the parasite-vector-host interplay. Here, we investigated how LPG from (.) , the principal etiological agent of VL in the New World, influences the initial establishment of infection during interaction with human neutrophils in an experimental setting . Human neutrophils obtained from peripheral blood samples were infected with either the wild-type (WT) strain or LPG-deficient mutant (). In this setting, parasites displayed reduced viability compared to WT ; such finding was reverted in the complemented + parasites at 3- and 6-h post-infection. Confocal microscopy experiments indicated that this decreased survival was related to enhanced lysosomal fusion. In fact, LPG-deficient parasites more frequently died inside neutrophil acidic compartments, a phenomenon that was reverted when host cells were treated with Wortmannin. We also observed an increase in the secretion of the neutrophil collagenase matrix metalloproteinase-8 (MMP-8) by cells infected with compared to those that were infected with WT parasites. Furthermore, collagen I matrix degradation was found to be significantly increased in parasite-infected cells but not in WT-infected controls. Flow cytometry analysis revealed a substantial boost in production of reactive oxygen species (ROS) during infection with either WT or . In addition, killing of parasites was shown to be more dependent on the ROS production than that of WT . Notably, inhibition of the oxidative stress with Apocynin potentially fueled fitness as it increased the intracellular parasite viability. Thus, our observations demonstrate that LPG may be a critical molecule fostering parasite survival in human neutrophils through a mechanism that involves cellular activation and generation of free radicals.
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http://dx.doi.org/10.3389/fcimb.2022.788196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9019130PMC
April 2022

DC-SIGN Mediates the Interaction Between Neutrophils and -Infected Dendritic Cells to Promote DC Maturation and Parasite Elimination.

Front Immunol 2021 1;12:750648. Epub 2021 Nov 1.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.

Background: Leishmaniasis is a neglected arthropod-borne disease that affects millions of people worldwide. Successful infections require the mitigation of immune cell functions leading to parasite survival and proliferation. A large body of evidence highlights the involvement of neutrophils (PMNs) and dendritic cells (DCs) in the establishment of immunological responses against these parasites. However, few studies, contemplate to what extent these cells interact synergistically to constrain infection.

Objective: We sought to investigate how PMNs and infected DCs interact in an model of infection.

Material And Methods: Briefly, human PMNs and DCs were purified from the peripheral blood of healthy donors. Next, PMNs were activated with fibronectin and subsequently co-cultured with -infected DCs.

Results: We observed that -infected DC exhibited lower rates of infection when co-cultivated with either resting or activated PMNs. Surprisingly, we found that the release of neutrophil enzymes was not involved in killing. Next, we showed that the interaction between PMNs and infected-DCs was intermediated by DC-SIGN, further suggesting that parasite elimination occurs in a contact-dependent manner. Furthermore, we also observed that TNFα and ROS production was dependent on DC-SIGN-mediated contact, as well as parasite elimination is dependent on TNFα production in the co-culture. Finally, we observed that direct contact between PMNs and DCs are required to restore the expression of DC maturation molecules during infection.

Conclusion: Our findings suggest that the engagement of direct contact between PMNs and -infected DC DC-SIGN is required for the production of inflammatory mediators with subsequent parasite elimination and DC maturation.
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http://dx.doi.org/10.3389/fimmu.2021.750648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591281PMC
January 2022

-Induced Dendritic Cell Migration and Its Potential Contribution to Parasite Dissemination.

Microorganisms 2021 Jun 11;9(6). Epub 2021 Jun 11.

Laboratory of Host-Parasite Interaction and Epidemiology, Gonçalo Moniz Institute, Salvador 40296-710, BA, Brazil.

, an intracellular parasite species, causes lesions on the skin and in the mucosa and internal organs. The dissemination of infected host cells containing is crucial to parasite survival and the establishment of infection. Migratory phenomena and the mechanisms underlying the dissemination of -infected human dendritic cells (hDCs) remain poorly understood. The present study aimed to investigate differences among factors involved in hDC migration by comparing infection with visceral leishmaniasis (VL) induced by with diverse clinical forms of tegumentary leishmaniasis (TL) induced by or . Following the infection of hDCs by isolates obtained from patients with different clinical forms of , the formation of adhesion complexes, actin polymerization, and CCR7 expression were evaluated. We observed increased hDC migration following infection with isolates of (VL), as well as disseminated (DL) and diffuse (DCL) forms of cutaneous leishmaniasis (CL) caused by and , respectively. Increased expression of proteins involved in adhesion complex formation and actin polymerization, as well as higher CCR7 expression, were seen in hDCs infected with , DL and DCL isolates. Together, our results suggest that hDCs play an important role in the dissemination of parasites in the vertebrate host.
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http://dx.doi.org/10.3390/microorganisms9061268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230586PMC
June 2021

Effect of lysed and non-lysed sickle red cells on the activation of NLRP3 inflammasome and LTB4 production by mononuclear cells.

Inflamm Res 2021 Jul 1;70(7):823-834. Epub 2021 Jul 1.

Instituto Gonçalo Moniz, FIOCRUZ Bahia, Fundação Oswaldo Cruz / FIOCRUZ, Rua Waldemar Falcão, n. 121, Candeal, Salvador, Bahia, 40296710, Brazil.

Objective And Design: This study tested the hypothesis that sickle red blood cell (SS-RBC) can induce inflammasome NLRP3 components gene expression in peripheral blood mononuclear cells (PBMCs) as well as interleukin-1β (IL-1β) and leukotriene B4 (LTB4) production. Additionally, we investigated the effect of hydroxyurea (HU) treatment in these inflammatory markers.

Methods: PBMCs from healthy donors (AA-PBMC) were challenged with intact and lysed RBCs from SCA patients (SS-RBC) and from healthy volunteers (AA-RBC). NLRP3, IL-1β, IL-18 and Caspase-1 gene expression levels were assessed by quantitative PCR (qPCR). IL-1β protein levels and LTB4 were measured by ELISA.

Results: We observed that lysed SS-RBC induced the expression of inflammasome NLRP3 components, but this increase was more prominent for CASP1 and IL18 expression levels. Moreover, we observed that intact SS-RBC induced higher production of IL-1β and LTB4 than lysed SS-RBC. Although SCA patients treated with HU have a reduction in NLRP3 gene expression and LTB4 production, this treatment did not modulate the expression of other inflammasome components or IL-1β production.

Conclusions: Thus, our data suggest that caspase-1, IL-1β and IL-18 may contribute to the inflammatory status observed in SCA and that HU treatment may not interfere in this inflammatory pathway.
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http://dx.doi.org/10.1007/s00011-021-01461-2DOI Listing
July 2021

Associations between TGF-1 Levels and Markers of Hemolysis, Inflammation, and Tissue Remodeling in Pediatric Sickle Cell Patients.

Mediators Inflamm 2021 13;2021:4651891. Epub 2021 Mar 13.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, 40.296-710 Salvador, Brazil.

Transforming growth factor beta (TGF-) is a cytokine with important involvement in biological processes related to the pathogenesis of sickle cell disease (SCD), including endothelial and vascular dysfunction, inflammation, and hematopoietic homeostasis. This study is aimed at investigating associations between levels of TGF-1 and classical laboratory biomarkers and inflammatory mediators, as well as the tissue inhibitor of metalloproteases-1 (TIMP-1) and matrix metalloproteinase-9 (MMP-9), in pediatric patients ( = 123) with SCD in steady state: 84 with sickle cell anemia (HbSS) and 39 with hemoglobin SC disease (HbSC). A healthy control (HC) group of 59 individuals was also included. Hematological and biochemical analyses were carried out using electronic methods. TGF-1, TIMP-1, and MMP-9 plasma quantifications were performed by ELISA. TGF-1 plasma levels were higher in HbSS individuals than in HbSC and HC. In individuals with HbSS, TGF-1 levels were positively correlated with red blood cells, hemoglobin, hematocrit, platelets, and TIMP-1. In addition, HbSS individuals with TGF-1 levels above the median (≥72.29 ng/mL) also presented increased monocyte counts and decreased albumin levels. In patients with HbSC, TGF-1 levels were positively correlated with leukocytes, eosinophils, lymphocytes, monocytes, and platelets, as well as levels of TIMP-1, VLDL-C, triglycerides, heme, and AST. Additionally, HbSC individuals with TGF-1 levels above the median (≥47.80 ng/mL) presented increased leukocyte and platelet counts, as well as increased levels of triglycerides, VLDL-C, MMP-9, and TIMP-1, and decreased HDL-C. Our findings suggest that TGF-1 may play important roles in vascular remodeling, vasculopathy, angiogenesis, and inflammation in pediatric patients with SCD.
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http://dx.doi.org/10.1155/2021/4651891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984885PMC
March 2022

Multi-omic Analyses of Plasma Cytokines, Lipidomics, and Transcriptomics Distinguish Treatment Outcomes in Cutaneous Leishmaniasis.

iScience 2020 Dec 23;23(12):101840. Epub 2020 Nov 23.

Faculdade de Medicina da Bahia (FAMED), Universidade Federal da Bahia, Salvador, Brazil.

infection frequently results in cutaneous leishmaniasis (CL). An increase in incidence of drug-resistant CL leading to treatment failure has been reported. Identification of reliable predictors of treatment outcomes is necessary to optimize patient care. Here, we performed a prospective case-control study in which plasma levels of cytokines and lipid mediators were assessed at different time points during antileishmanial therapy in patients with CL from Brazil. Multidimensional analyses were employed to describe a combination of biomarkers able to predict and characterize treatment failure. We found a biosignature influenced mainly by plasma levels of lipid mediators that accurately predicted treatment failure. Furthermore, transcriptomic analysis of a publicly available data set revealed that expression levels of genes related to lipid metabolism measured in skin lesions could distinguish treatment outcomes in CL. Thus, activation of pathways linked to lipid biosynthesis predicts treatment failure in CL. The biomarkers identified may be further explored as therapeutic targets.
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http://dx.doi.org/10.1016/j.isci.2020.101840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721649PMC
December 2020

Evaluation of in vitro and in vivo Efficacy of a Novel Amphotericin B-Loaded Nanostructured Lipid Carrier in the Treatment of Infection.

Int J Nanomedicine 2020 5;15:8659-8672. Epub 2020 Nov 5.

Laboratory of Inflammation and Biomarkers, Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil.

Background: Leishmaniasis is a neglected disease, and the current therapeutic arsenal for its treatment is seriously limited by high cost and toxicity. Nanostructured lipid carriers (NLCs) represent a promising approach due to high drug loading capacity, controlled drug release profiles and superior stability. Here, we explore the efficacy of a unique pH-sensitive amphotericin B-loaded NLC (AmB-NLC) in infection in vitro and in vivo.

Methods And Results: AmB-NLC was assessed by dynamic light scattering and atomic force microscopy assays. The carrier showed a spherical shape with a nanometric size of 242.0 ± 18.3 nm. Zeta potential was suggestive of high carrier stability (-42.5 ± 1.5 mV), and the NLC showed ~99% drug encapsulation efficiency (EE%). In biological assays, AmB-NLC presented a similar IC as free AmB and conventional AmB deoxycholate (AmB-D) (11.7 ± 1.73; 5.3 ± 0.55 and 13 ± 0.57 ng/mL, respectively), while also presenting higher selectivity index and lower toxicity to host cells, with no observed production of nitric oxide or TNF-α by in vitro assay. Confocal microscopy revealed the rapid uptake of AmB-NLC by infected macrophages after 1h, which, in association with more rapid disruption of AmB-NLC at acidic pH levels, may directly affect intracellular parasites. Leishmanicidal effects were evaluated in vivo in BALB/c mice infected in the ear dermis with and treated with a pentavalent antimonial (Sb), liposomal AmB (AmB-L) or AmB-NLC. After 6 weeks of infection, AmB-NLC treatment resulted in smaller ear lesion size in all treated mice, indicating the efficacy of the novel formulation.

Conclusion: Here, we preliminarily demonstrate the effectiveness of an innovative and cost-effective AmB-NLC formulation in promoting the killing of intracellular . This novel carrier system could be a promising alternative for the future treatment of cutaneous leishmaniasis.
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http://dx.doi.org/10.2147/IJN.S262642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652360PMC
December 2020

Heme Oxygenase-1 Induction by Blood-Feeding Arthropods Controls Skin Inflammation and Promotes Disease Tolerance.

Cell Rep 2020 10;33(4):108317

Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA. Electronic address:

Hematophagous vectors lacerate host skin and capillaries to acquire a blood meal, resulting in leakage of red blood cells (RBCs) and inflammation. Here, we show that heme oxygenase-1 (HO-1), a pleiotropic cytoprotective isoenzyme that mitigates heme-mediated tissue damage, is induced after bites of sand flies, mosquitoes, and ticks. Further, we demonstrate that erythrophagocytosis by macrophages, including a skin-residing CD163CD91 professional iron-recycling subpopulation, produces HO-1 after bites. Importantly, we establish that global deletion or transient inhibition of HO-1 in mice increases inflammation and pathology following Leishmania-infected sand fly bites without affecting parasite number, whereas CO, an end product of the HO-1 enzymatic reaction, suppresses skin inflammation. This indicates that HO-1 induction by blood-feeding sand flies promotes tolerance to Leishmania infection. Collectively, our data demonstrate that HO-1 induction through erythrophagocytosis is a universal mechanism that regulates skin inflammation following blood feeding by arthropods, thus promoting early-stage disease tolerance to vector-borne pathogens.
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http://dx.doi.org/10.1016/j.celrep.2020.108317DOI Listing
October 2020

Binding of Leishmania infantum Lipophosphoglycan to the Midgut Is Not Sufficient To Define Vector Competence in Sand Flies.

mSphere 2020 09 9;5(5). Epub 2020 Sep 9.

Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA

The major surface lipophosphoglycan (LPG) of parasites is critical to vector competence in restrictive sand fly vectors in mediating attachment to the midgut epithelium, considered essential to parasite survival and development. However, the relevance of LPG for sand flies that harbor multiple species of remains elusive. We tested binding of wild-type (WT), LPG-defective (Δ mutants), and add-back (Δ+) lines to sand fly midguts and their survival in sand flies WT parasites attached to the midgut , with late-stage parasites binding to midguts in significantly higher numbers than were seen with early-stage promastigotes. Δ mutants did not bind to midguts, and this was rescued in the Δ+ lines, indicating that midgut binding is mediated by LPG. When sand flies were infected with the WT or Δ or Δ+ line of the BH46 or BA262 strains, the BH46 Δ mutant, but not the BA262 Δ mutant, survived and grew to numbers similar to those seen with the WT and Δ+ lines. Exposure of BH46 and BA262 Δ mutants to blood-engorged midgut extracts led to mortality of the BA262 Δ but not the BH46 Δ parasites. These findings suggest that LPG protects parasites on a strain-specific basis early in infection, likely against toxic components of blood digestion, but that it is not necessary to prevent evacuation along with the feces in the permissive vector It is well established that the presence of LPG is sufficient to define the vector competence of restrictive sand fly vectors with respect to parasites. However, the permissiveness of other sand flies with respect to multiple species suggests that other factors might define vector competence for these vectors. In this study, we investigated the underpinnings of survival and development in its natural vector, We found that LPG-mediated midgut binding persists in late-stage parasites. This observation is of relevance for the understanding of vector-parasite molecular interactions and suggests that only a subset of infective metacyclic-stage parasites (metacyclics) lose their ability to attach to the midgut, with implications for parasite transmission dynamics. However, our data also demonstrate that LPG is not a determining factor in retention in the midgut of , a permissive vector. Rather, LPG appears to be more important in protecting some parasite strains from the toxic environment generated during blood meal digestion in the insect gut. Thus, the relevance of LPG in parasite development in permissive vectors appears to be a complex issue and should be investigated on a strain-specific basis.
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http://dx.doi.org/10.1128/mSphere.00594-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485685PMC
September 2020

Immunomodulatory Properties of Extracellular Vesicles During Host-Parasite Interaction: Differential Activation of TLRs and NF-κB Translocation by Dermotropic and Viscerotropic Species.

Front Cell Infect Microbiol 2020 29;10:380. Epub 2020 Jul 29.

Instituto René Rachou, Fundação Oswaldo Cruz - FIOCRUZ, Belo Horizonte, Brazil.

infection causes considerable human morbidity and may develop into a deadly visceral form in endemic regions. The parasite infects macrophages where they can replicate intracellularly. Furthermore, they modulate host immune responses by using virulence factors (lipophosphoglycan, glycoprotein-63, and others) that promote survival inside the cells. Extracellular vesicles (EVs) released by parasites are important for cell-cell communication in the proinflammatory milieu modulating the establishment of infection. However, information on the ability of EVs from different species to modulate inflammatory responses is scarce, especially from those species causing different clinical manifestations (visceral vs. cutaneous). The purpose of this study was to compare macrophage activation using EVs from three species from New World including , and . EVs were released from promastigote forms, purified by ultracentrifugation and quantitated by Nanoparticle Tracking Analysis (NTA) prior to murine macrophage exposure. NTA analysis did not show any differences in the EV sizes among the strains. EVs from and failed to induce a pro-inflammatory response. EVs from both WT and LPG-deficient mutant (LPG-KO) did not show any differences in their interaction with macrophages, suggesting that LPG solely was not determinant for activation. On the other hand, EVs from were immunomodulatory inducing NO, TNF-α, IL-6, and IL-10 via TLR4 and TLR2. To determine whether such activation was related to NF-κB p65 translocation, THP-1 macrophage cells were exposed to EVs. In the same way, only EVs from exhibited a highly percentage of cells positive for NF-κB. Our results suggest an important role of EVs in determining the pattern of immune response depending on the parasite species. For , LPG was not determinant for the activation.
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http://dx.doi.org/10.3389/fcimb.2020.00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403210PMC
June 2021

Differential expression of polyamine biosynthetic pathways in skin lesions and in plasma reveals distinct profiles in diffuse cutaneous leishmaniasis.

Sci Rep 2020 06 29;10(1):10543. Epub 2020 Jun 29.

Universidade Federal da Bahia, Salvador, Brazil.

Tegumentary leishmaniasis (TL) is a parasitic disease that can result in wide spectrum clinical manifestations. It is necessary to understand host and parasite determinants of clinical outcomes to identify novel therapeutic targets. Previous studies have indicated that the polyamine biosynthetic pathway is critical for Leishmania growth and survival. Despite its importance, expression of the such pathway has not been previously investigated in TL patients. We performed an exploratory analysis employing Systems Biology tools to compare circulating polyamines and amino acid concentration as well as polyamine pathway gene expression in cutaneous lesions patients presenting with distinct TL disease presentations. Diffuse cutaneous leishmaniasis (DCL) was associated with higher concentrations of amino acids, polyamines and its substrate transporters than mucosal cutaneous leishmaniasis or localized cutaneous leishmaniasis. In addition, the RNA expression of polyamine-related genes of patients lesions from two separate cohorts demonstrated that differential activation of this pathway is associated with parasite loads and able to discriminate the clinical spectrum of TL. Taken together, our findings highlight a new aspect of DCL immunopathogenesis indicating that the polyamine pathway may be explored as a novel therapeutic target to control disease burden.
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http://dx.doi.org/10.1038/s41598-020-67432-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324605PMC
June 2020

Inflammasome Activation by CD8 T Cells from Patients with Cutaneous Leishmaniasis Caused by Leishmania braziliensis in the Immunopathogenesis of the Disease.

J Invest Dermatol 2021 01 13;141(1):209-213.e2. Epub 2020 Jun 13.

Fiocruz-BA, Instituto Gonçalo Moniz, Salvador, Bahia, Brazil; Faculdade de Medicina da Universidade Federal da Bahia, Salvador, Bahia, Brazil; Instituto Nacional de Ciência e Tecnologia de Instituto de Investigação de Imunologia (Conselho Nacional de Pesquisa/Ministério da Ciência e Tecnologia), São Paulo, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.05.106DOI Listing
January 2021

Heightened Plasma Levels of Transforming Growth Factor Beta (TGF-β) and Increased Degree of Systemic Biochemical Perturbation Characterizes Hepatic Steatosis in Overweight Pediatric Patients: A Cross-Sectional Study.

Nutrients 2020 Jun 2;12(6). Epub 2020 Jun 2.

Escola Bahiana de Medicina e Saúde Pública, Salvador 41150-100, Brazil.

Nonalcoholic Fatty Liver Disease (NAFLD) is a common cause of chronic liver disease in childhood and strongly associated with obesity. Routine biochemical non-invasive tests remain with low accuracy for diagnosis of NAFLD. We performed a cross-sectional study to examine potential associations between anthropometric and biochemical parameters, specially TGF-β, a prognosis marker for hepatic steatosis (HS). Between May and October 2019, seventy-two overweight adolescents were enrolled, of which 36 had hepatic steatosis. Hepatic, lipidic and glycemic profiles, and levels of vitamin D, ferritin and TGF-β were analyzed. Hierarchical cluster and a discriminant model using canonical correlations were employed to depict the overall expression profile of biochemical markers and the biochemical degree of perturbation. Median values of alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), and TGF-β were higher in the adolescents with HS. Values of body mass index (BMI)/age and ALT, but not of TGF-β, were gradually increased proportionally to augmentation of steatosis severity. In a multivariate analysis, TGF-β plasma concentrations were associated with occurrence of hepatic steatosis independent of other covariates. Discriminant analysis confirmed that TGF-β concentrations can identify HS cases. Our data reveal that HS patients exhibit a distinct biosignature of biochemical parameters and imply TGF-β as an important biomarker to evaluate risk of steatosis development.
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http://dx.doi.org/10.3390/nu12061650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352859PMC
June 2020

Hydroxyurea alters circulating monocyte subsets and dampens its inflammatory potential in sickle cell anemia patients.

Sci Rep 2019 10 15;9(1):14829. Epub 2019 Oct 15.

Laboratório de Investigação em Genética e Hematologia Translacional, Instituto Gonçalo Moniz, FIOCRUZ-BA, Salvador, Bahia, Brazil.

Sickle cell anemia (SCA) is a hemolytic disease in which vaso-occlusion is an important pathophysiological mechanism. The treatment is based on hydroxyurea (HU), which decreases leukocyte counts and increases fetal hemoglobin synthesis. Different cell types are thought to contribute to vaso-occlusion. Nevertheless, the role of monocytes subsets remains unclear. We investigated frequencies of monocytes subsets in blood and their response to HU therapy, testing their ability to express pro-inflammatory molecules and tissue factor (TF). We identified major changes in monocyte subsets, with classical monocytes (CD14CD16) appearing highly frequent in who were not taking HU, whereas those with patrolling phenotype (CD14CD16) were enriched in individuals undergoing therapy. Additionally, HU decreased the production of TNF-α, IL1-β, IL-6, IL-8 as well as TF by the LPS-activated monocytes. Likewise, frequency of TF-expressing monocytes is increased in patients with previous vaso-occlusion. Moreover, activated monocytes expressing TF produced several pro-inflammatory cytokines simultaneously. Such polyfunctional capacity was dramatically dampened by HU therapy. The frequency of classical monocytes subset was positively correlated with percentage cytokine producing cells upon LPS stimulation. These findings suggest that classical monocytes are the subset responsible for multiple pro-inflammatory cytokine production and possibly drive inflammation and vaso-occlusion in SCA which is damped by HU.
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http://dx.doi.org/10.1038/s41598-019-51339-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794261PMC
October 2019

Saliva Induces Heme Oxygenase-1 Expression at Bite Sites.

Front Immunol 2018 28;9:2779. Epub 2018 Nov 28.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.

Sand flies bite mammalian hosts to obtain a blood meal, driving changes in the host inflammatory response that support the establishment of infection. This effect is partially attributed to components of sand fly saliva, which are able to recruit and activate leukocytes. Our group has shown that heme oxygenase-1 (HO-1) favors survival in infected cells by reducing inflammatory responses. Here, we show that exposure to sand fly bites is associated with induction of HO-1 . Histopathological analyses of skin specimens from human volunteers experimentally exposed to sand fly bites revealed that HO-1 and Nrf2 are produced at bite sites in the skin. These results were recapitulated in mice ears injected with a salivary gland sonicate (SGS) or exposed to sand fly bites, indicating that vector saliva may be a key factor in triggering HO-1 expression. Resident skin macrophages were the main source HO-1 at 24-48 h after bites. Additionally, assays after bites and after stimulation with saliva both demonstrated that HO-1 production by macrophages was Nrf2-dependent. Collectively, our data demonstrates that vector saliva induces early HO-1 production at the bite sites, representing a major event associated with establishment of naturally-transmitted infections.
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http://dx.doi.org/10.3389/fimmu.2018.02779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279893PMC
October 2019

Chemical characterization and biological activity of six different extracts of propolis through conventional methods and supercritical extraction.

PLoS One 2018 4;13(12):e0207676. Epub 2018 Dec 4.

Federal University of Bahia, Salvador, Bahia, Brazil.

Propolis is a natural product with many demonstrated biological activities and propolis extract has been used in the food, pharmaceutical and cosmetics industries. Different works have showed the variations in the chemical composition, and consequently, on the biological activity of the propolis that are associated with its type and geographic origin. Due to this study evaluated propolis extracts obtained through supercritical extraction and ethanolic extraction (conventional) in three samples of different types of propolis (red, green and brown), collected from different regions in Brazil (state of Bahia). Analyses were performed to determine the humidity, water activity, the content of total ash, proteins, lipids and fiber in raw propolis samples. The content of phenolic compounds, flavonoids, in vitro antioxidant activity (DPPH), catechin, ferulic acid and luteolin and antimicrobial activity against two bacteria (Staphylococcus aureus and Escherichia coli) were determined for all extracts. For the green and red ethanolic extracts the anti-leishmanicidal potential was also evaluated. The physicochemical profiles showed agreement in relation to the literature. The results identified significant differences among the extracts (p>0.05), which are in conformity with their extraction method, as well as with type and botanical origin of the samples. The extraction with supercritical fluid was not efficient to obtain extracts with the highest contents of antioxidants compounds, when compared with the ethanolic extracts. The best results were shown for the extracts obtained through the conventional extraction method (ethanolic) indicating a higher selectivity for the extraction of antioxidants compounds. The red variety showed the largest biological potential, which included the content of antioxidants compounds. The results found in this study confirm the influence of the type of the raw material on the composition and characteristics of the extracts. The parameters analysis were important to characterize and evaluate the quality of the different Brazilian propolis extracts based on the increased use of propolis by the natural products industry.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207676PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279037PMC
May 2019

Subverts Necroptosis by Modulating RIPK3 Expression.

Front Microbiol 2018 28;9:2283. Epub 2018 Sep 28.

Instituto Gonçalo Moniz, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.

infection causes skin ulcers, typically found in localized cutaneous leishmaniasis (LCL). This tissue pathology associates with different modalities of cell necrosis, which are subverted by the parasite as a survival strategy. Herein we examined the participation of necroptosis, a specific form of programmed necrosis, in LCL lesions and found reduced RIPK3 and PGAM5 gene expression compared to normal skin. Assays using infected macrophages demonstrated that the parasite deactivates both RIPK3 and MLKL expression and that these molecules are important to control the intracellular replication. Thus, LCL-related necroptosis may be targeted to control infection and disease immunopathology.
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http://dx.doi.org/10.3389/fmicb.2018.02283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172319PMC
September 2018

RIPK1-RIPK3-MLKL-Associated Necroptosis Drives Killing in Neutrophils.

Front Immunol 2018 14;9:1818. Epub 2018 Aug 14.

Laboratório de Inflamação e Biomarcadores, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.

Necroptosis is a pro-inflammatory cell death, which happens in the context of caspase-8 inhibition, allowing activation of the receptor interacting protein kinase 1-receptor interacting protein kinase 3-mixed lineage kinase domain-like (RIPK1-RIPK3-MLKL) axis. Recently, necroptosis has emerged as a key component of resistance against pathogens including infected macrophage by , the ethiologic agent of Visceral leishmaniasis (VL). VL is the most severe form of Leishmaniasis, characterized by systemic inflammation and neutropenia. However, the role of neutrophil cell death in VL has not been characterized. Here, we showed that VL patients exhibited increased lactate dehydrogenase levels in the serum, a hallmark of cell death and tissue damage. We investigated the effect of necroptosis in neutrophil infection . Human neutrophils pretreated with zVAD-fmk (pan-caspase inhibitor) and zIETD-fmk (caspase-8 inhibitor) increased reactive oxygen species (ROS) level in response to infection, which is associated with necroptotic cell death. MLKL, an important effector molecule downstream of necroptosis pathway, was also required for killing. Moreover, in absence of caspases-8, murine neutrophils displayed loss of membrane integrity, higher levels of ROS, and decreased viability. Pharmacological inhibition of RIPK1 or RIPK3 increased parasite survival when caspase-8 was blocked. Electron microscopy assays revealed morphological features associated with necroptotic death in infected-neutrophils pretreated with caspase inhibitor, whereas infected cells pretreated with RIPK1 and RIPK3 inhibitors did not show ultra-structural alterations in membrane integrity and presented viable within parasitophorous vacuoles. Taken together, these findings suggest that inhibition of caspase-8 contributes to elimination of in neutrophils by triggering necroptosis. Thus, targeting necroptosis may represent a new strategy to control replication.
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http://dx.doi.org/10.3389/fimmu.2018.01818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102393PMC
September 2019

Tamoxifen and meglumine antimoniate combined therapy in cutaneous leishmaniasis patients: a randomised trial.

Trop Med Int Health 2018 09 11;23(9):936-942. Epub 2018 Jul 11.

Departamento de Parasitologia, Universidade de São Paulo, São Paulo, Brazil.

Objectives: There is a clear need for new strategies of leishmaniasis treatment. This work was conducted to evaluate the efficacy of the co-administration of tamoxifen and meglumine antimoniate (Sb ) in a phase II pilot clinical trial in localised cutaneous leishmaniasis patients.

Methods: A randomised controlled pilot clinical trial was conducted to evaluate the efficacy and safety of oral (40 mg/day for 20 days) or topical tamoxifen (0.1% tamoxifen citrate for 20 days) combined with meglumine antimoniate (20 mg Sb /kg/day for 20 days) vs. a standard Sb protocol (20 mg/kg/day for 20 days) for the treatment of cutaneous leishmaniasis. Primary outcome was complete epithelisation of the lesion 6 months after the end of treatment. Secondary outcomes were lesion healing 2 months after the end of treatment and frequency and severity of adverse events.

Results: A total of 38 subjects were included in the trial, 15 were treated with standard Sb and 23 with the combination of tamoxifen and Sb . Of the patients treated with the co-administration scheme, 12 received tamoxifen orally and 11 were treated with topical tamoxifen. Tamoxifen administered by the oral or topical routes was well tolerated. Cure rates 6 months after the end of treatment per intention to treat were 40% in the group treated with the standard Sb scheme, and 36.4% and 58%, respectively, for groups treated with Sb plus topical or oral tamoxifen.

Conclusions: In the doses and schemes used in this study, co-administration of oral tamoxifen and Sb resulted in higher cure rates in comparison with the standard scheme of treatment, although not to statistically significant levels.
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http://dx.doi.org/10.1111/tmi.13119DOI Listing
September 2018

Saliva Drives Interleukin-17-Induced Neutrophil Recruitment Favoring Infection.

Front Microbiol 2018 8;9:881. Epub 2018 May 8.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.

During bloodfeeding, the presence of sand fly saliva in the hemorrhagic pool where is also inoculated modulates the development of host immune mechanisms creating a favorable environment for disease progression. To date, information obtained through experimental models suggests that sand fly saliva induces cellular recruitment and modulates production of eicosanoids. However, the effect of sand fly saliva in the different steps of the inflammatory response triggered by remains undefined. Here we further investigate if interaction of salivary gland sonicate (SGS) with different host cells present during the initial inflammatory events regulate infectivity. Initially, we observed that incubation of human peripheral blood mononuclear cells (PBMC) with SGS in the presence of significantly increased IL-10 but did not alter expression of IFN-γ and TNF-α by CD4 T cells induced by the parasite alone. Interestingly, incubation of PBMC with SGS alone or in the presence of resulted in increased IL-17 production. The presence of IL-17 is related to neutrophil recruitment and plays an important role at the site of infection. Here, we also observed increased migration of neutrophil using an chemotactic assay following incubation with supernatants from PBMC stimulated with and SGS. Neutrophil migration was abrogated following neutralization of IL-17 with specific antibodies. Moreover, culture of human neutrophils with in the presence of SGS promoted neutrophil apoptosis resulting in increased parasite viability. Neutrophils operate as the first line of defense in the early stages of infection and later interact with different cells, such as macrophages. The crosstalk between neutrophils and macrophages is critical to determine the type of specific immune response that will develop. Here, we observed that co-culture of human macrophages with autologous neutrophils previously infected in the presence of SGS resulted in a higher infection rate, accompanied by increased production of TGF-β and PGE. Our results provide new insight into the contribution of SGS to -induced regulation of important inflammatory events, creating a favorable environment for parasite survival inside different host cells.
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http://dx.doi.org/10.3389/fmicb.2018.00881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953329PMC
May 2018

Lipophosphoglycan-Deficient Mutants: A Tool to Study Host Cell-Parasite Interplay.

Front Microbiol 2018 5;9:626. Epub 2018 Apr 5.

Laboratory of Inflammation and Biomarkers, Gonçalo Moniz Institut, Oswaldo Cruz Foundation, Salvador, Brazil.

Lipophosphoglycan (LPG) is the major surface glycoconjugate of metacyclic promastigotes and is associated with virulence in various species of this parasite. Here, we generated a LPG-deficient mutant of , the foremost etiologic agent of visceral leishmaniasis in Brazil. The LPG-deficient mutant (Δ) was obtained by homologous recombination and complemented via episomal expression of (Δ + ). Deletion of had no observable effect on parasite morphology or on the presence of subcellular organelles, such as lipid droplets. While both wild-type and add-back parasites reached late phase in axenic cultures, the growth of Δ parasites was delayed. Additionally, the deletion of impaired the outcome of infection in murine bone marrow-derived macrophages. Although no significant differences were observed in parasite load after 4 h of infection, survival of Δ parasites was significantly reduced at 72 h post-infection. Interestingly, . LPG-deficient mutants induced a strong NF-κB-dependent activation of the inducible nitric oxide synthase (iNOS) promoter compared to wild type and Δ + parasites. In conclusion, the Δ mutant constitutes a powerful tool to investigate the role(s) played by LPG in host cell-parasite interactions.
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http://dx.doi.org/10.3389/fmicb.2018.00626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896263PMC
April 2018

Increased thiol levels in antimony-resistant Leishmania infantum isolated from treatment-refractory visceral leishmaniasis in Brazil.

Mem Inst Oswaldo Cruz 2018 Feb;113(2):119-125

Laboratório de Biologia Molecular, Hospital Universitário, Universidade Federal de Sergipe, Aracaju, SE, Brasil.

BACKGROUND Treatment-refractory visceral leishmaniasis (VL) has become an important problem in many countries. OBJECTIVES We evaluated the antimony-resistance mechanisms of Leishmania infantum isolated from VL patients refractory or responsive to treatment with pentavalent antimony. METHODS Strains isolated from antimony-refractory patients (in vitro antimony-resistant isolates) and antimony-responsive patients (in vitro antimony-sensitive isolates) were examined. Morphological changes were evaluated by transmission electron microscopy after trivalent antimony exposure. P-glycoprotein (P-gp) efflux pump activity was evaluated using the pump-specific inhibitor verapamil hydrochloride, and the role of thiol in trivalent antimony resistance was investigated using the enzymatic inhibitor L-buthionine sulfoximine. FINDINGS Antimony treatment induced fewer alterations in the cellular structure of L. infantum resistant isolates than in that of sensitive isolates. P-gp efflux activity was not involved in antimony resistance in these isolates. Importantly, the resistant isolates contained higher levels of thiol compared to the sensitive isolates, and inhibition of thiol synthesis in the resistant isolates recovered their sensitivity to trivalent antimony treatment, and enhanced the production of reactive oxygen species in promastigotes exposed to the drug. MAIN CONCLUSIONS Our results demonstrate that isolates from patients with antimony-refractory VL exhibited higher thiol levels than antimony-sensitive isolates. This indicates that redox metabolism plays an important role in the antimony-resistance of New World VL isolates.
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http://dx.doi.org/10.1590/0074-02760170289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722267PMC
February 2018

Heme Drives Oxidative Stress-Associated Cell Death in Human Neutrophils Infected with .

Front Immunol 2017 23;8:1620. Epub 2017 Nov 23.

Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.

Free heme is an inflammatory molecule capable of inducing migration and activation of neutrophils. Here, we examine the heme-driven oxidative stress-associated cell death mechanisms in human neutrophils infected with , an etiologic agent of visceral leishmaniasis (VL). We first performed exploratory analyses in a population of well characterized treatment-naïve VL patients as well as uninfected controls, who were part of previously reported studies. We noted a positive correlation between serum concentrations of heme with heme oxygenase-1 (HO-1) and lactate deydrogenase, as well as, a negative correlation between heme values and peripheral blood neutrophils counts. Moreover, infection with . in the presence of heme enhanced parasite burden in neutrophils, while increasing the production of reactive oxygen species and release of neutrophilic enzymes. Additional experiments demonstrated that treatment of infected neutrophils with ferrous iron (Fe), a key component of the heme molecule, resulted in increased parasite survival without affecting neutrophil activation status. Furthermore, stimulation of infected neutrophils with heme triggered substantial increases in HO-1 mRNA expression as well as in superoxide dismutase-1 enzymatic activity. Heme, but not Fe, induced oxidative stress-associated cell death. These findings indicate that heme promotes intracellular . survival via activation of neutrophil function and oxidative stress. This study opens new perspectives for the understanding of immunopathogenic mechanisms involving neutrophils in VL.
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http://dx.doi.org/10.3389/fimmu.2017.01620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703736PMC
November 2017

Induces the Release of sTREM-1 in Visceral Leishmaniasis.

Front Microbiol 2017 16;8:2265. Epub 2017 Nov 16.

Laboratório de Biologia Molecular-Hospital Universitário, Universidade Federal de Sergipe-Aracaju, Sergipe, Brazil.

Visceral leishmaniasis (VL) is a systemic transmissible disease that remains to be a major global health problem. The inflammatory response during VL is characterized by the release of several cytokines and other pro-inflammatory mediators. Triggering Receptor Expressed on Myeloid Cells (TREM) are a group of evolutionarily conserved membrane-bound surface receptors expressed on neutrophils and monocytes. Engagement of TREM-1 directs intracellular signaling events that drive cytokine production, degranulation, and phagocytosis. In certain inflammatory-associated diseases, TREM-1 can also be found as a soluble form (sTREM-1), which can negatively regulate TREM-1 receptor signaling. In these studies, we now find that high levels of circulating sTREM-1 correlate directly with VL disease severity. In particular, high levels of sTREM-1 were observed in non-survivor VL patients. Furthermore, these levels of sTREM-1 positively correlated with liver size and negatively correlated with leukocyte counts and hemoglobin concentration. Moreover, we found that neutrophils exposure to modulates TREM-1, DAP12, and IL-8 gene expression, while also increasing release of sTREM-1. Finally, results revealed that higher sTREM-1 levels are associated with increasing parasite ratio. Taken together, these studies suggest that may modulate TREM-1 in neutrophils and high levels of this molecule is associated with severe VL.
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http://dx.doi.org/10.3389/fmicb.2017.02265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696592PMC
November 2017

Parasite Killing of by Standardized Propolis Extracts.

Evid Based Complement Alternat Med 2017 13;2017:6067172. Epub 2017 Jun 13.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil.

Treatments based on antimonials to cutaneous leishmaniasis (CL) entail a range of toxic side effects. Propolis, a natural compound widely used in traditional medical applications, exhibits a range of biological effects, including activity against infectious agents. The aim of this study was to test the potential leishmanicidal effects of different propolis extracts against promastigotes and intracellular amastigotes in vitro. Stationary-phase promastigotes were incubated with medium alone or treated with dry, alcoholic, or glycolic propolis extract (10, 50, or 100 g/mL) for 96 h. Our data showed that all extracts exhibited a dose-dependent effect on the viability of promastigotes, while controlling the parasite burden inside infected macrophages. Dry propolis extract significantly modified the inflammatory profile of murine macrophages by downmodulating TGF- and IL-10 production, while upmodulating TNF-. All three types of propolis extract were found to reduce nitric oxide and superoxide levels in activated . -infected macrophages. Altogether, our results showed that propolis extracts exhibited a leishmanicidal effect against both stages of . The low cell toxicity and efficient microbicidal effect of alcoholic or glycolic propolis extracts make them candidates to an additive treatment for cutaneous leishmaniasis.
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http://dx.doi.org/10.1155/2017/6067172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485350PMC
June 2017

Anti-parasite therapy drives changes in human visceral leishmaniasis-associated inflammatory balance.

Sci Rep 2017 06 28;7(1):4334. Epub 2017 Jun 28.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, 40296-710, Salvador, Brazil.

Visceral leishmaniasis (VL) remains a major public health problem worldwide. Cytokine balance is thought to play a critical role in the development of this disease. Here, we perform a prospective exploratory study addressing whether simultaneous assessment of circulating levels of different lipid mediators and cytokines could highlight specific pathways involved with VL pathogenesis. VL patients displayed substantial increases in serum levels of Prostaglandin Fα (PGFα), Leukotriene B (LTB), Resolvin D1 (RvD1), IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α compared with uninfected endemic control group, while exhibiting decreased levels of TGF-β1. Hierarchical cluster analysis of the prospective changes in the expression level of theses parameters upon anti-Leishmania treatment initiation revealed that the inflammatory profile observed in active disease gradually changed over time and was generally reversed at day 30 of therapy. Furthermore, not only the individual concentrations of most of the inflammatory biomarkers changed upon treatment, but the correlations between those and several biochemical parameters used to characterize VL disease activity were also modified over time. These results demonstrate that an inflammatory imbalance hallmarks active VL disease and open perspective for manipulation of these pathways in future studies examining a potential host-directed therapy against VL.
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http://dx.doi.org/10.1038/s41598-017-04595-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489532PMC
June 2017

Molecular signatures of neutrophil extracellular traps in human visceral leishmaniasis.

Parasit Vectors 2017 Jun 6;10(1):285. Epub 2017 Jun 6.

Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

Background: Infections with parasites of the Leishmania donovani complex result in clinical outcomes that range from asymptomatic infection to severe and fatal visceral leishmaniasis (VL). Neutrophils are major players of the immune response against Leishmania, but their contribution to distinct states of infection is unknown. Gene expression data suggest the activation of the NETosis pathway during human visceral leishmaniasis. Thus, we conducted an exploratory study to evaluate NET-related molecules in retrospective sera from VL patients, asymptomatic individuals and uninfected endemic controls.

Results: We demonstrate that VL patients and asymptomatic individuals exhibit differential regulation of molecules associated with neutrophil extracellular traps (NET). These differences were observed at the transcriptional level of genes encoding NET-associated proteins; in quantifications of cell free DNA and metalloproteinase 9; and in enzymatic activity of DNAse and elastase. Moreover, multivariate analysis resulted in class-specific signatures, and ROC curves demonstrate the ability of these molecules in discriminating asymptomatic infection from uninfected controls.

Conclusion: Molecules that are associated with NETs are differentially regulated between distinct states of infection with L. infantum, suggesting that NETs might have distinct roles depending on the clinical status of infection. Although unlikely to be exclusive for VL, these signatures can be useful to better characterize asymptomatic infections in endemic regions of this disease.
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http://dx.doi.org/10.1186/s13071-017-2222-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460406PMC
June 2017

Resolvin D1 drives establishment of Leishmania amazonensis infection.

Sci Rep 2017 04 10;7:46363. Epub 2017 Apr 10.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.

Previous studies have indicated that the balance between different eicosanoids reflect the intensity of the inflammatory profile in patients with tegumentary leishmaniasis. More recently, pro-resolution lipid mediators have been shown to play critical roles in dampening pathological inflammatory processes to reestablish homeostasis in a diverse range of experimental settings. Among these lipid mediator, resolvins from D series have been described as potent anti-inflammatory and immunomodulatory mediators, and its activities include inhibition of leukocyte chemotaxis and blockage production of proinflammatory cytokines, while increasing the expression of regulatory mediators. Whether resolvins play significant roles in establishment and persistence of Leishmania infection is currently unknown. We addressed this question in the current study by assessing circulating levels of D-series resolvins in tegumentary leishmaniasis patients presenting with localized or diffuse disease. We found heightened expression of resolvin D1 in diffuse cutaneous leishmaniasis which was correlated with expression profile of biomarkers associated with disease pathogenesis. Additional in vitro experiments using primary human macrophages indicated that resolvin D1 may promote intracellular Leishmania amazonensis replication through a mechanism associated with induction of heme oxygenase-1. These results suggest that targeting resolvin D1 could serve as potential strategy for host directed therapy in diffuse cutaneous leishmaniasis.
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http://dx.doi.org/10.1038/srep46363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385529PMC
April 2017

sCD163 levels as a biomarker of disease severity in leprosy and visceral leishmaniasis.

PLoS Negl Trop Dis 2017 03 29;11(3):e0005486. Epub 2017 Mar 29.

Laboratório de Biologia Molecular-Hospital Universitário-Universidade Federal de Sergipe-Aracaju-Brazil.

Background: CD163, receptor for the haptoglobin-hemoglobin complex, is expressed on monocytes/macrophages and neutrophils. A soluble form of CD163 (sCD163) has been associated with the M2 macrophage phenotype, and M2 macrophages have been shown to down-modulate inflammatory responses. In particular, previous studies have shown that M2 is closely associated with the most severe clinical presentation of leprosy (i.e. lepromatous leprosy (LL)), as well as tuberculosis. We hypothesized that sCD163 correlates with severity of diseases caused by intracellular pathogens.

Methodology/principal Findings: To assess this hypothesis, sCD163 levels were measured in the serum of leprosy and visceral leishmaniasis (VL) patients stratified by severity of the clinical presentation. sCD163 levels were significantly higher in patients with these diseases than those observed in healthy control individuals. Further analyses on infection and disease status of leprosy and VL patients revealed a clear association of sCD163 levels with clinical parameters of disease severity. In vitro culture assays revealed that Leishmania infection induced CD163 expression on the surface of both monocyte/macrophages and neutrophils, suggesting these cells as possible sources of sCD163. FACS analyses shows that the cells expressing CD163 produces both TNF-α and IL-4.

Conclusions/significance: Taken together, our results reveal sCD163 as a potential biomarker of severity of diseases caused by intracellular pathogens M. leprae and Leishmania spp. and have a modulatory role, with a mix of an inflammatory property induced by TNF-α release, but that potentially induces an anti-inflammatory T cell response, related to IL-4 release.
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http://dx.doi.org/10.1371/journal.pntd.0005486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386291PMC
March 2017
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