Protective Role of 5-Lipoxigenase duringLeishmania infantumInfection Is Associated with Th17 Subset

Sacramento, Laís Amorim; Cunha, Fernando; Almeida, Roque Pacheco de; Silva, João; Carregaro, Vanessa

doi:10.1155/2014/264270

Cited by 22 publications

(20 citation statements)

References 68 publications

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“…In fact, neutrophil influx correlated with the number of Leishmania infantum parasites present at the infection site. We do not rule out the possible role of adaptive immunity cytokines such as IFN-␥ and IL-17 in TLR9-dependent neutrophil recruitment because both are potent neutrophil modulators (30,31). In fact, levels of both Th1 and Th17 subtypes were reduced in the spleens of infected TLR9 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 89%

“…Because both IFN-␥ and IL-17 play a key role in neutrophil recruitment (30,31), we analyzed both Th1 and Th17 T cells in the spleens of infected WT and TLR9 Ϫ/Ϫ mice. Spleen cells from naive WT and TLR9 Ϫ/Ϫ mice at 6 wpi were restimulated in vitro with polyclonal PMA plus ionomycin, and intracellular cytokine production was analyzed.…”

Section: Infantum Upregulates Tlr9 Expression During Infectionmentioning

confidence: 99%

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Toll-Like Receptor 9 Signaling in Dendritic Cells Regulates Neutrophil Recruitment to Inflammatory Foci following Leishmania infantum Infection

et al. 2015

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Leishmania infantum is a protozoan parasite that causes visceral leishmaniasis (VL). This infection triggers dendritic cell (DC)activation through the recognition of microbial products by Toll-like receptors (TLRs). Among the TLRs, TLR9 is required for DC activation by different Leishmania species. We demonstrated that TLR9 is upregulated in vitro and in vivo during infection. We show that C57BL/6 mice deficient in TLR9 expression (TLR9 ؊/؊ mice) are more susceptible to infection and display higher parasite numbers in the spleen and liver. The increased susceptibility of TLR9 ؊/؊ mice was due to the impaired recruitment of neutrophils to the infection foci associated with reduced levels of neutrophil chemoattractants released by DCs in the target organs. Moreover, both Th1 and Th17 cells were also committed in TLR9 ؊/؊ mice. TLR9-dependent neutrophil recruitment is mediated via the MyD88 signaling pathway but is TIR domain-containing adapter-inducing interferon beta (TRIF) independent. Furthermore, L. infantum failed to activate both plasmacytoid and myeloid DCs from TLR9 ؊/؊ mice, which presented reduced surface costimulatory molecule expression and chemokine release. Interestingly, neutrophil chemotaxis was affected both in vitro and in vivo when DCs were derived from TLR9 ؊/؊ mice. Our results suggest that TLR9 plays a critical role in neutrophil recruitment during the protective response against L. infantum infection that could be associated with DC activation. L eishmania intracellular protozoan parasites cause a heterogeneous disease that can range from cutaneous lesions to visceral disease. Visceral disease can be caused by both Leishmania donovani and Leishmania infantum and is the most severe manifestation of this type of parasite infection. Therefore, Leishmania infections remain an important cause of human mortality and morbidity around the world (www.paho.org/english/ad/dpc/cd /res-dch-leish-priorities.pdf).Host defenses against Leishmania spp. depend on the activation of an inflammatory response initiated by the innate immune system (1), followed by specific immune responses mediated by gamma interferon (IFN-␥)-or interleukin-17 (IL-17)-producing CD4 ϩ T lymphocytes (2, 3). The innate immune system has specific mechanisms to rapidly recognize the parasite. A major component of pathogen recognition comprises a family of Toll-like receptors (TLRs) that detect common pathogen-associated molecular patterns (PAMPs) of various groups of microorganisms (4-7), including Leishmania spp. (8, 9).The role of TLRs in Leishmania infection control has been supported by the observations that mice lacking MyD88, an adaptor molecule required for TLR signaling, display enhanced susceptibility to infection (10, 11). It has been described that resistance to Leishmania species infection is dependent on parasite lipophosphoglycan (LPG) recognition by TLR2 (8), the induction of IL-12, and the development of a Th1 immune response (12) together with NO production (13). Previous studies demonstrated a role for TLR2 and TLR3 i...

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Section: Discussionmentioning

confidence: 89%

Section: Infantum Upregulates Tlr9 Expression During Infectionmentioning

confidence: 99%

Toll-Like Receptor 9 Signaling in Dendritic Cells Regulates Neutrophil Recruitment to Inflammatory Foci following Leishmania infantum Infection

et al. 2015

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“…Other T helper cell populations have also been implicated in the immune response to VL, though they are less prominent than Th1 and Tr1 cells. Th17 cells are predominantly associated with protection [183][184][185] . Vaccination using live attenuated L. donovani in mice was able to induce an IL-23 dependent protective Th17 cell response 186 , and Th17 cellassociated cytokine production (IL-17A and IL-22) in human PBMCs has been strongly associated with protection against VL 187 .…”

Section: Th17 Tfh and Th2 Cellsmentioning

confidence: 99%

Characterisation of anti-parasitic CD4+ T cell responses during malaria

Edwards¹

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1 AbstractThe CD4 + T cell response during malaria is critical for control of Plasmodium infection.Unfortunately, this response is commonly dysfunctional or absent in individuals living in malaria endemic regions, and current vaccination efforts have been unable to effectively overcome these short comings. Therefore, a better understanding of host immune responses during Plasmodium infection is required if we are to improve vaccine efficacy and promote long-lived protective immunity. To improve our understanding of the CD4 + T cell response, we assessed changes in the transcriptional profile of these cells, over the course of Plasmodium falciparum infection, in volunteers who had not previously been exposed toPlasmodium, who were taking part in controlled human malaria infection (CHMI) studies.Bioinformatic analysis identified CXCL8 expression as a biomarker of sub-microscopic infection. Additionally, the degree of CXCL8 expression was indicative of initial parasite growth rate. We also identified the emergence of a significant regulatory profile in the CD4 + T cell population which developed with drug-mediated clearance of infection. This profile included checkpoint inhibitors PD-1, LAG-3, TIM-3, and CTLA-4. The degree of PD-1 expression on putative Tr1 (CD49b+ LAG-3+) cells negatively correlated with initial parasite growth rate. However, only PD-1 blockade affected antigen specific expression of the Tr1 cell related cytokines IFNγ and IL-10 by peripheral blood mononuclear cells (PBMCs) from CHMI study volunteers. Another transcriptional change following drug-mediated control was down-regulation of the master transcription factor BACH2. BACH2 plays an important role in T cell homeostasis and facilitates the stability and function of the FOXP3 + regulatory T (Treg) cell population while modulating effector T cell differentiation. Using transgenic mice with T cell specific BACH2 deficiency we showed that BACH2 was an important intrinsic factor in CD4 + T cells during cell differentiation in vitro. In the context of experimental malaria and a second parasitic infection, visceral leishmaniasis (VL), we showed that T cell-specific BACH2 modulated Th2, Th17 and Tfh cell differentiation, and suppressed effector CD4 + T cell responses. However, BACH2 was also important for the expansion and/or maintenance of splenic Treg cells during parasitic infection. Using pathway analysis to further assess the Plasmodium induced change in the transcriptional profile of CD4 + T cells we identified differential regulation of the IL-10 Abstract 42325972 2 signalling pathway after drug-mediated clearance of infection. In a number of parasitic infections, IL-10 signalling is primarily mediated by a FOXP3 -IL-10-producing regulatory CD4 + T (Tr1) cell subset. Tr1 cell frequency has been positively correlated with chronic malaria exposure in Ugandan children, and in mouse models of VL and malaria. We recently reported that Tr1 cells suppressed anti-parasitic immune responses, but also played a key role in preventing immunopathology. To i...

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“…Os relatos recentes da participação da resposta Th17 na resposta imune da LVC corroboram com esses achados (NASCIMENTO et al, 2015a). A resposta Th17 coopera com a resposta Th1 no controle da infecção, porém é também associada ao recrutamento de neutrófilos, liberação de mediadores inflamatórios e exacerbação de doenças inflamatórias como a artrite reumatoide (YAMAGUCHI et al, 2007;RUDENSKY, 2010;SACRAMENTO et al, 2014).…”

Section: A Proliferação De Pbmc Foi Dependente Da Carga Parasitária Nunclassified

“…Além do quadro fibrótico decorrente da exacerbação dos processos inflamatórios, as alterações vasculares e trombocitopenia mediadas por autoanticorpos e a deposição de complexos de anticorpos específicos e inespecíficos como parte da patogênese das nefropatias reforçam a ideia de que a LVC é uma doença imunomediada pelo excesso de imunoestimulação (NIETO et al, 1992;GINEL;CAMACHO;LUCENA, 2008;CORTESE et al, 2009;MORAES, 2009;KOUTINAS, 2014 A imunoativação adequada ocorre quando parasitos inoculados na pele do cão provocam o desencadeamento de um processo inflamatório que é em seguida amplificado pela cascata do sistema complemento ou por cadeias de sinalização deflagradas pelos receptores do tipo toll (TLR) (REIS E SOUSA; SHER; KAYE, 1999;SACRAMENTO et al, 2014). O teor de quimiocinas e citocinas pró inflamatórias como IL-1α, IL-1β e IL-6 proporcionado por neutrófilos, macrófagos, células epiteliais, endoteliais e fibroblastos, presentes no tecido invadido, favorecem o recrutamento e maturação de fagócitos como macrófagos e células dendríticas que fagocitam Leishmania e adquirem características de células apresentadoras de antígeno (APC).…”

Section: Introductionunclassified

Identificação de marcadores genéticos associados às imunidades celular, humoral e aos status clínico e de infecção natural pela Leishmania (Leishmania) infantum em cães

Batista¹

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Por todo amor, dedicação, preparo, incentivo, confiança, pelos exemplos de honestidade, dignidade e pela valorização da busca pelo conhecimento. Vocês foram fundamentais em cada etapa dessa conquista e a razão para nunca pensar em desistir. Aos meus irmãos Manuela e Moisés, sobrinhos, primos, primas, tios e tias Por todo incentivo, amizade, pelas boas energias, pelos exemplos de união, perseverança e pela torcida para que o sucesso dessa etapa fosse alcançado. Ao companheiro Alberto Legutke Pelas demonstrações incondicionais de dedicação, bondade, apoio em momentos decisivos, paciência, companheirismo, pelas ilustrações, por nunca desanimar, pela torcida e comemoração por cada etapa superada. Minha eterna gratidão e companheirismo...

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Protective Role of 5-Lipoxigenase duringLeishmania infantumInfection Is Associated with Th17 Subset

Cited by 22 publications

References 68 publications

Toll-Like Receptor 9 Signaling in Dendritic Cells Regulates Neutrophil Recruitment to Inflammatory Foci following Leishmania infantum Infection

Toll-Like Receptor 9 Signaling in Dendritic Cells Regulates Neutrophil Recruitment to Inflammatory Foci following Leishmania infantum Infection

Characterisation of anti-parasitic CD4+ T cell responses during malaria

<b>Identificação de marcadores genéticos associados às imunidades celular, humoral e aos status clínico e de infecção natural pela <i>Leishmania </i>(<i>Leishmania</i>) <i>infantum</i> em cães</b>

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