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Search Results: 1 - 10 of 10513 matches for " Alexandre Morrot "
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The Role of Sialic Acid-Binding Receptors (Siglecs) in the Immunomodulatory Effects of Trypanosoma cruzi Sialoglycoproteins on the Protective Immunity of the Host
Alexandre Morrot
Scientifica , 2013, DOI: 10.1155/2013/965856
Abstract: Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and is an important endemic infection in Latin America. Lately, it has also become a health concern in the United States and Europe. Most of the immunomodulatory mechanisms associated with this parasitic infection have been attributed to mucin-like molecules on the T. cruzi surface. Mucins are high molecular weight glycoproteins that are involved in regulating diverse cellular activities in both normal and pathological conditions. In Trypanosoma cruzi infection, the parasite-derived mucins are the main acceptors of sialic acid and it has been suggested that they play a role in various host-parasite interactions during the course of Chagas disease. Recently, we have presented evidence that sialylation of the mucins is required for the inhibitory effects on CD4+ T cells. In what follows we propose that signaling via sialic acid-binding Ig-like lectin receptors for these highly sialylated structures on host cells contributes to the arrest of cell cycle progression in the G1 phase and may allow the parasite to modulate the immune system of the host. 1. Trypanosoma cruzi Infection and the Immunopathology of Chagas Disease Chagas’ disease or American trypanosomiasis is a tropical parasitic illness affecting nearly 20 million people in the Americas [1, 2]. The disease is caused by the protozoan flagellated parasite Trypanosoma cruzi, transmitted to humans by haematophagous insects known as triatomines (Reduviidae family). The complex life cycle of T. cruzi includes epimastigote and metacyclic trypomastigote stages in the insect vector and bloodstream trypomastigote and intracellular amastigotes in the vertebrate host [3]. In the latter, the Trypanosoma cruzi infects several cell types, including monocytes, fibroblasts, endothelial cells, and muscle cells [4–9]. This capacity to invade a wide range of host cells is associated with increased tissue inflammation and evokes a strong immunological response. This host protective response results from host tissue damage due to increased infiltration of leukocytes to the inflammatory sites, producing proinflammatory mediators, including cytokines, chemokines, and nitric oxide, among other factors [10–14]. Approximately 30% of infected patients develop symptoms of the disease in their lifetime; these include cardiomyopathy, neuropathies, and dilatation of the colon or esophagus [15]. The pathogenesis of Chagas disease is controversial and distinct hypotheses have been considered, including autoimmune manifestations and parasite-driven tissue damage
A role for extracellular amastigotes in the immunopathology of Chagas disease
Scharfstein, Julio;Morrot, Alexandre;
Memórias do Instituto Oswaldo Cruz , 1999, DOI: 10.1590/S0074-02761999000700005
Abstract: in spite of the growing knowledge obtained about immune control of trypanosoma cruzi infection, the mechanisms responsible for the variable clinico-pathological expression of chagas disease remain unknown. in a twist from previous concepts, recent studies indicated that tissue parasitism is a pre-requisite for the development of chronic myocarditis. this fundamental concept, together with the realization that t. cruzi organisms consist of genetically heterogeneous clones, offers a new framework for studies of molecular pathogenesis. in the present article, we will discuss in general terms the possible implications of genetic variability of t. cruzi antigens and proteases to immunopathology. peptide epitopes from a highly polymorphic subfamily of trans-sialidase (ts) antigens were recently identified as targets of killer t cell (ctl) responses, both in mice and humans. while some class i mhc restricted ctl recognize epitopes derived from amastigote-specific ts-related antigens (tsra), others are targeted to peptide epitopes originating from trypomastigote-specific tsra. a mechanistic hypothesis is proposed to explain how the functional activity and specificity of class i mhc restricted killer t cells may control the extent to which tissue are exposed to prematurely released amastigotes. chronic immunopathology may be exacerbated due the progressive accumulation of amastigote-derived antigens and pro-inflammatory molecules (eg. gpi-mucins and kinin-releasing proteases) in dead macrophage bodies.
A role for extracellular amastigotes in the immunopathology of Chagas disease
Scharfstein Julio,Morrot Alexandre
Memórias do Instituto Oswaldo Cruz , 1999,
Abstract: In spite of the growing knowledge obtained about immune control of Trypanosoma cruzi infection, the mechanisms responsible for the variable clinico-pathological expression of Chagas disease remain unknown. In a twist from previous concepts, recent studies indicated that tissue parasitism is a pre-requisite for the development of chronic myocarditis. This fundamental concept, together with the realization that T. cruzi organisms consist of genetically heterogeneous clones, offers a new framework for studies of molecular pathogenesis. In the present article, we will discuss in general terms the possible implications of genetic variability of T. cruzi antigens and proteases to immunopathology. Peptide epitopes from a highly polymorphic subfamily of trans-sialidase (TS) antigens were recently identified as targets of killer T cell (CTL) responses, both in mice and humans. While some class I MHC restricted CTL recognize epitopes derived from amastigote-specific TS-related antigens (TSRA), others are targeted to peptide epitopes originating from trypomastigote-specific TSRA. A mechanistic hypothesis is proposed to explain how the functional activity and specificity of class I MHC restricted killer T cells may control the extent to which tissue are exposed to prematurely released amastigotes. Chronic immunopathology may be exacerbated due the progressive accumulation of amastigote-derived antigens and pro-inflammatory molecules (eg. GPI-mucins and kinin-releasing proteases) in dead macrophage bodies.
Perspectivas de desenvolvimento sustentável para o setor florestal na América Latina
Castro, Alexandre Grimaldi de;Morrot, Sérgio;
Estudos Avan?ados , 1996, DOI: 10.1590/S0103-40141996000200019
Abstract: nowadays the sustainable development proposals represent a keystone in discussions of the actual meaning of the progress and social/economic development and welfare. the urgency for alternatives established by environmental and natural resources crises has induced the search for new strategies that must represent continually solution without threatening the sustainability of productive activities. the perspectives for sustainable development of the latin american forest sector, specifically pulp and paper, is closed related to: the establishment of politic negotiation and trading procedures amongst this productive segment and other representative society actors; the understanding to these enterprises in a broader scale, where they must be completely integrated in multisectorial regional development programs. also, it is very important to consider regional and local features related to social, economic and environmental states and functions. specially considering latin american societies it is essential to evaluate the whole process over an historic and contextual perspective. the state-of-the-art in science and technology allows the development of new concepts in management and exploitation of natural resources, although one must considers the intrinsic uncertainty levels. the sustainable management, represented by environmental processes management procedures, represents an actual alternative for transition to models of enhanced sustainability. environmental planning programs, together with dynamic and flexible management procedures, constitute available tools to implement and improve forest and environmental management strategies.
Resistance to visceral leishmaniasis is severely compromised in mice deficient of bradykinin B2-receptors
Nico Dirlei,Feijó Daniel,Maran Naiara,Morrot Alexandre
Parasites & Vectors , 2012, DOI: 10.1186/1756-3305-5-261
Abstract: Background Kinins liberated from plasma–borne kininogens, are potent innate stimulatory signals. We evaluated whether resistance to infection by Leishmania (L.) chagasi depends on activation of G-protein coupled bradykinin B2 receptors (B2R). Findings B2R / C57BL/6 knock-out (KOB2) and B2R+/+ C57BL/6-wild type control mice (C57) were infected with amastigotes of Leishmania (L.) chagasi. Thirty days after infection, the KOB2 mice showed 14% and 32% relative increases of liver (p< 0.017) and spleen weights (p<0.050), respectively, whereas liver parasite load increased 65% (p< 0.011) in relation to wild type mice. The relative weight increases of liver and spleen and the parasite load were positively correlated (R = 0.6911; p< 0.007 to R = 0.7629; p< 0.001, respectively). Conversely, we found a negative correlation between the increased liver relative weight and the weakened DTH response (a strong correlate to protection or natural resistance to VL) or the decreased levels of IgG2b antibodies to leishmanial antigen. Finally, we also found that IFN-γ secretion by splenocytes, an adaptive response that was significantly decreased in KOB2 mice (p< 0.002), was (i) negatively correlated to the increase in liver LDU (R = 0.6684; p = 0.035) and liver/body relative weight (R = 0.6946; p = 0.026) and (ii) positively correlated to serum IgG2b levels (R = 0.8817; p = 0.001). Conclusions We found that mice lacking B2R display increased susceptibility to the infection by Leishmania (L.) chagasi. Our findings suggest that activation of the bradykinin/B2R pathway contributes to development of host resistance to visceral leishmaniasis.
Effects of 5-Fluorouracil in Nuclear and Cellular Morphology, Proliferation, Cell Cycle, Apoptosis, Cytoskeletal and Caveolar Distribution in Primary Cultures of Smooth Muscle Cells
Marcelo de Carvalho Filgueiras, Alexandre Morrot, Pedro Marcos Gomes Soares, Manoel Luis Costa, Cláudia Mermelstein
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063177
Abstract: Colon cancer is one of the most prevalent types of cancer in the world and is one of the leading causes of cancer death. The anti-metabolite 5- fluorouracil (5-FU) is widely used in the treatment of patients with colon cancer and other cancer types. 5-FU-based chemotherapy has been shown to be very efficient in the improvement of overall survival of the patients and for the eradication of the disease. Unfortunately, common side effects of 5-FU include severe alterations in the motility of the gastrointestinal tissues. Nevertheless, the molecular and cellular effects of 5-FU in smooth muscle cells are poorly understood. Primary smooth muscle cell cultures are an important tool for studies of the biological consequences of 5-FU at the cellular level. The avian gizzard is one of the most robust organs of smooth muscle cells. Here we studied the molecular and cellular effects of the chemotherapic drug 5-FU in a primary culture of chick gizzard smooth muscle cells. We found that treatment of smooth muscle cells with 5-FU inhibits cell proliferation by the arrest of cells in the G1 phase of cell cycle and induce apoptosis. 5-FU induced a decrease in the percentage of histone H3-positive cells. Treatment of cells with 5-FU induced changes in cellular and nuclear morphology, a decrease in the number of stress fibers and a major decrease in the number of caveolin-3 positive cells. Our results suggest that the disorganization of the actin cytoskeleton and the reduction of caveolin-3 expression could explain the alterations in contractility observed in patients treated with 5-FU. These findings might have an impact in the understanding of the cellular effects of 5-FU in smooth muscle tissues and might help the improvement of new therapeutic protocols for the treatment of colon cancer.
Dynamics of Lymphocyte Populations during Trypanosoma cruzi Infection: From Thymocyte Depletion to Differential Cell Expansion/Contraction in Peripheral Lymphoid Organs
Alexandre Morrot,Juliana Barreto de Albuquerque,Luiz Ricardo Berbert,Carla Eponina de Carvalho Pinto,Juliana de Meis,Wilson Savino
Journal of Tropical Medicine , 2012, DOI: 10.1155/2012/747185
Abstract: The comprehension of the immune responses in infectious diseases is crucial for developing novel therapeutic strategies. Here, we review current findings on the dynamics of lymphocyte subpopulations following experimental acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. In the thymus, although the negative selection process of the T-cell repertoire remains operational, there is a massive thymocyte depletion and abnormal release of immature CD4+CD8+ cells to peripheral lymphoid organs, where they acquire an activated phenotype similar to activated effector or memory T cells. These cells apparently bypassed the negative selection process, and some of them are potentially autoimmune. In infected animals, an atrophy of mesenteric lymph nodes is also observed, in contrast with the lymphocyte expansion in spleen and subcutaneous lymph nodes, illustrating a complex and organ specific dynamics of lymphocyte subpopulations. Accordingly, T- and B-cell activation is seen in subcutaneous lymph nodes and spleen, but not in mesenteric lymph nodes. Lastly, although the function of peripheral CD4+CD8+ T-cell population remains to be defined in vivo, their presence may contribute to the immunopathological events found in both murine and human Chagas disease. 1. Introduction Trypanosoma cruzi is the causative agent of Chagas disease affecting more than 10 million people in Latin America. The parasite is transmitted by feces of infected insect vectors belonging to the family Reduviidae [1–3]. After infection, the initial acute phase of the disease progresses to an asymptomatic indeterminate period with virtually undetectable parasitemia and a strong humoral and cellular anti-T. cruzi responses. Up to several years after the initial infection, approximately 20 to 30% of all infected individuals develop a chronic inflammatory disease primarily affecting the heart [2–4]. Although different mechanisms have been proposed to trigger this pathology, there is a growing body of evidence that parasite persistence is associated with a chronic inflammatory response, which is the primary cause of Chagas disease [5, 6]. Experimental models of T. cruzi infection have been widely used to study various aspects of the infection. Acute infection in mice leads to strong activation of innate and adaptive immune response [7, 8]. In the course of infection, there is a fine change in the dynamics on the size of lymphocyte populations that contributes to regional specificities of the immune response in central and peripheral lymphoid organs: while there is an expansion
Differential Regional Immune Response in Chagas Disease
Juliana de Meis ,Alexandre Morrot,Désio Aurélio Farias-de-Oliveira,Déa Maria Serra Villa-Verde,Wilson Savino
PLOS Neglected Tropical Diseases , 2009, DOI: 10.1371/journal.pntd.0000417
Abstract: Following infection, lymphocytes expand exponentially and differentiate into effector cells to control infection and coordinate the multiple effector arms of the immune response. Soon after this expansion, the majority of antigen-specific lymphocytes die, thus keeping homeostasis, and a small pool of memory cells develops, providing long-term immunity to subsequent reinfection. The extent of infection and rate of pathogen clearance are thought to determine both the magnitude of cell expansion and the homeostatic contraction to a stable number of memory cells. This straight correlation between the kinetics of T cell response and the dynamics of lymphoid tissue cell numbers is a constant feature in acute infections yielded by pathogens that are cleared during the course of response. However, the regional dynamics of the immune response mounted against pathogens that are able to establish a persistent infection remain poorly understood. Herein we discuss the differential lymphocyte dynamics in distinct central and peripheral lymphoid organs following acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. While the thymus and mesenteric lymph nodes undergo a severe atrophy with massive lymphocyte depletion, the spleen and subcutaneous lymph nodes expand due to T and B cell activation/proliferation. These events are regulated by cytokines, as well as parasite-derived moieties. In this regard, identifying the molecular mechanisms underlying regional lymphocyte dynamics secondary to T. cruzi infection may hopefully contribute to the design of novel immune intervention strategies to control pathology in this infection.
Trypanosoma cruzi Disrupts Thymic Homeostasis by Altering Intrathymic and Systemic Stress-Related Endocrine Circuitries
Ailin Lepletier,Vinicius Frias de Carvalho,Patricia Machado Rodrigues e Silva,Silvina Villar,Ana Rosa Pérez,Wilson Savino ,Alexandre Morrot
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002470
Abstract: We have previously shown that experimental infection caused by Trypanosoma cruzi is associated with changes in the hypothalamus-pituitary-adrenal axis. Increased glucocorticoid (GC) levels are believed to be protective against the effects of acute stress during infection but result in depletion of CD4+CD8+ thymocytes by apoptosis, driving to thymic atrophy. However, very few data are available concerning prolactin (PRL), another stress-related hormone, which seems to be decreased during T. cruzi infection. Considering the immunomodulatory role of PRL upon the effects caused by GC, we investigated if intrathymic cross-talk between GC and PRL receptors (GR and PRLR, respectively) might influence T. cruzi-induced thymic atrophy. Using an acute experimental model, we observed changes in GR/PRLR cross-activation related with the survival of CD4+CD8+ thymocytes during infection. These alterations were closely related with systemic changes, characterized by a stress hormone imbalance, with progressive GC augmentation simultaneously to PRL reduction. The intrathymic hormone circuitry exhibited an inverse modulation that seemed to counteract the GC-related systemic deleterious effects. During infection, adrenalectomy protected the thymus from the increase in apoptosis ratio without changing PRL levels, whereas an additional inhibition of circulating PRL accelerated the thymic atrophy and led to an increase in corticosterone systemic levels. These results demonstrate that the PRL impairment during infection is not caused by the increase of corticosterone levels, but the opposite seems to occur. Accordingly, metoclopramide (MET)-induced enhancement of PRL secretion protected thymic atrophy in acutely infected animals as well as the abnormal export of immature and potentially autoreactive CD4+CD8+ thymocytes to the periphery. In conclusion, our findings clearly show that Trypanosoma cruzi subverts mouse thymus homeostasis by altering intrathymic and systemic stress-related endocrine circuitries with major consequences upon the normal process of intrathymic T cell development.
Thymus Atrophy and Double-Positive Escape Are Common Features in Infectious Diseases
Juliana de Meis,Désio Aurélio Farias-de-Oliveira,Pedro H. Nunes Panzenhagen,Naiara Maran,Déa Maria Serra Villa-Verde,Alexandre Morrot,Wilson Savino
Journal of Parasitology Research , 2012, DOI: 10.1155/2012/574020
Abstract: The thymus is a primary lymphoid organ in which bone marrow-derived T-cell precursors undergo differentiation, leading to migration of positively selected thymocytes to the T-cell-dependent areas of secondary lymphoid organs. This organ can undergo atrophy, caused by several endogenous and exogenous factors such as ageing, hormone fluctuations, and infectious agents. This paper will focus on emerging data on the thymic atrophy caused by infectious agents. We present data on the dynamics of thymus lymphocytes during acute Trypanosoma cruzi infection, showing that the resulting thymus atrophy comprises the abnormal release of thymic-derived T cells and may have an impact on host immune response. 1. Introduction The thymus is a primary lymphoid organ in which bone marrow-derived T-cell precursors undergo differentiation, leading to migration of positively selected thymocytes to the T-cell-dependent areas of secondary lymphoid organs [2]. Interactions between thymocytes and specialized thymic microenvironmental cells (thymic epithelial cells, macrophages, dendritic cells, and fibroblasts) support and drive T-cell differentiation from bone marrow-derived precursors, by means of a series of interactions including receptor/coreceptor interactions, cytokines, chemokines, and hormones [3–7], as illustrated in Figure 1. Figure 1: Intrathymic differentiation of T cells. Lymphocyte differentiation initiates when T-cell precursors enter the thymus through postcapillary venules located at corticomedullary junction. After entering the organ, cells interact with the thymic microenvironment (thymic epithelial cells, macrophages, dendritic cells, and fibroblasts), which ultimately lead to their proliferation and TCR rearrangement. Interactions between thymocytes and specialized thymic microenvironmental cells support and direct T cell differentiation by means of a series of interactions including receptor/coreceptor interactions (MHC-TCR, Integrin/ECM Proteins), cytokines (IL-1, IL-2, IL-3, IL-6, IL-7, IL-8, IFN-gamma), chemokines (as CCL25, CXCL12, CCL21), and hormones, with corresponding receptors. At the subcapsular zone, these thymocytes undergo TCR beta chain rearrangement and selection. Double-positive thymocytes migrate through the cortex and initiate TCR testing (positive selection). Positively selected thymocytes, located at the medulla, are screened for self-reactivity through negative selection. Residence in the medulla is followed by emigration, which is regulated by sphingosine-1-phosphate and its receptor (S1P1). Adapted from [ 1]. Thymopoiesis starts at
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