Subversion of Immunity by Leishmania amazonensis Parasites: Possible Role of Phosphatidylserine as a Main Regulator

Leishmania amazonensis parasites cause progressive disease in most inbred mouse strains and are associated with the development of diffuse cutaneous leishmaniasis in humans. The poor activation of an effective cellular response is correlated with the ability of these parasites to infect mononuclear phagocytic cells without triggering their activation or actively suppressing innate responses of these cells. Here we discuss the possible role of phosphatidylserine exposure by these parasites as a main regulator of the mechanism underlying subversion of the immune system at different steps during the infection

CD4+ T Cell-Dependent Macrophage Activation Modulates Sustained PS Exposure on Intracellular Amastigotes of Leishmania amazonensis

Leishmania amazonensis amastigotes can make use of surface-exposed phosphatidylserine (PS) molecules to promote infection and non-classical activation of macrophages (MΦ), leading to uncontrolled intracellular proliferation of the parasites. This mechanism was quoted as apoptotic mimicry. Moreover, the amount of PS molecules exposed on the surface of amastigotes correlates with the susceptibility of the host. In this study, we tested whether host cellular responses influence PS expression on intracellular amastigotes. We found that the level of PS exposure on intracellular amastigotes was modulated by CD4+ T cell and MΦ activation status in vitro and in vivo. L. amazonensis infection generated a Th1/Th2-mixed cytokine profile, providing the optimal MΦ stimulation that favored PS exposure on intracellular amastigotes. Maintenance of PS exposed on the parasite was dependent on low, but sustained, levels of nitric oxide and polyamine production. Amastigotes obtained from lymphopenic nude mice did not expose PS on their surface, and adoptive transfer of CD4+ T cells reversed this phenotype. In addition, histopathological analysis of mice treated with anti-PS antibodies showed increased inflammation and similarities to nude mouse lesions. Collectively, our data confirm the role of pathogenic CD4+ T cells for disease progression and point to PS as a critical parasite strategy to subvert host immune responses

Exposure of Phosphatidylserine on Leishmania amazonensis Isolates Is Associated with Diffuse Cutaneous Leishmaniasis and Parasite Infectivity

Diffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of leishmaniasis, characterized by an inefficient parasite-specific cellular response and heavily parasitized macrophages. In Brazil, Leishmania (Leishmania) amazonensis is the main species involved in DCL cases. In the experimental model, recognition of phosphatidylserine (PS) molecules exposed on the surface of amastigotes forms of L. amazonensis inhibits the inflammatory response of infected macrophages as a strategy to evade the host immune surveillance. In this study, we examined whether PS exposure on L. amazonensis isolates from DCL patients operated as a parasite pathogenic factor and as a putative suppression mechanism of immune response during the infection. Peritoneal macrophages from F1 mice (BALB/c×C57BL/6) were infected with different L. amazonensis isolates from patients with localized cutaneous leishmaniasis (LCL) or DCL. DCL isolates showed higher PS exposure than their counterparts from LCL patients. In addition, PS exposure was positively correlated with clinical parameters of the human infection (number of lesions and time of disease) and with characteristics of the experimental infection (macrophage infection and anti-inflammatory cytokine induction). Furthermore, parasites isolated from DCL patients displayed an increased area in parasitophorous vacuoles (PV) when compared to those isolated from LCL patients. Thus, this study shows for the first time that a parasite factor (exposed PS) might be associated with parasite survival/persistence in macrophages and lesion exacerbation during the course of DCL, providing new insights regarding pathogenic mechanism in this rare chronic disease

Cooperation between Apoptotic and Viable Metacyclics Enhances the Pathogenesis of Leishmaniasis

Mimicking mammalian apoptotic cells by exposing phosphatidylserine (PS) is a strategy used by virus and parasitic protozoa to escape host protective inflammatory responses. With Leishmania amazonensis (La), apoptotic mimicry is a prerogative of the intramacrophagic amastigote form of the parasite and is modulated by the host. Now we show that differently from what happens with amastigotes, promastigotes exposing PS are non-viable, non-infective cells, undergoing apoptotic death. As part of the normal metacyclogenic process occurring in axenic cultures and in the gut of sand fly vectors, a sub-population of metacyclic promastigotes exposes PS. Apoptotic death of the purified PS-positive (PSPOS) sub-population was confirmed by TUNEL staining and DNA laddering. Transmission electron microscopy revealed morphological alterations in PSPOS metacyclics such as DNA condensation, cytoplasm degradation and mitochondrion and kinetoplast destruction, both in in vitro cultures and in sand fly guts. TUNELPOS promastigotes were detected only in the anterior midgut to foregut boundary of infected sand flies. Interestingly, caspase inhibitors modulated parasite death and PS exposure, when added to parasite cultures in a specific time window. Efficient in vitro macrophage infections and in vivo lesions only occur when PSPOS and PS-negative (PSNEG) parasites were simultaneously added to the cell culture or inoculated in the mammalian host. The viable PSNEG promastigote was the infective form, as shown by following the fate of fluorescently labeled parasites, while the PSPOS apoptotic sub-population inhibited host macrophage inflammatory response. PS exposure and macrophage inhibition by a subpopulation of promastigotes is a different mechanism than the one previously described with amastigotes, where the entire population exposes PS. Both mechanisms co-exist and play a role in the transmission and development of the disease in case of infection by La. Since both processes confer selective advantages to the infective microorganism they justify the occurrence of apoptotic features in a unicellular pathogen

Molecular aspects of prostate cancer: implications for future directions

Many studies have been developed trying to understand the complex molecular mechanisms involved in oncogenesis and progression of prostate cancer (PCa). Current biotechnological methodologies, especially genomic studies, are adding important aspects to this area. The construction of extensive DNA sequence data and gene expression profiles have been intensively explored to search for candidate biomarkers to evaluate PCa. The use of DNA micro-array robotic systems constitutes a powerful approach to simultaneously monitor the expression of a great number of genes. The resulting gene expressing profiles can be used to specifically describe tumor staging and response to cancer therapies. Also, it is possible to follow PCa pathological properties and to identify genes that anticipate the behavior of clinical disease. The molecular pathogenesis of PCa involves many contributing factors, such as alterations in signal transduction pathways, angiogenesis, adhesion molecules expression and cell cycle control. Also, molecular studies are making clear that many genes, scattered through several different chromosomal regions probably cause predisposition to PCa. The discovery of new molecular markers for PCa is another relevant advance resulting from molecular biology studies of prostate tumors. Interesting tissue and serum markers have been reported, resulting in many cases in useful novelties to diagnostic and prognostic approaches to follow-up PCa. Finally, gene therapy comes as an important approach for therapeutic intervention in PCa. Clinical trials for PCa have been demonstrating that gene therapy is relatively safe and well tolerated, although some improvements are yet to be developed

Apoptotic cell and phagocyte interplay: recognition and consequences in different cell systems

Cell death by apoptosis is characterized by specific biochemical changes, including the exposure of multiple ligands, expected to tag the dying cell for prompt recognition by phagocytes. In non-pathological conditions, an efficient clearance is assured by the redundant interaction between apoptotic cell ligands and multiple receptor molecules present on the engulfing cell surface. This review concentrates on the molecular interactions operating in mammalian and non-mammalian systems for apoptotic cell recognition, as well as on the consequences of their signaling. Furthermore, some cellular models where the exposure of the phosphatidylserine (PS) phospholipid, a classical hallmark of the apoptotic phenotype, is not followed by cell death will be discussed

NOVEL 17-KILODALTON LEISHMANIA ANTIGEN REVEALED BY IMMUNOCHEMICAL STUDIES OF A PURIFIED GLYCOPROTEIN FRACTION RECOGNIZED BY MURINE LYMPHOCYTES-T

FED UNIV RIO DE JANEIRO,INST MICROBIOL,BR-21941 RIO DE JANEIRO,RJ,BRAZILFED UNIV RIO DE JANEIRO,CARLOS CHAGAS FILHO INST BIOPHYS,BR-21941 RIO DE JANEIRO,RJ,BRAZILWeb of Scienc

Apoptosis and apoptotic mimicry in Leishmania: an evolutionary perspective

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2015-02-11T12:11:12Z No. of bitstreams: 1 El-Hani CN Apoptosis....pdf: 356580 bytes, checksum: 3f6b4ac466b009c2fcb8dd839a7bc952 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2015-02-11T12:11:23Z (GMT) No. of bitstreams: 1 El-Hani CN Apoptosis....pdf: 356580 bytes, checksum: 3f6b4ac466b009c2fcb8dd839a7bc952 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2015-02-11T12:29:31Z (GMT) No. of bitstreams: 1 El-Hani CN Apoptosis....pdf: 356580 bytes, checksum: 3f6b4ac466b009c2fcb8dd839a7bc952 (MD5)Made available in DSpace on 2015-02-11T12:29:31Z (GMT). No. of bitstreams: 1 El-Hani CN Apoptosis....pdf: 356580 bytes, checksum: 3f6b4ac466b009c2fcb8dd839a7bc952 (MD5) Previous issue date: 2012Universidade Federal da Bahia. Instituto de Biologia. Laboratório de Ensino, História e Filosofia de Biologia. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia. Salvador, BA, Brasil.Universidade Federal do Rio de Janeiro. Pólo Universitário Macaé. Macaé, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Apoptotic death and apoptotic mimicry are defined respectively as a non-accidental death and as the mimicking of an apoptotic-cell phenotype, usually by phosphatidylserine (PS) exposure. In the case of the murine infection by Leishmania spp, apoptotic death has been described in promastigotes and apoptotic mimicry in amastigotes. In both situations they are important events of the experimental murine infection by this parasite. In the present review we discuss what features we need to consider if we want to establish if a behavior shown by Leishmania is altruistic or not: does the behavior increases the fitness of organisms other than the one showing it? Does this behavior have a cost for the actor? If we manage to show that a given behavior is costly for the actor and beneficial for the recipient of the action, we will be able to establish it as altruistic. From this perspective, we can argue that apoptotic-like death and apoptotic mimicry are both altruistic with the latter representing a weaker altruistic behavior than the former