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Lipofosfoglicanos (LPGs) de Leishmania braziliensis e Leishmania infantum na ativa????o de macr??fagos murinos e vias de sinaliza????o celular

By Izabela Coimbra Ibraim

Abstract

O LPG apresenta varia????es estruturais que s??o importantes para os diferentes est??gios de desenvolvimento do parasito. Nas formas proc??clicas, o LPG de L. braziliensis (cepa M2903), n??o apresenta cadeias laterais enquanto um a dois res??duos de ??-glicose podem aparecer nas unidades repetitivas da forma metac??clica. O LPG de L. infantum (cepa BH46), apresenta at?? tr??s cadeias laterais de glicoses nas unidades repetitivas da forma proc??clica e ainda n??o foi caracterizado nas formas metac??clicas. Esses polimorfismos nas unidades repetitivas do LPG e seu papel na intera????o com o hospedeiro vertebrado e invertebrado j?? foram amplamente estudados, sobretudo, para as esp??cies do Velho Mundo. Entretanto, para a maioria das esp??cies do Novo Mundo, o papel desses polimorfismos no perfil imunopatol??gico da doen??a ?? ainda desconhecido. Este projeto teve como objetivo avaliar o estudo da intera????o entre os LPGs de duas esp??cies epidemiologicamente importantes no Brasil e macr??fagos murinos. Estas incluem L. braziliensis e L. infantum, respons??veis pela forma cut??nea e visceral, respectivamente. Neste estudo, os macr??fagos peritoneais de camundongos BALB/c, C57BL/6 e C57BL/6 knock-out (TLR2 -/- e TLR4 -/-), foram primados com IFN-??? e estimulados com LPG de ambas as esp??cies. A produ????o de citocinas (IL-1??, IL-2; IL-4, IL-6, IL-10, IL-12p40, IFN-??? e TNF-??) foi determinada por citometria de fluxo e a concentra????o de nitrito pelo m??todo de Griess. A ativa????o de ERK e p38 foi avaliada por Western blot. Os macr??fagos estimulados com LPG de L. braziliensis, apresentaram uma maior produ????o de TNF-??, IL-1??, IL-6 e NO em compara????o aos estimulados com LPG de L. infantum. Tamb??m foi observada uma cin??tica de ativa????o diferencial das MAPK entre os LPGs. Leishmania infantum apresentou uma ativa????o constante at?? 45 minutos ap??s estimula????o, enquanto L. braziliensis apresentou um ??nico pico de ativa????o ap??s 15 minutos. Estes dados sugerem que varia????es interespec??ficas no LPG de Leishmania podem ter um papel importante nos eventos iniciais do compartimento imune inato do hospedeiro.The structural variations observed on LPG are important for the different parasite developmental stages. The procyclic form of L. braziliensis LPG (strain M2903), is devoid of side chains, while one to two ??-glucose side chains are added in the repeat units of the metacyclic LPG. The L. infantum LPG has with up to 3 glucoses residues in the repeat units in the procyclic parasites, while those structures are not known in the metacyclic stage. Those polymorphisms in the composition and sequence of the sugars branching off the repeat units of the LPG have been assessed in the interaction with vertebrate and invertebrate hosts, especially for the Old World Leishmania species. However, for most of New World species of Leishmania, the role of those polymorphisms in the mmunopathology of the disease is still unknown. This study aimed to evaluate the interaction between the LPGs of two epidemiologically important Brazilian species and murine macrophages. Those include L. braziliensis and L. infantum, causative agents of cutaneous and visceral leishmaniasis, respectivelly. Mice peritoneal macrophages from BALB/c, C57BL/6, and C57BL/6 knock-out (TLR2 -/- e TLR4 -/-) lineages were primed with IFN-??? and stimulated with LPG from both species. Cytokine production (IL-1??, IL-2; IL-4, IL-6, IL-10, IL-12p40, IFN-??? and TNF-??) and nitrite concentration were determined by flow cytometry and Griess reaction, respectivelly. Western blot was performed to evaluate the activation of the MAPKs ERK and p38. Macrophages stimulated with L. braziliensis LPG, had a higher TNF-??, IL-1??, IL-6 e NO production than those stimulated with L. infantum???s. A different MAPK activation kinetics between the two species was detected. Leishmania infantum LPG exhibited a gradual activation profile until 45 min after stimulation, whereas L. braziliensis LPG showed an activation peak at 15 min. These data suggest that interpecies variations in Leishmania LPG may have an important role during initial steps of infection in the host???s innate imune system

Topics: Leishmaniose/genetica, Leishmania/parasitologia, Polimorfismo Gen??tico/gen??tica
Year: 2012
OAI identifier: oai:agregador.ibict.br.RI_FIOCRUZ:oai:localhost:icict/6194
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