Publications (11) View all
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Article: Type I IFN receptor regulates neutrophil functions and innate immunity to Leishmania parasites.
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ABSTRACT: Type I IFNs exert diverse effector and regulatory functions in host immunity to viral and nonviral infections; however, the role of endogenous type I IFNs in leishmaniasis is unclear. We found that type I IFNR-deficient (IFNAR-/-) mice developed attenuated lesions and reduced Ag-specific immune responses following infection with Leishmania amazonensis parasites. The marked reduction in tissue parasites, even at 3 d in IFNAR-/- mice, seemed to be indicative of an enhanced innate immunity. Further mechanistic analyses indicated distinct roles for neutrophils in parasite clearance; IFNAR-/- mice displayed a rapid and sustained infiltration of neutrophils, but a limited recruitment of CD11b+Ly-6C+ inflammatory monocytes, into inflamed tissues; interactions between IFNAR-/-, but not wild-type (WT) or STAT1-/-, neutrophils and macrophages greatly enhanced parasite killing in vitro; and infected IFNAR-/- neutrophils efficiently released granular enzymes and had elevated rates of cell apoptosis. Furthermore, although coinjection of parasites with WT neutrophils or adoptive transfer of WT neutrophils into IFNAR-/- recipients significantly enhanced infection, the coinjection of parasites with IFNAR-/- neutrophils greatly reduced parasite survival in WT recipients. Our findings reveal an important role for type I IFNs in regulating neutrophil/monocyte recruitment, neutrophil turnover, and Leishmania infection and provide new insight into innate immunity to protozoan parasites.The Journal of Immunology 06/2010; 184(12):7047-56. · 5.79 Impact Factor -
Article: CXCL10 production by human monocytes in response to Leishmania braziliensis infection.
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ABSTRACT: Leishmania (subgenus Viannia) braziliensis is the causative agent of mucocutaneous leishmaniasis (ML) in South America, and ML is characterized by excessive T- and B-cell responses to the parasite. We speculate that the unbalanced production of inflammatory mediators in response to L. braziliensis infection contributes to cell recruitment and disease severity. To test this hypothesis, we first examined the response of peripheral blood mononuclear cells (PBMCs) from healthy volunteers to L. braziliensis infection. We observed that while L. braziliensis infection induced the production of chemokine (C-X-C motif) ligand 10 (CXCL10) and interleukin-10 (IL-10) in human PBMCs and macrophages (MPhis), enhanced expression of CXCL10 and its receptor, chemokine CXC receptor (CXCR3), was predominantly detected in CD14(+) monocytes. The chemoattractant factors secreted by L. braziliensis-infected cells were highly efficient in recruiting uninfected PBMCs (predominantly CD14(+) cells) through Transwell membranes. Serum samples from American tegumentary leishmaniasis (ATL) patients (especially the ML cases) had significantly higher levels of CXCL10, CCL4, and soluble tumor necrosis factor (TNF) receptor II (sTNFRII) than did those of control subjects. Our results suggest that, following L. braziliensis infection, the production of multiple inflammatory mediators by the host may contribute to disease severity by increasing cellular recruitment.Infection and immunity 11/2009; 78(1):301-8. · 4.21 Impact Factor -
Article: Leishmania braziliensis infection induces dendritic cell activation, ISG15 transcription, and the generation of protective immune responses.
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ABSTRACT: Leishmania (Viannia) braziliensis is the causative agent of cutaneous and mucosal leishmaniasis in South America, and the latter is a severe and disfiguring form of the disease. Our understanding of how L. braziliensis parasites interact with dendritic cells (DCs) is limited, partially due to the difficulty in generating axenic amastigotes. In this study, we successfully generated axenic amastigotes of L. braziliensis and used them to test the hypothesis that L. braziliensis infection efficiently triggers innate responses in DCs and the subsequent adaptive immune responses for parasite clearance. This study has revealed unique immunological features of L. braziliensis infection. Firstly, axenic amastigotes showed higher infectivity and the potential to stimulate C57BL/6 (B6) bone marrow-derived dendritic cells to produce IL-12p40 when compared with their promastigote counterparts. Both parasite-carrying and bystander DCs displayed an activated (CD11c(high)CD45RB(-)CD83(+)CD40(+)CD80(+)) phenotype. Secondly, L. braziliensis infection triggered transcription and phosphorylation of STAT molecules and IFN-stimulated gene 15 (ISG15). Finally, the self-healing of the infection in mice was correlated to the expansion of IFN-gamma- and IL-17-producing CD4(+) cells, suggesting the existence of active mechanisms to regulate local inflammation. Collectively, this study supports the view that innate responses at the DC level determine parasite-specific T cell responses and disease outcomes.The Journal of Immunology 07/2008; 180(11):7537-45. · 5.79 Impact Factor -
Article: Patrones de guía-tutela en la interacción entre iguales enre los 2;0 y 3;0 años
Revista de psicología general y aplicada: Revista de la Federación Española de Asociaciones de Psicología, ISSN 0373-2002, Vol. 56, Nº. 3, 2003, pags. 297-309. -
Article: Distinct roles for MyD88 and Toll-like receptor 2 during Leishmania braziliensis infection in mice.
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ABSTRACT: We have previously reported that Leishmania braziliensis infection can activate murine dendritic cells (DCs) and upregulate signaling pathways that are essential for the initiation of innate immunity. However, it remains unclear whether Toll-like receptors (TLRs) are involved in L. braziliensis-mediated DC activation. To address this issue, we generated bone marrow-derived DCs from MyD88(-/-) and TLR2(-/-) mice and examined their responsiveness to parasite infection. While wild-type DCs were efficiently activated to produce cytokines and prime naïve CD4(+) T cells, L. braziliensis-infected MyD88(-/-) DCs exhibited less activation and decreased production of interleukin-12 (IL-12) p40. Furthermore, MyD88(-/-) mice were more susceptible to infection in that they developed larger and prolonged lesions compared to those in control mice. In sharp contrast, the lack of TLR2 resulted in an enhanced DC activation and increased IL-12 p40 production after infection. As such, L. braziliensis-infected TLR2(-/-) DCs were more competent in priming naïve CD4(+) T cells in vitro than were their controls, findings which correlated with an increased gamma interferon production in vivo and enhanced resistance to infection. Our results suggest that while MyD88 is indispensable for the generation of protective immunity to L. braziliensis, TLR2 seems to have a regulatory role during infection.Infection and immunity 05/2009; 77(7):2948-56. · 4.21 Impact Factor
