Cláudia Brodskyn - Academia.edu (original) (raw)

Papers by Cláudia Brodskyn

Frontiers in Public Health, 2014

Leishmaniasis, caused by infection with parasites of the Leishmania genus, affects millions of in... more Leishmaniasis, caused by infection with parasites of the Leishmania genus, affects millions of individuals worldwide. This disease displays distinct clinical manifestations ranging from self-healing skin lesions to severe tissue damage. The control of Leishmania infection is dependent on cellular immune mechanisms, and evidence has shown that CD4 and CD8 T lymphocytes play different roles in the outcome of leishmaniasis. Although the presence of CD4 T cells is important for controlling parasite growth, the results in the literature suggest that the inflammatory response elicited by these cells could contribute to the pathogenesis of lesions. However, recent studies on CD8 T lymphocytes show that these cells are mainly involved in tissue damage through cytotoxic mechanisms. In this review, we focus on the recent advances in the study of the human adaptive immunological response in the pathogenesis of tegumentary leishmaniasis.

Journal of Investigative Dermatology, 2014

In this study, we used proteomics and biological network analysis to evaluate the potential biolo... more In this study, we used proteomics and biological network analysis to evaluate the potential biological processes and components present in the identified proteins of biopsies from cutaneous leishmaniasis (CL) patients infected by Leishmania braziliensis in comparison with normal skin. We identified 59 proteins differently expressed in samples from infected and normal skin. Biological network analysis employing identified proteins showed the presence of networks that may be involved in the cell death mediated by cytotoxic T lymphocytes. After immunohistochemical analyses, the expression of caspase-9, caspase-3, and granzyme B was validated in the tissue and positively correlated with the lesion size in CL patients. In conclusion, this work identified differentially expressed proteins in the inflammatory site of CL, revealed enhanced expression of caspase-9, and highlighted mechanisms associated with the progression of tissue damage observed in lesions.

BMC INFECTIOUS DISEASES, 2005

Background: Leishmaniasis remains a serious public health problem in several parts of the develop... more Background: Leishmaniasis remains a serious public health problem in several parts of the developing world. Effective prophylactic measurements are hampered by imprecise comprehension of different aspects of the disease, including its immunoregulation. A better comprehension of immunoregulation in human VL may be useful both for designing and evaluating immunoprophylaxis.

When an haematophagous sand fly vector insect bites a vertebrate host, it introduces its mouthpar... more When an haematophagous sand fly vector insect bites a vertebrate host, it introduces its mouthparts into the skin and lacerates blood vessels, forming a hemorrhagic pool which constitutes an intricate environment of cell interactions. In this scenario, the initial performance of host, parasite, and vector "authors" will heavily influence the course of Leishmania infection. Recent advances in vector-parasite-host interaction have elucidated "co-authors" and "new roles" not yet described. We review here the stimulatory role of Lutzomyia longipalpis saliva leading to inflammation and try to connect them in an early context of Leishmania infection.

PLOS Neglected Tropical Diseases, 2015

Several intracellular Leishmania antigens have been identified in order to find a potential vacci... more Several intracellular Leishmania antigens have been identified in order to find a potential vaccine capable of conferring long lasting protection against Leishmania infection. Histones and Acid Ribosomal proteins are already known to induce an effective immune response and have successfully been tested in the cutaneous leishmaniasis mouse model. Here, we investigate the protective ability of L. infantum nucleosomal histones (HIS) and ribosomal acidic protein P0 (LiP0) against L. infantum infection in the hamster model of visceral leishmaniasis using two different strategies: homologous (plasmid DNA only) or heterologous immunization (plasmid DNA plus recombinant protein and adjuvant).

Parasitology International, 2009

The miniexon gene has a central role in the processing of polycistronic pre-mRNA of kinetoplastid... more The miniexon gene has a central role in the processing of polycistronic pre-mRNA of kinetoplastids. It is added to the 5′ extremity of each mRNA, supplying the 5′-capped structure to the molecule. Previous studies in Leishmania (Leishmania) major showed that the overexpression of the miniexon array attenuates the virulence of the parasite in in vivo assays. The results presented here extend those findings to Viannia subgenus. Leishmania (Viannia) braziliensis was transfected with a cosmid harboring a tandem array of one hundred miniexon gene copies and then characterized by Northern blot analysis. The overexpression of the exogenous gene was confirmed and its effect on the virulence of L. (V.) braziliensis was investigated in hamsters. In BALB/c mice we could not detect parasites during the course of 15 weeks of infection. In addition, hamsters infected with transfectants overexpressing the miniexon gene exhibited only a minor footpad swelling of late onset and failed to develop progressive lesion, these attenuated parasites could be recovered from the inoculation site 1 year after infection. The persistence of parasites in the host indicates that a stable line overexpressing the miniexon may be tested as live vaccine against leishmaniasis.

Parasites & vectors, Jan 20, 2014

BackgroundEicosanoids and sand fly saliva have a critical role in the Leishmania infection. Here,... more BackgroundEicosanoids and sand fly saliva have a critical role in the Leishmania infection. Here, we evaluated the effect of Lutzomyia longipalpis salivary gland sonicate (SGS) on neutrophil and monocyte recruitment and activation of eicosanoid production in a murine model of inflammation.MethodsC57BL/6 mice were inoculated intraperitonealy with Lutzomyia longipalpis SGS or Leishmania infantum or both, followed by analyses of cell recruitment, parasite load and eicosanoid production.ResultsIntraperitoneal injection of Lutzomyia longipalpis SGS together with Leishmania infantum induced an early increased parasite viability in monocytes and neutrophils. L. longipalpis SGS increased prostaglandin E2 (PGE2), but reduced leukotriene B4 (LTB4) production ex vivo in peritoneal leukocytes. In addition, the pharmacological inhibition of cyclooxygenase 2 (COX-2) with NS-398 decreased parasite viability inside macrophages during Leishmania infection in the presence of L. longipalpis SGS arguin...

Scholarly Research Exchange, 2009

Leishmaniases are a wide spectrum of parasitic diseases caused by the infection of different spec... more Leishmaniases are a wide spectrum of parasitic diseases caused by the infection of different species of the genus Leishmania. Currently, these diseases are one of the most neglected diseases threatening 350 million people in different countries around the world. Thus, these diseases require better screening, diagnostics and treatment. An effective vaccine, that is not currently available, would be the best way to confront leishmaniases. In the past 20 years the molecular characterization of Leishmania genes encoding parasite antigens has been carried out. In this review we summarize the most common strategies employed for the isolation and characterization of genes encoding Leishmania antigens. To provide a collective view, we also discuss the results related with diagnosis and protection based on different recombinant DNA-derived Leishmania products.

Vaccine, 2008

Canine visceral leishmaniasis; Cell and humoral immune response; Flow cytometry

PLoS Neglected Tropical Diseases, 2011

PLoS Neglected Tropical Diseases, 2010

Background: Sand flies deliver Leishmania parasites to a host alongside salivary molecules that a... more Background: Sand flies deliver Leishmania parasites to a host alongside salivary molecules that affect infection outcomes. Though some proteins are immunogenic and have potential as markers of vector exposure, their identity and vector specificity remain elusive.

PLoS Neglected Tropical Diseases, 2007

Background: Sand fly saliva has an array of pharmacological and immunomodulatory components, and ... more Background: Sand fly saliva has an array of pharmacological and immunomodulatory components, and immunity to saliva protects against Leishmania infection. In the present study, we have studied the immune response against Lutzomyia intermedia saliva, the main vector of Leishmania braziliensis in Brazil, and the effects of saliva pre-exposure on L. braziliensis infection employing an intradermal experimental model.

Journal of Infectious Diseases, 2014

Neutrophils are rapidly recruited to the site of Leishmania infection and play an active role in ... more Neutrophils are rapidly recruited to the site of Leishmania infection and play an active role in capturing and killing parasites. They are the main source of leukotriene B4 (LTB4), a potent proinflammatory lipid mediator. However, the role of LTB4 in neutrophil infection by Leishmania amazonensis is not clear. In this study, we show that L. amazonensis or its lipophosphoglycan can induce neutrophil activation, degranulation, and LTB4 production. Using pharmacological inhibitors of leukotriene synthesis, our findings reveal an LTB4-driven autocrine/paracrine regulatory effect. In particular, neutrophil-derived LTB4 controls L. amazonensis killing, degranulation, and reactive oxygen species production. In addition, L. amazonensis infection induces an early increase in Toll-like receptor 2 expression, which facilitates parasite internalization. Nuclear factor kappa B (NFkB) pathway activation represents a required upstream event for L. amazonensis-induced LTB4 synthesis. These leishmanicidal mechanisms mediated by neutrophil-derived LTB4 act through activation of its receptor, B leukotriene receptor 1 (BLT1).

International Journal for Parasitology, 2012

Leishmania spp. cause a broad spectrum of diseases collectively known as leishmaniasis. Leishmani... more Leishmania spp. cause a broad spectrum of diseases collectively known as leishmaniasis. Leishmania braziliensis is the main etiological agent of American cutaneous leishmaniasis and mucocutaneous leishmaniasis. During experimental infection with L. braziliensis, BALB/c mice develop an adaptive immune response that is associated with lesion healing and, in parallel, parasite persistence within draining lymph nodes (dLNs). In the Leishmania major model of cutaneous leishmaniasis, regulatory T cells (Tregs) play an important role in immune regulation, preventing pathological immune responses but at the same time precluding sterile cure. In this study we investigated the role of Tregs during experimental infection with L. braziliensis. CD4 + CD25 + T cells were detected throughout the duration of clinical disease both at the ear and in dLNs of infected mice. These cells expressed Treg markers such as glucocorticoid-induced TNF-receptor-related protein (GITR), the a chain of the aeb7 integrin (CD103), and the forkhead/winged helix transcription factor, Foxp3, and were able to suppress the proliferation of CD4 + CD25 À cells. Importantly, a high frequency of Foxp3 + cells accumulated at the site of infection and in dLNs. We next investigated the outcome of a reinfection with L. braziliensis in terms of Treg distribution and disease reactivation. Interestingly, a secondary inoculation with L. braziliensis did not preclude an efficient recall response to L. braziliensis at a distal site, despite the presence of Tregs. Within dLNs, reinfection did not promote parasite dissemination or a differential recruitment of either CD4 + CD25 + Foxp3 + or CD4 + IL-10 + T cells. On the contrary, parasites were mainly detected in the LN draining the primary infection site where a high frequency of CD4 + IFN-c + T cells was also present. Collectively these data show that during experimental infection, Tregs are present in healed mice but this population does not compromise an effective immune response upon reinfection with L. braziliensis. Ó

Infection and Immunity, 2002

To investigate the possible effects of glycoinositolphospholipid (GIPL) from Trypanosoma cruzi on... more To investigate the possible effects of glycoinositolphospholipid (GIPL) from Trypanosoma cruzi on human antigen presenting cells, we tested their effects on lipopolysaccharide (LPS)-stimulated human macrophages and dendritic cells (DC). Human macrophages or DC were incubated with GIPL (50 g/ml) and LPS (500 pg/ml) and tumor necrosis factor alpha (TNF-␣), interleukin 8 (IL-8), IL-10, and IL-12p40 levels in supernatants were analyzed by enzyme-linked immunosorbent assay. TNF-␣, IL-10, and IL-12 secretion were significantly decreased by GIPL both in macrophages and DC. In contrast, GIPL did not alter IL-8 production. We also analyzed the expression of CD80, CD86, HLA-DR, CD40, and CD57 on the macrophage surface after stimulation with LPS in the presence or absence of T. cruzi GIPL. GIPL led to a down-regulation in the expression of all tested molecules. We additionally examined the influence of T. cruzi GIPL on the response of human DC to LPS. LPS-induced HLA-DR, CD83, and CD86 up-regulation was significantly inhibited by GIPL. A slight down-regulation in CD80 and CD40 expression on DC surfaces in the presence of GIPL was also noticed. Similarly, GIPL led to down-modulation of CD83, CD80, CD86, and HLA-DR surface expression and TNF-␣ and IL-10 production when DC were stimulated by CD40L. The ceramide portion of GIPL was responsible for most of the activity exhibited by the whole molecule. Considering the important role of the immune response in determining the fate of the host-parasite relationship, the immunoregulatory activities of T. cruzi GIPL are potentially important for parasite evasion and then pathogenesis of infection with protozoan parasites.

Clinical and Vaccine Immunology, 2007

Leishmania (Leishmania) major could also induce protective immunity against a challenge with Leis... more Leishmania (Leishmania) major could also induce protective immunity against a challenge with Leishmania (Viannia) braziliensis, the species responsible for 90% of the 28,712 annual cases of cutaneous and mucocutaneous leishmaniasis recorded in Brazil during the year of 2004. Initially, we isolated the homolog genes encoding four L. (V.) braziliensis antigens: (i) homologue of receptor for activated C kinase, (ii) thiol-specific antioxidant, (iii) Leishmania elongation and initiation factor, and (iv) L. (L.) major stressinducible protein 1. At the deduced amino acid level, all four open reading frames had a high degree of identity with the previously described genes of L. (L.) major being expressed on promastigotes and amastigotes of L. (V.) braziliensis. These genes were inserted into the vector pcDNA3 or expressed as bacterial recombinant proteins. After immunization with recombinant plasmids or proteins, BALB/c mice generated specific antibody or cell-mediated immune responses (gamma interferon production). After an intradermal challenge with L. (V.) braziliensis infective promastigotes, no significant reduction on the lesions was detected. We conclude that the protective immunity afforded by these four vaccine candidates against experimental cutaneous leishmaniasis caused by L. (L.) major could not be reproduced against a challenge with L. (V.) braziliensis. Although negative, we consider our results important since they suggest that studies aimed at the development of an effective vaccine against L. (V.) braziliensis, the main causative agent of cutaneous leishmaniasis in the New World, should be redirected toward distinct antigens or different vaccination strategies.

BMC Immunology, 2008

Background: Sand fly saliva contains potent and complex pharmacologic molecules that are able to ... more Background: Sand fly saliva contains potent and complex pharmacologic molecules that are able to modulate the host's hemostatic, inflammatory, and immune systems. In this study, we evaluated the effects of salivary gland sonicate (SGS) of Lutzomyia intermedia, the natural vector of Leishmania braziliensis, on monocytes obtained from the peripheral blood mononuclear cells (PBMC) of healthy volunteers. We investigated the effects of sand fly saliva on cytokine production and surface molecule expression of LPS-stimulated human monocytes uninfected or infected with L. braziliensis.

Journal of Leukocyte Biology, 2011

Neutrophils are considered the host's first line of defense against infections and have been impl... more Neutrophils are considered the host's first line of defense against infections and have been implicated in the immunopathogenesis of Leishmaniasis. Leishmania parasites are inoculated alongside vectors' saliva, which is a rich source of pharmacologically active substances that interfere with host immune response. In the present study, we tested the hypothesis that salivary components from Lutzomyia longipalpis, an important vector of visceral Leishmaniasis, enhance neutrophil apoptosis. Murine inflammatory peritoneal neutrophils cultured in the presence of SGS presented increased surface expression of FasL and underwent caspase-dependent and FasL-mediated apoptosis. This proapoptosis effect of SGS on neutrophils was abrogated by pretreatment with protease as well as preincubation with antisaliva antibodies. Furthermore, in the presence of Leishmania chagasi, SGS also increased apoptosis on neutrophils and increased PGE 2 release and decreased ROS production by neutrophils, while enhancing parasite viability inside these cells. The increased parasite burden was abrogated by treatment with z-VAD, a pan caspase inhibitor, and NS-398, a COX-2 inhibitor. In the presence of SGS, Leishmaniainfected neutrophils produced higher levels of MCP-1 and attracted a high number of macrophages by chemotaxis in vitro assays. Both of these events were abrogated by pretreatment of neutrophils with bindarit, an inhibitor of CCL2/MCP-1 expression. Taken together, our data support the hypothesis that vector salivary proteins trigger caspase-dependent and FasL-medi-ated apoptosis, thereby favoring Leishmania survival inside neutrophils, which may represent an important mechanism for the establishment of Leishmania infection. J. Leukoc. Biol. 90: 000 -000; 2011.