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Edgar M Carvalho - One of the best experts on this subject based on the ideXlab platform.
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Leishmania braziliensis infection enhances toll like receptors 2 and 4 expression and triggers tnf α and il 10 production in human cutaneous Leishmaniasis
Frontiers in Cellular and Infection Microbiology, 2019Co-Authors: Edgar M Carvalho, Phillip Scott, Paulo Machado, Olivia Bacellar, Ludmila Polari, Pedro Paulo Carneiro, Michael MacedoAbstract:Cutaneous Leishmaniasis (CL) caused by infection with Leishmania braziliensis is characterized by an exaggerated inflammatory response that controls the parasite burden, but also contributes to pathology. While myeloid cells are required to eliminate the parasite, recent studies indicate that they may also participate in the inflammatory response driving disease progression. The innate immune response to Leishmania is driven in part by the Toll-like receptors (TLRs) TLR2, TLR4, and TLR9. In this study, we used flow cytometric analysis to compare TLR2 and TLR4 expression in monocyte subsets (classical, intermediate, and non-classical) from CL patients and healthy subjects (HS). We also determined if there was an association of either the pro-inflammatory cytokine TNF or the anti-inflammatory cytokine IL-10 with TLR2 or TLR4 expression levels after L. braziliensis infection. In vitro infection with L. braziliensis caused CL monocytes to up-regulate TLR2 and TLR4 expression. We also found that intermediate monocytes expressed the highest levels of TLR2 and TLR4 and that infected monocytes produced more TNF and IL-10 than uninfected monocytes. Finally, while classical and intermediate monocytes were mainly responsible for TNF production, classical monocytes were the main source of IL-10. Collectively, our studies revealed that up-regulated TLR2/4 expression and TNF production by intermediate/inflammatory subsets of monocytes from patients correlates with detrimental outcome of cutaneous Leishmaniasis.
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a th2 type response is associated with exuberant lesions in pregnant women infected with Leishmania braziliensis
The Journal of Infectious Diseases, 2019Co-Authors: Luiz Henrique Guimaraes, Edgar M Carvalho, Daniel J. Morgan, Walderez O Dutra, Daniela Faria Barbosa, Shelene Poetker, Olivia Bacelar, Kenneth J Gollob, Paulo Eduardo Alencar SouzaAbstract:Background Cutaneous Leishmaniasis (CL) is characterized by an exaggerated inflammatory response. During pregnancy there is a decreased inflammatory response, and we have shown that pregnant women with CL develop exuberant lesions. Methods Cytokine production by peripheral blood mononuclear cells and the frequency of cells expressing cytokines in lesions from pregnant and nonpregnant women with CL were evaluated. Results We observed that CL lesions from pregnant women displayed a more intense cellular infiltrate, associated with an increase in neutrophils and CD4+ cells. While no difference was observed regarding the number of interferon-gamma (IFN-γ)+ cells in lesions from pregnant compared to nonpregnant women with CL, interleukin-10 (IL-10) and IL-4 expression were approximately 3-times higher in lesions in pregnant women. Main sources of IL-4 and IL-10 were CD4+ and CD68+ cells, respectively. Expression of IL-4, but not IFN-γ or IL-10, was positively correlated with the intensity of inflammatory infiltrate in lesions from pregnant women. Conclusions These results provide evidence of an IL-4-mediated pathology in Leishmania braziliensis-infected pregnant women. These differences in lesion pathogenesis in pregnant and nonpregnant women may open possibilities for new therapies for CL treatment during pregnancy, which are currently lacking.
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early suppression of macrophage gene expression by Leishmania braziliensis
Frontiers in Microbiology, 2018Co-Authors: Rosana S Sousa, Paulo R L Machado, Luiz Henrique Guimaraes, Edgar M Carvalho, Viviane M Andrade, Thomas B Bair, Nicholas Ettinger, Luana Guimaraes, Laura AndradeAbstract:Leishmania braziliensis is an intracellular parasite that resides mostly in macrophages. Both the parasite genome and the clinical disease manifestations show considerable polymorphism. Clinical syndromes caused by L. braziliensis include localized cutaneous (CL), mucosal (ML) and disseminated Leishmaniasis (DL). Our prior studies showed that genetically distinct L. braziliensis clades associate with different clinical types. Herein we hypothesized that: (1) L. braziliensis induces changes in macrophage gene expression that facilitates infection; (2) infection of macrophages with strains associated with CL (clade B), ML (clade C) or DL (clade A) will differentially affect host cell gene expression, reflecting their different pathogenic mechanisms; and (3) differences between the strains will be reflected by differences in macrophage gene expression after initial exposure to the parasite. Human monocyte derived macrophages (MDMs) were infected with L. braziliensis isolates from clades A, B, or C. Patterns of gene expression were compared using Affymetrix DNA microarrays. Many transcripts were significantly decreased by infection with all isolates. The most dramatically decreased transcripts encoded proteins involved in signaling pathways, apoptosis or mitochondrial oxidative phosphorylation. Some transcripts encoding stress response proteins were up-regulated. Differences between L. braziliensis clades were observed in the magnitude of change, rather than the identity of transcripts. Isolates from subjects with metastatic disease (ML, DL) induced a greater magnitude of change than isolates from CL. We conclude that L. braziliensis enhances its intracellular survival by inhibiting macrophage pathways leading to microbicidal activity. Parasite strains destined for dissemination may exert a more profound suppression than less invasive L. braziliensis strains that remain near the cutaneous site of inoculation.
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analysis of expression of fli1 and mmp1 in american cutaneous Leishmaniasis caused by Leishmania braziliensis infection
Infection Genetics and Evolution, 2017Co-Authors: Lucas Almeida, Paulo R L Machado, Juliana A Silva, Viviane M Andrade, Sarra E Jamieson, Jenefer M Blackwell, Lea Cristina Castellucci, Edgar M CarvalhoAbstract:FLI1 (Friend leukemia virus integration 1) and IL6 (interleukin 6; IL-6) are associated with Leishmania braziliensis susceptibility. Cutaneous lesions show exaggerated matrix metalloproteinase 1 (MMP1). In other skin diseases, FLI1 promoter methylation reduces FLI1 expression, and low FLI1 down-regulates MMP1. IL-6 increases FLI1 expression. We hypothesized that epigenetic regulation of FLI1 in cutaneous Leishmaniasis, together with IL-6, might determine MMP1 expression. While generally low (<10%), percent FLI1 promoter methylation was lower (P=0.001) in lesion biopsies than normal skin. Contrary to expectation, a strong positive correlation occurred between FLI1 methylation and gene expression in lesions (r=0.98, P=0.0005) and in IL-6-treated L. braziliensis-infected macrophages (r=0.99, P=0.0004). In silico analysis of the FLI1 promoter revealed co-occurring active H3K27ac and repressive DNA methylation marks to enhance gene expression. FLI1 expression was enhanced between 3 and 24hour post infection in untreated (P=0.0002) and IL-6-treated (P=0.028) macrophages. MMP1 was enhanced in lesion biopsies (P=0.0002), induced (P=0.007) in infected macrophages, but strongly inhibited by IL-6. No correlations occurred between FLI1 and MMP1 expression in lesions or infected macrophages (with/without IL-6). We conclude that MMP1 is regulated by factors other than FLI1, and that the influence of IL-6 on MMP1 was independent of its effect on FLI1.
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meta transcriptome profiling of the human Leishmania braziliensis cutaneous lesion
PLOS Neglected Tropical Diseases, 2016Co-Authors: Stephen M Christensen, Edgar M Carvalho, Sara Passos, Lucas P Carvalho, Fernanda O Novais, Daniel P Beiting, Phillip Scott, Laura A L Dillon, Keith V Hughitt, Najib M ElsayedAbstract:Host and parasite gene expression in skin biopsies from Leishmania braziliensis-infected patients were simultaneously analyzed using high throughput RNA-sequencing. Biopsies were taken from 8 patients with early cutaneous Leishmaniasis and 17 patients with late cutaneous Leishmaniasis. Although parasite DNA was found in all patient lesions at the time of biopsy, the patients could be stratified into two groups: one lacking detectable parasite transcripts (PTNeg) in lesions, and another in which parasite transcripts were readily detected (PTPos). These groups exhibited substantial differences in host responses to infection. PTPos biopsies contained an unexpected increase in B lymphocyte-specific and immunoglobulin transcripts in the lesions, and an upregulation of immune inhibitory molecules. Biopsies without detectable parasite transcripts showed decreased evidence for B cell activation, but increased expression of antimicrobial genes and genes encoding skin barrier functions. The composition and abundance of L. braziliensis transcripts in PTPos lesions were surprisingly conserved among all six patients, with minimal meaningful differences between lesions from patients with early and late cutaneous Leishmaniasis. The most abundant parasite transcripts expressed in lesions were distinct from transcripts expressed in vitro in human macrophage cultures infected with L. amazonensis or L. major. Therefore in vitro gene expression in macrophage monolayers may not be a strong predictor of gene expression in lesions. Some of the most highly expressed in vivo transcripts encoded amastin-like proteins, hypothetical genes, putative parasite virulence factors, as well as histones and tubulin. In summary, RNA sequencing allowed us to simultaneously analyze human and L. braziliensis transcriptomes in lesions of infected patients, and identify unexpected differences in host immune responses which correlated with active transcription of parasite genes.
Claudia Brodskyn - One of the best experts on this subject based on the ideXlab platform.
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immunization with ljm11 salivary protein protects against infection with Leishmania braziliensis in the presence of lutzomyia longipalpis saliva
Acta Tropica, 2018Co-Authors: Jurema Cunha, Melissa Abbehusen, Martha Suarez, Clarissa Teixeira, Claudia Brodskyn, Jesus G ValenzuelaAbstract:Abstract Leishmania is transmitted in the presence of sand fly saliva. Protective immunity generated by saliva has encouraged identification of a vector salivary-based vaccine. Previous studies have shown that immunization with LJM11, a salivary protein from Lutzomyia longipalpis, is able to induce a Th1 immune response and protect mice against bites of Leishmania major -infected Lutzomyia longipalpis . Here, we further investigate if immunization with LJM11 recombinant protein is able to confer cross-protection against infection with Leishmania braziliensis associated with salivary gland sonicate (SGS) from Lutzomyia intermedia or Lu. longipalpis . Mice immunized with LJM11 protein exhibited an increased production of anti-LJM11 IgG, IgG1 and IgG2a and a DTH response characterized by an inflammatory infiltrate with the presence of CD4 + IFN-γ + T cells. LJM11-immunized mice were intradermally infected in the ear with L. braziliensis in the presence of Lu. longipalpis or Lu. intermedia SGS. A significant reduction of parasite numbers in the ear and lymph node in the group challenged with L. braziliensis plus Lu. longipalpis SGS was observed, but not when the challenge was performed with L. braziliensis plus Lu. intermedia SGS. A higher specific production of IFN-γ and absence of IL-10 by lymph node cells were only observed in LJM11 immunized mice after infection. After two weeks, a similar frequency of CD4 + IFN-γ + T cells was detected in LJM11 and BSA groups challenged with L. braziliensis plus Lu. longipalpis SGS, suggesting that early events possibly triggered by immunization are essential for protection against Leishmania infection. Our findings support the specificity of saliva-mediated immune responses and reinforce the importance of identifying cross-protective salivary antigens.
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dual effect of lutzomyia longipalpis saliva on Leishmania braziliensis infection is mediated by distinct saliva induced cellular recruitment into balb c mice ear
BMC Microbiology, 2013Co-Authors: Claudia Brodskyn, Aldina Barral, Manoel Barralnetto, Vanessa Carregaro, Diego L Costa, Fernando Q Cunha, Joao S SilvaAbstract:Background: Leishmania parasites are transmitted to their vertebrate hosts by infected Phlebotomine sand flies during the blood meal of the flies. Sand fly saliva is known to enhance Leishmania spp. infection, while preexposure to saliva protects mice against parasitic infections. In this study, we investigated the initial inflammatory leucocyte composition induced by one or three inocula of salivary gland extract (SGE) from Lutzomyia longipalpis in the presence or absence of Leishmania braziliensis. Results: We demonstrated that inoculating SGE once (SGE-1X) or three times (SGE-3X), which represented a coinoculation or a pre-exposure to saliva, respectively, resulted in different cellular infiltrate profiles. Whereas SGE-1X led to the recruitment of all leucocytes subtypes including CD4 + T cells, CD4 + CD25 + T cells, dendritic cells, macrophages and neutrophils, the immune cell profile in the SGE-3X group differed dramatically, as CD4 + T cells, CD4 + CD25 + T cells, dendritic cells, macrophages and neutrophils were decreased and CD8 + T cells were increased. The SGE-1X group did not show differences in the ear lesion size; however, the SGE-1X group harbored a higher number of parasites. On the other hand, the SGE-3X group demonstrated a protective effect against parasitic disease, as the parasite burden was lower even in the earlier stages of the infection, a period in which the SGE-1X group presented with larger and more severe lesions. These effects were also reflected in the cytokine profiles of both groups. Whereas the SGE-1X group presented with a substantial increase in IL-10 production, the SGE-3X group showed an increase in IFN-γ production in the draining lymph nodes. Analysis of the inflammatory cell populations present within the ear lesions, the SGE-1X group showed an increase in CD4 + FOXP3 + cells, whereas the CD4 + FOXP3 + population was reduced in the SGE-3X group. Moreover, CD4 + T cells and CD8 + T cells producing IFN-γ were highly detected in the ears of the SGE-3X mice prior to infection. In addition, upon treatment of SGE-3X mice with anti-IFN-γ monoclonal antibody, we observed a decrease in the protective effect of SGE-3X against L. braziliensis infection. Conclusions: These results indicate that different inocula of Lutzomyia longipalpis salivary gland extract can markedly modify the cellular immune response, which is reflected in the pattern of susceptibility or resistance to Leishmania braziliensis infection.
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immunity to lutzomyia intermedia saliva modulates the inflammatory environment induced by Leishmania braziliensis
PLOS Neglected Tropical Diseases, 2010Co-Authors: Tatiana R De Moura, Claudia Brodskyn, Fabiano Oliveira, Kiyoshi F Fukutani, Jose Carlos Miranda, Manoel Barralnetto, Marcia W Carneiro, Fernanda O Novais, Gabriele C RodriguesAbstract:BACKGROUND: During blood feeding, sand flies inject Leishmania parasites in the presence of saliva. The types and functions of cells present at the first host-parasite contact are critical to the outcome on infection and sand fly saliva has been shown to play an important role in this setting. Herein, we investigated the in vivo chemotactic effects of Lutzomyia intermedia saliva, the vector of Leishmania braziliensis, combined or not with the parasite. METHODS AND FINDINGS: We tested the initial response induced by Lutzomyia intermedia salivary gland sonicate (SGS) in BALB/c mice employing the air pouch model of inflammation. L. intermedia SGS induced a rapid influx of macrophages and neutrophils. In mice that were pre-sensitized with L. intermedia saliva, injection of SGS was associated with increased neutrophil recruitment and a significant up-regulation of CXCL1, CCL2, CCL4 and TNF-alpha expression. Surprisingly, in mice that were pre-exposed to SGS, a combination of SGS and L. braziliensis induced a significant migration of neutrophils and an important modulation in cytokine and chemokine expression as shown by decreased CXCL10 expression and increased IL-10 expression. CONCLUSION: These results confirm that sand fly saliva modulates the initial host response. More importantly, pre-exposure to L. intermedia saliva significantly modifies the host's response to L. braziliensis, in terms of cellular recruitment and expression of cytokines and chemokines. This particular immune modulation may, in turn, favor parasite multiplication.
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immunity to lutzomyia intermedia saliva modulates the inflammatory environment induced by Leishmania braziliensis
PLOS Neglected Tropical Diseases, 2010Co-Authors: Claudia Brodskyn, Fabiano Oliveira, Kiyoshi F Fukutani, Jose Carlos Miranda, Manoel Barralnetto, Marcia W Carneiro, Fernanda O Novais, Tatiana Rodrigues De Moura, Gabriele C RodriguesAbstract:BACKGROUND: During blood feeding, sand flies inject Leishmania parasites in the presence of saliva. The types and functions of cells present at the first host-parasite contact are critical to the outcome on infection and sand fly saliva has been shown to play an important role in this setting. Herein, we investigated the in vivo chemotactic effects of Lutzomyia intermedia saliva, the vector of Leishmania braziliensis, combined or not with the parasite. METHODS AND FINDINGS: We tested the initial response induced by Lutzomyia intermedia salivary gland sonicate (SGS) in BALB/c mice employing the air pouch model of inflammation. L. intermedia SGS induced a rapid influx of macrophages and neutrophils. In mice that were pre-sensitized with L. intermedia saliva, injection of SGS was associated with increased neutrophil recruitment and a significant up-regulation of CXCL1, CCL2, CCL4 and TNF-alpha expression. Surprisingly, in mice that were pre-exposed to SGS, a combination of SGS and L. braziliensis induced a significant migration of neutrophils and an important modulation in cytokine and chemokine expression as shown by decreased CXCL10 expression and increased IL-10 expression. CONCLUSION: These results confirm that sand fly saliva modulates the initial host response. More importantly, pre-exposure to L. intermedia saliva significantly modifies the host's response to L. braziliensis, in terms of cellular recruitment and expression of cytokines and chemokines. This particular immune modulation may, in turn, favor parasite multiplication.
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neutrophils and macrophages cooperate in host resistance against Leishmania braziliensis infection
Journal of Immunology, 2009Co-Authors: Fernanda O Novais, Claudia Brodskyn, Aldina Barral, Manoel Barralnetto, Ricardo Khouri, Romulo C Santiago, Andre Bafica, Lilian Afonso, Valeria M Borges, Camila I De OliveiraAbstract:Neutrophils play an active role in the control of infections caused by intracellular pathogens such as Leishmania. In the present study, we investigated the effect of neutrophil depletion at the time of Leishmania braziliensis infection of BALB/c mice and how neutrophils interact with the infected macrophage to promote parasite elimination. The in vivo depletion of neutrophils led to a significant increase in parasite load and enhanced the Th1-Th2 immune response in this experimental model of infection. BALB/c mice coinoculated with both parasites and live neutrophils displayed lower parasite burdens at the site of infection and in the draining lymph nodes. In vitro, we observed that live neutrophils significantly reduced the parasite load in L. braziliensis-infected murine macrophages, an effect not observed with Leishmania major. L. braziliensis elimination was dependent on the interaction between neutrophils and macrophages and was associated with TNF-alpha as well as superoxide production. Furthermore, cooperation between neutrophils and macrophages toward parasite elimination was also observed in experiments performed with L. braziliensis-infected human cells and, importantly, with two other New World Leishmania species. These results indicate that neutrophils play an important and previously unappreciated role in L. braziliensis infection, favoring the induction of a protective immune response.
Manoel Barralnetto - One of the best experts on this subject based on the ideXlab platform.
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dual effect of lutzomyia longipalpis saliva on Leishmania braziliensis infection is mediated by distinct saliva induced cellular recruitment into balb c mice ear
BMC Microbiology, 2013Co-Authors: Claudia Brodskyn, Aldina Barral, Manoel Barralnetto, Vanessa Carregaro, Diego L Costa, Fernando Q Cunha, Joao S SilvaAbstract:Background: Leishmania parasites are transmitted to their vertebrate hosts by infected Phlebotomine sand flies during the blood meal of the flies. Sand fly saliva is known to enhance Leishmania spp. infection, while preexposure to saliva protects mice against parasitic infections. In this study, we investigated the initial inflammatory leucocyte composition induced by one or three inocula of salivary gland extract (SGE) from Lutzomyia longipalpis in the presence or absence of Leishmania braziliensis. Results: We demonstrated that inoculating SGE once (SGE-1X) or three times (SGE-3X), which represented a coinoculation or a pre-exposure to saliva, respectively, resulted in different cellular infiltrate profiles. Whereas SGE-1X led to the recruitment of all leucocytes subtypes including CD4 + T cells, CD4 + CD25 + T cells, dendritic cells, macrophages and neutrophils, the immune cell profile in the SGE-3X group differed dramatically, as CD4 + T cells, CD4 + CD25 + T cells, dendritic cells, macrophages and neutrophils were decreased and CD8 + T cells were increased. The SGE-1X group did not show differences in the ear lesion size; however, the SGE-1X group harbored a higher number of parasites. On the other hand, the SGE-3X group demonstrated a protective effect against parasitic disease, as the parasite burden was lower even in the earlier stages of the infection, a period in which the SGE-1X group presented with larger and more severe lesions. These effects were also reflected in the cytokine profiles of both groups. Whereas the SGE-1X group presented with a substantial increase in IL-10 production, the SGE-3X group showed an increase in IFN-γ production in the draining lymph nodes. Analysis of the inflammatory cell populations present within the ear lesions, the SGE-1X group showed an increase in CD4 + FOXP3 + cells, whereas the CD4 + FOXP3 + population was reduced in the SGE-3X group. Moreover, CD4 + T cells and CD8 + T cells producing IFN-γ were highly detected in the ears of the SGE-3X mice prior to infection. In addition, upon treatment of SGE-3X mice with anti-IFN-γ monoclonal antibody, we observed a decrease in the protective effect of SGE-3X against L. braziliensis infection. Conclusions: These results indicate that different inocula of Lutzomyia longipalpis salivary gland extract can markedly modify the cellular immune response, which is reflected in the pattern of susceptibility or resistance to Leishmania braziliensis infection.
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photodynamic antimicrobial chemotherapy pact using phenothiazine derivatives as photosensitizers against Leishmania braziliensis
Lasers in Surgery and Medicine, 2012Co-Authors: Artur Felipe Santos Barbosa, Manoel Barralnetto, Bruno B Sangiorgi, Suely Lins Galdino, Ivan Da Rocha Pitta, Antonio Luiz Barbosa PinheiroAbstract:Cutaneous and mucocutaneous Leishmaniasis are diseases characterized by skin or mucosal manifestations. In the new world, Leishmania braziliensis is the main etiological agent of cutaneous Leishmaniasis, condition that may evolve to the mucocutaneous form. The therapeutic arsenal routinely employed to treat infected patients is unsatisfactory, especially for pentavalent antimonials, treatment recommended by the WHO, as they are often highly toxic, poorly tolerated and of variable effectiveness. This work aimed to evaluate in vitro the effectiveness of photodynamic antimicrobial chemotherapy as a new approach for the treatment of Leishmaniasis. MATERIALS AND METHODS: A laser (I» = 660 nm, 40 mW, 4.2 J/cm2 , and 8.4 J/cm2 , CW) associated to phenothiazine's derivatives (5 and 10 µg/ml, toluidine blue O, methylene blue, or phenothiazine) on the promastigote forms of L. braziliensis in a single session. Samples were removed and analyzed in a hemocytometer 72 hours after PACT and viability of the parasites was assessed in quadruplicates. RESULTS: An important decrease in the number of viable parasites on all treated groups in comparison to their controls was observed as all tested compounds lead to significant parasite lethality being the highest lethality achieved with 10 µg/ml of TBO. No lethality was observed on groups treated with laser or with any of the compounds separately. CONCLUSIONS: TBO presented higher parasite lethality in comparison to MB with impressive reduction from 1 hour to 5 minutes of pre-incubation time.
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immunity to lutzomyia intermedia saliva modulates the inflammatory environment induced by Leishmania braziliensis
PLOS Neglected Tropical Diseases, 2010Co-Authors: Tatiana R De Moura, Claudia Brodskyn, Fabiano Oliveira, Kiyoshi F Fukutani, Jose Carlos Miranda, Manoel Barralnetto, Marcia W Carneiro, Fernanda O Novais, Gabriele C RodriguesAbstract:BACKGROUND: During blood feeding, sand flies inject Leishmania parasites in the presence of saliva. The types and functions of cells present at the first host-parasite contact are critical to the outcome on infection and sand fly saliva has been shown to play an important role in this setting. Herein, we investigated the in vivo chemotactic effects of Lutzomyia intermedia saliva, the vector of Leishmania braziliensis, combined or not with the parasite. METHODS AND FINDINGS: We tested the initial response induced by Lutzomyia intermedia salivary gland sonicate (SGS) in BALB/c mice employing the air pouch model of inflammation. L. intermedia SGS induced a rapid influx of macrophages and neutrophils. In mice that were pre-sensitized with L. intermedia saliva, injection of SGS was associated with increased neutrophil recruitment and a significant up-regulation of CXCL1, CCL2, CCL4 and TNF-alpha expression. Surprisingly, in mice that were pre-exposed to SGS, a combination of SGS and L. braziliensis induced a significant migration of neutrophils and an important modulation in cytokine and chemokine expression as shown by decreased CXCL10 expression and increased IL-10 expression. CONCLUSION: These results confirm that sand fly saliva modulates the initial host response. More importantly, pre-exposure to L. intermedia saliva significantly modifies the host's response to L. braziliensis, in terms of cellular recruitment and expression of cytokines and chemokines. This particular immune modulation may, in turn, favor parasite multiplication.
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immunity to lutzomyia intermedia saliva modulates the inflammatory environment induced by Leishmania braziliensis
PLOS Neglected Tropical Diseases, 2010Co-Authors: Claudia Brodskyn, Fabiano Oliveira, Kiyoshi F Fukutani, Jose Carlos Miranda, Manoel Barralnetto, Marcia W Carneiro, Fernanda O Novais, Tatiana Rodrigues De Moura, Gabriele C RodriguesAbstract:BACKGROUND: During blood feeding, sand flies inject Leishmania parasites in the presence of saliva. The types and functions of cells present at the first host-parasite contact are critical to the outcome on infection and sand fly saliva has been shown to play an important role in this setting. Herein, we investigated the in vivo chemotactic effects of Lutzomyia intermedia saliva, the vector of Leishmania braziliensis, combined or not with the parasite. METHODS AND FINDINGS: We tested the initial response induced by Lutzomyia intermedia salivary gland sonicate (SGS) in BALB/c mice employing the air pouch model of inflammation. L. intermedia SGS induced a rapid influx of macrophages and neutrophils. In mice that were pre-sensitized with L. intermedia saliva, injection of SGS was associated with increased neutrophil recruitment and a significant up-regulation of CXCL1, CCL2, CCL4 and TNF-alpha expression. Surprisingly, in mice that were pre-exposed to SGS, a combination of SGS and L. braziliensis induced a significant migration of neutrophils and an important modulation in cytokine and chemokine expression as shown by decreased CXCL10 expression and increased IL-10 expression. CONCLUSION: These results confirm that sand fly saliva modulates the initial host response. More importantly, pre-exposure to L. intermedia saliva significantly modifies the host's response to L. braziliensis, in terms of cellular recruitment and expression of cytokines and chemokines. This particular immune modulation may, in turn, favor parasite multiplication.
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neutrophils and macrophages cooperate in host resistance against Leishmania braziliensis infection
Journal of Immunology, 2009Co-Authors: Fernanda O Novais, Claudia Brodskyn, Aldina Barral, Manoel Barralnetto, Ricardo Khouri, Romulo C Santiago, Andre Bafica, Lilian Afonso, Valeria M Borges, Camila I De OliveiraAbstract:Neutrophils play an active role in the control of infections caused by intracellular pathogens such as Leishmania. In the present study, we investigated the effect of neutrophil depletion at the time of Leishmania braziliensis infection of BALB/c mice and how neutrophils interact with the infected macrophage to promote parasite elimination. The in vivo depletion of neutrophils led to a significant increase in parasite load and enhanced the Th1-Th2 immune response in this experimental model of infection. BALB/c mice coinoculated with both parasites and live neutrophils displayed lower parasite burdens at the site of infection and in the draining lymph nodes. In vitro, we observed that live neutrophils significantly reduced the parasite load in L. braziliensis-infected murine macrophages, an effect not observed with Leishmania major. L. braziliensis elimination was dependent on the interaction between neutrophils and macrophages and was associated with TNF-alpha as well as superoxide production. Furthermore, cooperation between neutrophils and macrophages toward parasite elimination was also observed in experiments performed with L. braziliensis-infected human cells and, importantly, with two other New World Leishmania species. These results indicate that neutrophils play an important and previously unappreciated role in L. braziliensis infection, favoring the induction of a protective immune response.
Fernanda O Novais - One of the best experts on this subject based on the ideXlab platform.
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meta transcriptome profiling of the human Leishmania braziliensis cutaneous lesion
PLOS Neglected Tropical Diseases, 2016Co-Authors: Stephen M Christensen, Edgar M Carvalho, Sara Passos, Lucas P Carvalho, Fernanda O Novais, Daniel P Beiting, Phillip Scott, Laura A L Dillon, Keith V Hughitt, Najib M ElsayedAbstract:Host and parasite gene expression in skin biopsies from Leishmania braziliensis-infected patients were simultaneously analyzed using high throughput RNA-sequencing. Biopsies were taken from 8 patients with early cutaneous Leishmaniasis and 17 patients with late cutaneous Leishmaniasis. Although parasite DNA was found in all patient lesions at the time of biopsy, the patients could be stratified into two groups: one lacking detectable parasite transcripts (PTNeg) in lesions, and another in which parasite transcripts were readily detected (PTPos). These groups exhibited substantial differences in host responses to infection. PTPos biopsies contained an unexpected increase in B lymphocyte-specific and immunoglobulin transcripts in the lesions, and an upregulation of immune inhibitory molecules. Biopsies without detectable parasite transcripts showed decreased evidence for B cell activation, but increased expression of antimicrobial genes and genes encoding skin barrier functions. The composition and abundance of L. braziliensis transcripts in PTPos lesions were surprisingly conserved among all six patients, with minimal meaningful differences between lesions from patients with early and late cutaneous Leishmaniasis. The most abundant parasite transcripts expressed in lesions were distinct from transcripts expressed in vitro in human macrophage cultures infected with L. amazonensis or L. major. Therefore in vitro gene expression in macrophage monolayers may not be a strong predictor of gene expression in lesions. Some of the most highly expressed in vivo transcripts encoded amastin-like proteins, hypothetical genes, putative parasite virulence factors, as well as histones and tubulin. In summary, RNA sequencing allowed us to simultaneously analyze human and L. braziliensis transcriptomes in lesions of infected patients, and identify unexpected differences in host immune responses which correlated with active transcription of parasite genes.
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intermediate monocytes contribute to pathologic immune response in Leishmania braziliensis infections
The Journal of Infectious Diseases, 2015Co-Authors: Sara Passos, Paulo R L Machado, Lucas P Carvalho, Rubia Costa, Tais M Campos, Fernanda O Novais, Andrea Magalhaes, Daniel P Beiting, David M Mosser, Edgar M CarvalhoAbstract:Ulcer development in patients with cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis is associated with high levels of tumor necrosis factor (TNF). We found that early after infection, before ulcer development, the frequency of CD16(+) (both intermediate [CD14(+)CD16(+)] and nonclassical [CD14(dim)CD16(+)]) monocytes was increased in the peripheral blood of patients with L. braziliensis, compared with uninfected controls. These results suggest that CD16(+) monocytes might promote disease. Also, we found that intermediate monocytes expressed CCR2 and that increased levels of CCL2 protein were present in lesions from patients, suggesting that intermediate monocytes are more likely than nonclassical monocytes to migrate to the lesion site. Finally, we found that the intermediate monocytes produced TNF. Our results show that intermediate monocytes are increased in frequency soon after infection; express CCR2, which would promote their migration into the lesions; and, owing to their production of TNF, can enhance the inflammatory response.
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genomic profiling of human Leishmania braziliensis lesions identifies transcriptional modules associated with cutaneous immunopathology
Journal of Investigative Dermatology, 2015Co-Authors: Fernanda O Novais, Edgar M Carvalho, Sara Passos, Lucas P Carvalho, David S Roos, Phillip Scott, Daniel P BeitingAbstract:The host immune response has a critical role not only in protection from human Leishmaniasis but also in promoting disease severity. Although candidate gene approaches in mouse models of Leishmaniasis have been extremely informative, a global understanding of the immune pathways active in lesions from human patients is lacking. To address this issue, genome-wide transcriptional profiling of Leishmania braziliensis-infected cutaneous lesions and normal skin controls was carried out. A signature of the L. braziliensis skin lesion was defined, which includes over 2,000 differentially regulated genes. Pathway-level analysis of this transcriptional response revealed key biological pathways present in cutaneous lesions, generating a testable 'metapathway' model of immunopathology and providing new insights for treatment of human Leishmaniasis.
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human classical monocytes control the intracellular stage of Leishmania braziliensis by reactive oxygen species
The Journal of Infectious Diseases, 2014Co-Authors: Fernanda O Novais, Edgar M Carvalho, Sara Passos, Lucas P Carvalho, Daniel P Beiting, Ba T Nguyen, Nelson D Glennie, Phillip ScottAbstract:Leishmania braziliensis are intracellular parasites that cause unique clinical forms of cutaneous Leishmaniasis. Previous studies with other Leishmania species demonstrated that reactive oxygen species (ROS) control promastigotes, the infective stage of the parasite, but not the amastigote form that exists in the mammalian host. Here we show that ROS inhibits growth of L. braziliensis amastigotes in resting monocytes, and that classical monocytes are primarily responsible for this control. ROS, but not nitric oxide, also contributed to killing of L. braziliensis by IFN-γ activated monocytes. Furthermore, by gene expression profiling of human lesions we found greater expression of genes associated with ROS, but not nitric oxide, compared to normal skin. This study shows that ROS are important for control of L. braziliensis both at the initial stages of infection, as well as at later time points, and highlights that monocyte subsets may play different roles during Leishmaniasis.
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immunity to lutzomyia intermedia saliva modulates the inflammatory environment induced by Leishmania braziliensis
PLOS Neglected Tropical Diseases, 2010Co-Authors: Tatiana R De Moura, Claudia Brodskyn, Fabiano Oliveira, Kiyoshi F Fukutani, Jose Carlos Miranda, Manoel Barralnetto, Marcia W Carneiro, Fernanda O Novais, Gabriele C RodriguesAbstract:BACKGROUND: During blood feeding, sand flies inject Leishmania parasites in the presence of saliva. The types and functions of cells present at the first host-parasite contact are critical to the outcome on infection and sand fly saliva has been shown to play an important role in this setting. Herein, we investigated the in vivo chemotactic effects of Lutzomyia intermedia saliva, the vector of Leishmania braziliensis, combined or not with the parasite. METHODS AND FINDINGS: We tested the initial response induced by Lutzomyia intermedia salivary gland sonicate (SGS) in BALB/c mice employing the air pouch model of inflammation. L. intermedia SGS induced a rapid influx of macrophages and neutrophils. In mice that were pre-sensitized with L. intermedia saliva, injection of SGS was associated with increased neutrophil recruitment and a significant up-regulation of CXCL1, CCL2, CCL4 and TNF-alpha expression. Surprisingly, in mice that were pre-exposed to SGS, a combination of SGS and L. braziliensis induced a significant migration of neutrophils and an important modulation in cytokine and chemokine expression as shown by decreased CXCL10 expression and increased IL-10 expression. CONCLUSION: These results confirm that sand fly saliva modulates the initial host response. More importantly, pre-exposure to L. intermedia saliva significantly modifies the host's response to L. braziliensis, in terms of cellular recruitment and expression of cytokines and chemokines. This particular immune modulation may, in turn, favor parasite multiplication.
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β glucan induced trained immunity protects against Leishmania braziliensis infection a crucial role for il 32
Cell Reports, 2019Co-Authors: Jessica Cristina Dos Santos, Ana Marina Barroso De Figueiredo, Muriel Vilela Teodoro Silva, Branko Cirovic, Charlotte L J De Bree, Michelle S M A DamenAbstract:Summary American tegumentary Leishmaniasis is a vector-borne parasitic disease caused by Leishmania protozoans. Innate immune cells undergo long-term functional reprogramming in response to infection or Bacillus Calmette-Guerin (BCG) vaccination via a process called trained immunity, conferring non-specific protection from secondary infections. Here, we demonstrate that monocytes trained with the fungal cell wall component β-glucan confer enhanced protection against infections caused by Leishmania braziliensis through the enhanced production of proinflammatory cytokines. Mechanistically, this augmented immunological response is dependent on increased expression of interleukin 32 (IL-32). Studies performed using a humanized IL-32 transgenic mouse highlight the clinical implications of these findings in vivo. This study represents a definitive characterization of the role of IL-32γ in the trained phenotype induced by β-glucan or BCG, the results of which improve our understanding of the molecular mechanisms governing trained immunity and Leishmania infection control.
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il 32γ promotes the healing of murine cutaneous lesions caused by Leishmania braziliensis infection in contrast to Leishmania amazonensis
Parasites & Vectors, 2017Co-Authors: Jessica Cristina Dos Santos, Muriel Vilela Teodoro Silva, Lucas Luiz De Lima Silva, Miriam Leandro Dorta, Milton Adriano Pelli De Oliveira, Aline Carvalho Batista, Juliana Reis Machado, Mauro M Teixeira, Rodrigo Saar GomesAbstract:Interleukin 32 (IL-32) is a pro-inflammatory cytokine induced in patients with American tegumentary Leishmaniasis (ATL) caused by Leishmania braziliensis. Here, we investigated whether IL-32 is also expressed in patient lesions caused by L. amazonensis. In addition, we evaluated experimental L. amazonensis and L. braziliensis infections in C57BL/6 transgenic mice for human IL-32γ (IL-32γTg) in comparison with wild-type (WT) mice that do not express the IL-32 gene. Human cutaneous lesions caused by L. amazonensis express higher levels of IL-32 than healthy control skin. In mice, the presence of IL-32γ promoted the control of cutaneous lesions caused by L. braziliensis, but not lesions caused by L. amazonensis in an ear dermis infection model. In addition, IL-32γTg mice displayed less tissue parasitism and inflammation in IL-32γTg than WT mice during the healing phase of L. braziliensis infection. Production of antigen-specific pro-inflammatory cytokines was higher in IL-32γTg mice than in WT mice during L. braziliensis infection but not during L. amazonensis infection. Human cutaneous lesions caused by L. amazonensis express high levels of IL-32. In mice, the presence of IL-32γ contributes to the lesion healing caused by L. braziliensis but not by L. amazonensis. Data suggest that despite the ability for both species to induce IL-32 in humans, the connections between this cytokine and other immune players induced by related species of parasites can lead to distinct outcomes of the murine infections.