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Item Antigenic dietary protein guides maturation of the host immune system promoting resistance to Leishmania major infection in C57BL/6 mice.(2010) Amaral, Joana Ferreira do; Santos, Ana Cristina Gomes; Silva, Josiely Paula; Nicoli, Jacques Robert; Vieira, Leda Quercia; Faria, Ana Maria Caetano de; Silva, Juscilene Menezes daThe immature immune system requires constant stimulation by foreign antigens during the early stages of life to develop properly and to create efficient immune responses against later infections. We have previously shown that intake of antigenic dietary protein is critical for inducing maturation of the immune system as well as for the development of T helper type 1 (Th1) immunity. In this study, we show that administration of an amino acid (aa)-based diet during the development of the immune system subsequently resulted in inefficient control of Leishmania major infection in adult C57BL/6 mice. Compared with mice fed a control protein-containing diet, adult aa-fed mice showed a decreased interferon (IFN)-c response to parasite antigens and insufficient production of nitric oxide (NO), which is crucial to parasite death. However, no deviation towards Th2-specific immunity to L. major was observed. Phenotypic analysis of antigen-presenting cells (APCs) from aa-fed mice revealed deficient levels of the costimulatory molecules CD40 and CD80, and low levels of interleukin (IL)-12 produced by peritoneal macrophages, revealing an early stage of maturation of these cells. APCs isolated from aa-fed mice were unable to stimulate a Th1 response in vitro. Both phenotypic features of T cells from aa-fed mice and their ability to produce a Th1 response in the presence of mature APCs were unaffected when compared with T cells from control mice. The results presented here support the notion that regulation of Th1 immunity to infection includes environmental factors such as dietary proteins, which provide a natural source of stimulation that contributes to the process of maturation of APCs.Item CD8þT cells are not required for vaccine-induced immunity against Leishmania amazonensis in IL-12/23P40_/_ C57BL/6 mice.(2007) Hernández Sanabria, Mayra Xiomara; Afonso, Luís Carlos Crocco; Golgher, Denise; Tafuri, Wagner Luiz; Vieira, Leda QuerciaVaccine-induced protection against leishmaniasis is largely dependent on cell-mediated type 1 response and IL-12-driven IFN-g production. Surprisingly, our previous data showed that IL-12/23p40_/_ mice could be vaccinated against L. amazonensis and were able to produce limited amounts of IFN-g. Since the role of CD8þT in immunization against L. amazonensis is obscure, the aim of this study was to evaluate the effects of CD8þ cells in protection against L. amazonensis in IL-12/23p40_/_ mice. In order to deplete CD8þ cells, one group of vaccinated animals was treated with anti-CD8 mAb. Infection was followed for 8 weeks. The vaccinated CD8þ-depleted group developed smaller lesions than the non-depleted group. CD8 depletion did not affect tissue parasitism or antibody response against the parasite, and treated animals displayed milder inflammation and better tissue integrity. IFN-g production in spleen and draining lymph node was impaired in the depleted group, suggesting that CD8þ cells produced this cytokine in IL-12-independent vaccination. Such results suggest that this T cell subset contributes to augmented pathology in IL12/23p40_/_ mice vaccinated and challenged with L. amazonensis. Although these cells could produce some IFN-g the in the absence of IL-12, they do not affect the parasite tissue load.Item Desenvolvimento e caracterização do modelo de infecção de leishmaniose mucocutânea no camundongo deficientes do receptor 1 do TNF- α e avaliação das lesões cutâneas crônicas nestes animais infectados com L. major após o tratamento com células mononucleares purificadas da medula óssea.(Programa de Pós-Graduação em Ciências Biológicas. Núcleo de Pesquisas em Ciências Biológicas, Pró-Reitoria de Pesquisa e Pós Graduação, Universidade Federal de Ouro Preto., 2012) Almeida, Daniel Manzoni de; Vieira, Leda Quercia; Arantes, Rosa Maria EstevesA leishmaniose é causada por parasitas do gênero Leishmania. A forma mucocutânea da leishmaniose apresenta lesões crônicas com baixo número de parasitas no local da infecção causando uma resposta inflamatória exagerada. Camundongos TNFR1 KO, quando infectados com L. major, conseguem controlar o crescimento do parasita no local da infecção, porém mantém um intenso infiltrado inflamatório quando comparados aos animais selvagens. O objetivo desse estudo foi a caracterização das lesões cutâneas crônicas desenvolvidas nos animais TNFR1 KO infectados por L. major e a análise do efeito da terapia celular nessas lesões. Os camundongos selvagens e TNFR1 KO foram inoculados na pata com L. major e foram acompanhados por 15 semanas de infecção para análise do perfil da imunopatologia desenvolvida. Os resultados mostraram que as lesões crônicas dos camundongos TNFR1 KO infectados por L. major apresentaram níveis elevados de citocinas pró-inflamatórias (IFN-γ, TNF-α e IL-17) e das quimiocinas CCL2 e CCL5 quando comparados aos animais selvagens. A persistência dessas lesões em camundongos TNFR1 KO é devida a um infiltrado inflamatório intenso e persistente, rico de células Ly6G+ e TCD8+ no local da infecção. Para testar a terapia celular, os camundongos TNFR1 KO foram tratados na fase crônica (15 semanas após a infecção) com três preparados de células mononucleares purificadas da medula óssea, semanalmente, por via endovenosa e as análises realizadas um e dois meses após o tratamento. O tratamento com células mononucleares derivadas da medula óssea mostrou eficácia no controle das lesões crônicas dos camundongos TNFR1 KO. Após sete dias da transferência, as células transferidas foram localizadas nas lesões diferenciadas em células CD11c+ e MHCII+; Após um e dois meses dos tratamentos, as lesões reduzidas apresentaram aumento da expressão de IL-10 e diminuição da expressão de IL-17; as análises histológicas mostraram porcentagens reduzidas de células polimorfonucleares nas lesões dos animais tratados com as células quando comparados aos animais tratados com veículo. Esses resultados mostraram que as células mononucleares purificadas da medula óssea promovem o controle das lesões crônicas desenvolvidas em camundongos TNFR1 KO infectados.Item Early infection with Leishmania major restrains pathogenic response to Leishmania amazonensis and parasite growth.(2008) Lombana, Claudia Zuleida Gonzalez; Santiago, Helton da Costa; Macedo, J. P.; Rego, Virgínia Aparecida Seixas; Russo, Remo de Castro; Tafuri, Wagner Luiz; Afonso, Luís Carlos Crocco; Vieira, Leda QuerciaExperimental models of infection with Leishmania spp. have provided knowledge of several immunological events involved in the resistance mechanism used by the host to restrain parasite growth. It is well accepted that concomitant immunity exists, and there is some evidence that it would play a major role in long-lasting acquired resistance to infection. In this paper, the resistance to Leishmania amazonensis infection in C57BL/6 mice infected with Leishmania major was investigated. C57BL/6 mice, which spontaneously heal lesions caused by infection with L. major, were infected with L. amazonensis at different times before and after L. major. We demonstrated that C57BL/6 mice previously infected with L. major restrain pathogenic responses induced by L. amazonensis infection and decrease parasite burdens by one order of magnitude. Coinfected mice showed production of IFN-_ in lesions similar to mice infected solely with L. major, but higher TNF-_ and nitric oxide synthase (iNOS) mRNA expression was observed. Surprisingly, the restrained pathogenic response was not related to IL-10 production, as evidenced by lower levels of both mRNA, protein expression in lesions from co-infected mice and in co-infections in IL-10−/− mice. Examination of the inflammatory infiltrate at the site of infection showed a reduced number of monocytes and lymphocytes in L. amazonensis lesions. Additionally, differential production of the CCL3/MIP-1_ and CCL5/RANTES was observed. We suggest that the control of lesion progression caused by L. amazonensis in C57BL/6 mice pre-infected with L. major is related to the induction of a down-regulatory environment at the site of infection with L. amazonensis.Item Efeitos da atorvastatina sobre a infecção experimental por Leishmania major no camundongo C57BL/6.(Programa de Pós-Graduação em Ciências Biológicas. Núcleo de Pesquisas em Ciências Biológicas, Pró-Reitoria de Pesquisa e Pós Graduação, Universidade Federal de Ouro Preto., 2008) Ferraz, Fernanda Oliveira; Vieira, Leda QuerciaAs estatinas, inibidores da b-hidroxi-b-metil-Co A redutase (enzima que catalisa a etapa limitante da síntese de colesterol e isoprenóides), são fármacos de primeira escolha para o tratamento de hipercolesterolemia. Atualmente, estão entre os medicamentos mais prescritos no mundo e seu uso como agentes profiláticos para doenças cardiovasculares tem sido sugerido. A atorvastatina, extremamente difundida, também é capaz de modular a resposta imunológica clinicamente e em modelos experimentais com efeito imunossupressor e antiinflamatório. Diante do potencial de suprimir a resposta pró-inflamatória Th1, nosso trabalho se concentra no estudo do efeito da atorvastatina sobre a infecção experimental por Leishmania major no camundongo C57BL/6, modelo de resistência a esse protozoário sensível à resposta Th1 desenvolvida nesse hospedeiro. De acordo com nossos resultados, o tratamento favoreceu a proliferação do parasito. O controle do horário de administração do fármaco promoveu um crescimento significativo da lesão na pata indicando que o efeito da atorvastatina no camundongo é modulado pelo ciclo circadiano. A atorvastatina não foi capaz de inibir a polarização da resposta imunológica para o tipo 1, pois a produção das citocinas IFN-g e TNF-a e da quimiocina CCL5/RANTES foi aumentada bem como a atividade de NOS II nos animais tratados. Por outro lado, a estatina induziu a ativação de mecanismos regulatórios da resposta imune como as células CD4+CD25high e conseqüente incremento na produção de TGF-b e IL-10 e na atividade de arginase I. Nossos resultados revelam que o tratamento a longo prazo com atorvastatina prejudica o controle da infecção por L. major no camundongo C57BL/6 e sugerem que a disseminação do uso das estatinas deve ser avaliada com cautela especialmente em populações de áreas endêmicas para parasitoses como a leishmaniose.Item Germ-free mice produce high levels of interferon-gamma in response to infection with Leishmania major but fail to heal lesions.(2005) Oliveira, Marcia Rosa de; Tafuri, Wagner Luiz; Afonso, Luís Carlos Crocco; Oliveira, Milton Adriano Pelli de; Nicoli, Jacques Robert; Vieira, Etel Rocha; Scott, Phillip; Melo, Maria Norma; Vieira, Leda QuerciaIn order to investigate the importance of the host microbiota on differentiation of T cell subsets in response to infection, Swiss/NIH germ-free mice and conventional (microbiota-bearing) mice were infected with Leishmania major, and lesion development, parasite loads, and cytokine production were assessed. Germ-free mice failed to heal lesions and presented a higher number of parasites at the site of infection than their conventional counterparts. In addition, histopathological analysis indicated a higher density of parasitized macrophages in lesions from germ-free mice than in conventional mice. The initial production of interleukin (IL)-12 and interferon-gamma (IFN-c) in germ-free mice was comparable to the conventional controls. Also, germ-free mice produced elevated levels of IFN-c and lower levels of IL-4 throughout the course of infection, suggesting the development of a Th1 response. Macrophages from germ-free mice exposed to IFN-c and infected with amastigotes in vitro were not as efficient at killing parasites as macrophages from conventional animals. These observations indicate that the microbiota is not essential for the development of Th1 immune responses, but seems to be important for macrophage activation.Item Histopathology of Leishmania major infection : revisiting L. major histopathology in the ear dermis infection model.(2009) Cangussú, Silvia Dantas; Souza, Carolina Carvalho de; Campos, Camila França; Vieira, Leda Quercia; Afonso, Luís Carlos Crocco; Arantes, Rosa Maria EstevesWe describe the relationship between lesion outcome and histopathological hallmarks in susceptible (BALB/c) and resistant (C57BL/6 and IL-4-deficient BALB/c) mouse strains over the course of a 12-week-infection with Leishmania major in the ear. The infiltration of mononuclear cells and polymorphonuclear cells occurred within 6 h and mononuclear cells predominated one week post-infection. Permissive intracellular growth of the pathogen was associated with non-healing lesions. In contrast, tissue damage and clearance of the parasite was observed in healing lesions and was associated with inducible nitric oxide synthase expression. The identification of the struc¬tural components of tissue reaction to the parasite in this study furthers our understanding of subjacent immune effector mechanisms.Item Infection with Leishmania major induces interleukin-12 production in vivo.(1994) Vieira, Leda Quercia; Hondowicz, Brian D.; Afonso, Luís Carlos Crocco; Wysocka, Maria; Trinchieri, Giorgio; Scott, PhillipExperimental infections of mice with the protozoan parasite Leishmania major provide an excellent model for defining the conditions required for generation of CD4 ÷ Thl and Th2 cells in vivo. Since interleukin-12 (IL-12) has been implicated in the development of Thl cells, we investigated whether L. major stimulates IL-12 production in vitro or in vivo. Surprisingly, macrophages cultured in vitro failed to produce IL-12 following L. major infection. In contrast, lymph node cells from C3H mice infected for 2 days with L. major produced elevated levels of IL-12. In order to determine if the inability to stimulate IL-12 production was limited to in vitro infections, we infected macrophages in vivo by inoculating L. major into the peritoneal cavity. Peritoneal cells isolated 24 h later exhibited a significant increase in the number of cells producing IL-12. In addition, supernatants harvested from these cells following culture contained elevated levels of IL-12. These data indicate that L. major infection induces increased IL-12 production in mice.Item Influence of normal microbiota on some aspects of the immune response during experimental infection with Trypanosoma cruzi in mice.(2004) Duarte, Rinaldo; Silva, Andréia Marçal da; Vieira, Leda Quercia; Afonso, Luís Carlos Crocco; Nicoli, Jacques RobertTo study the influence of normal associated microbiota on systemic immunological responses during experimental Chagas’ disease, germ-free and conventional NIH Swiss mice were infected with Y strain of Trypanosoma cruzi. Although no statistical differences in mortality and parasitaemia were found, conventional mice showed IFN-ª, TNF-Æ and NO production (P , 0.05) by spleen cell cultures and higher blood levels of immunoglobulins of the IgG2a isotype (P , 0.05) when compared to their germ-free counterparts. Moreover, higher levels of IgG1 were also found in conventional animals. On the other hand, no differences in IL10 production were found between germ-free and conventional mice after infection (P , 0.05). Interestingly, spleen cell cultures from non-infected germ-free mice spontaneously produced higher levels of IL10 than cultures from conventional mice. Moreover, cultures from non-infected germ-free mice responded to T. cruzi antigens with IFN-ª production, contrary to cultures from conventional animals. In conclusion, the presence of the normal microbiota skews the immune response towards production of inflammatory cytokines during experimental infection with T. cruzi in mice. However, the increase in production of cytokines that is linked to resistance to this parasite did not alter the outcome of infection significantly, probably due to high virulence of the Y strain.Item Involvement of the chemokine RANTES (CCL5) in resistance to experimental infection with Leishmania major.(2004) Santiago, Helton da Costa; Oliveira, Carolina Ferreira; Santiago, Luciana; Ferraz, Fernanda Oliveira; Souza, Daniele da Glória de; Freitas, Luiz Antônio Rodrigues de; Afonso, Luís Carlos Crocco; Teixeira, Mauro Martins; Gazzinelli, Ricardo Tostes; Vieira, Leda QuerciaThe expression and putative role of chemokines during infection with Leishmania major in mice were investigated. CCL5 expression correlates with resistance, and blockade of CCL5 rendered mice more susceptible to infection. CCL5 is part of the cascade of events leading to efficient parasite control in L. major infection.Item Lactobacillus delbrueckii UFV-H2b20 increases IFN-γ production and CD39+CD73+ Treg cell numbers in lungs, and protects mice against experimental allergic asthma.(2022) Andrade, Ana Clara Matoso Montuori de; Silva, Ana Elisa Nolasco e; Malacco, Nathalia Luisa Sousa de Oliveira; Vaz, Leonardo Gomes; Afonso, Luís Carlos Crocco; Russo, Remo de Castro; Vieira, Leda Quercia; Santos, Liliane Martins dosAsthma is a disorder characterized by airflow obstruction, inflammation, declining airway function, bronchial hyperresponsiveness and tissue remodelling. Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”. The use of probiotics is becoming increasingly studied and recent evidence has suggested that it may provide therapeutic benefits in asthma and other diseases. Lactobacillus delbrueckii UFV-H2b20 fulfils all the requirements to be classified as probiotic. Previous studies have already shown the ability of L. delbrueckii UFV-H2b20 to stimulate the immune system. Our objective was to evaluate the protective effects of L. delbrueckii UFV-H2b20 in experimental allergic asthma. We used a murine model of ovalbumin-induced allergic airway inflammation to mimic allergic asthma. Oral treatment with L. delbrueckii UFV-H2b20 improves respiratory parameters and inhibits the inflammatory response in the lungs by decreasing the numbers of inflammatory monocytes, eosinophils and alveolar macrophages, as well as IgE levels. Treatment increased the IFN-γ/IL-4 cytokine ratio. Levels of IL-10 in the lungs were also increased in treated animals. Our results also showed that the probiotic administration increases the number of CD39+CD73+ T regulatory lymphocytes in the lung, suggesting a role for purinergic signals in the regulation of inflammation promoted by the treatment. Understanding the mechanisms of modulation of the immune system by probiotics could allow the development of probiotic preparations that are safe and have a direct action. Our results suggest that oral administration of L. delbrueckii UFV-H2b20 could be helpful to treat chronic inflammatory airway diseases, such as asthma.Item Lactobacillus delbrueckii UFV-H2b20 induces type 1 cytokine production by mouse cells in vitro and in vivo.(2009) Neumann, Elisabeth; Ramos, M. G.; Santos, Liliane Martins dos; Rodrigues, Ana Cristina Persichini; Vieira, Enio Carlos; Afonso, Luís Carlos Crocco; Nicoli, Jacques Robert; Vieira, Leda QuerciaItem Leishmania braziliensis : partial control of experimental infection by Interleukin-12 p40 deficient mice.(2004) Souza Neto, Sebastião Martins de; Carneiro, Cláudia Martins; Vieira, Leda Quercia; Afonso, Luís Carlos CroccoResistance to infection by Leishmania major has been associated with the development of a Th1 type response that is dependent on the presence of interleukin 12 (IL-12). In this work the involvement of this cytokine in the response to infection by L. braziliensis, a less virulent species in the mouse model, was evaluated. Our results show that while interferon (IFN-γ) deficient (-/-) mice inoculated L. braziliensis develop severe uncontrolled lesions, chronic lesions that remained under control up to 12 weeks of infection were observed in IL-12p40 -/- mice. IL 12p40 -/- mice had fewer parasites in their lesions than IFN-γ-/- mice. Lymph node cells from IL-12p40 -/- were capable of producing low but consistent levels of IFN-γ suggestive of its involvement in parasite control. Furthermore, as opposed to previous reports on L. major-infected animals, no switch to a Th2 response was observed in IL- 12p40 -/- infected with L. braziliensis.Item Low and high-dose intradermal infection with Leishmania major and Leishmania amazonensis in C57BL/6 mice.(2010) Côrtes, Denise Fonseca; Carneiro, Matheus Batista Heitor; Santos, Liliane Martins dos; Souza, Talita Correia de Oliveira; Maioli, Tatiani Uceli; Duz, Ana Luiza Cassin; Jorge, Maria Letícia Ramos; Afonso, Luís Carlos Crocco; Carneiro, Cláudia Martins; Vieira, Leda QuerciaA model of skin infection with Leishmania amazonensis with low doses of parasites is compared to infection with high doses of L. amazonensis and low and high doses of Leishmania major. C57BL/6 mice were infected with 103 or 106 parasites in the ear and the outcome of infection was assessed. The appearance of lesions in mice infected with 103 parasites was delayed compared to mice infected with 106 Leishmania and parasites were detectable at the infection site before lesions became apparent. Mice infected with L. amazonensis displayed persistent lesions, whereas infection with L. major spontaneously healed in all groups, although lymphocytes persisted at the site of infection after healing. Macrophages persisted only in L. amazonensis-infected mice. High-dose L. amazonensis-infected mice produced lower levels of IFN-γ and TNF than mice infected with L. major. No correlation between the persistence of parasites and IL-10 levels and the production of nitric oxide or urea by macrophages was found. We conclude that infection with low doses of L. amazonensis in the dermis changes the course of infection by delaying the appearance of lesions. However, low-dose infection does not change the outcomes of susceptibility and cytokine production described for subcutaneous infection with high numbers of parasites.Item Miltefosina exerce sua ação leishmanicida através do receptor de PAF.(Programa de Pós-Graduação em Ciências Biológicas. Núcleo de Pesquisas em Ciências Biológicas, Pró-Reitoria de Pesquisa e Pós Graduação, Universidade Federal de Ouro Preto., 2011) Castro, Waldionê de; Vieira, Leda QuerciaA leishmaniose visceral, que pode ser causada pela Leishmania donovani, L. infantum e L. chagasi, é considerada pela Organização Mundial de Saúde (OMS) um dos seis principais problemas de saúde pública mundial, sendo fatal se não for tratada. A miltefosina (hexadecilfosfocolina), que primeiramente foi utilizada como tratamento em pacientes com câncer, vem sendo utilizada como uma droga oral efetiva na leishmaniose visceral. Existe uma semelhança estrutural entre a miltefosina e o fator de ativação de plaquetas (PAF). O PAF age ligando-se ao receptor de PAF (PAFR) presente nas células alvo. O mecanismo pelo qual a droga atua ainda não está bem estabelecido, nossa hipótese é que devido à semelhança estrutural entre PAF e a droga, a miltefosina utilize o receptor de PAF para se ligar à célula. Para testar esta hipótese utilizamos camundongos selvagens e deficientes no PAFR (PAFR-KO). Inicialmente verificamos que macrófagos de camundongos selvagens e de PAFR-KO apresentaram perfil de infecção semelhante quando infectados com L. donovani. Em seguida iniciamos os experimentos com infecções in vitro que revelaram que macrófagos de camundongos selvagens tratados com miltefosina eram mais eficientes no controle do crescimento dos parasitos que macrófagos de camundongos PAFR-KO. Entretanto, o tratamento com miltefosina não provocou a produção de quantidades significativas de óxido nítrico (NO), o que pode indicar um mecanismo citotóxico independente de NO. Ao avaliar a ação da droga sobre a atividade da enzima arginase percebemos que somente com a droga não há alteração da atividade da enzima, mas em associação com IFN-γ e LPS ocorre diminuição de sua atividade. Verificamos que a infecção in vivo com L. donovani não apresentou diferenças na suscetibilidade entre camundongos selvagens e PAFR-KO. Em experimentos in vivo, tratamos camundongos selvagens e PAFR- KO oralmente a partir do 14º dia após a infecção com L. donovani, durante sete dias consecutivos, em doses de 10 e 20mg/kg/dia. Nossos dados mostram que o tratamento de camundongos selvagens levou a uma redução na carga parasitária no fígado e baço destes animais. Interessantemente, camundongos PAFR-KO apresentaram maior carga parasitária nestes órgãos. Nossos resultados indicam que parte da ação leishmanicida da miltefosina é mediada pelo PAFR.Item Obesity impairs resistance to Leishmania major infection in C57BL/6 mice.(2020) Martins, Vinicius Dantas; Campos, Franciele Carolina Silva; Moreira, Felipe Caixeta; Carneiro, Matheus Batista Heitor; Goes, Grazielle Ribeiro; Torres, Lícia; Barbosa, Sara Cândida; Vaz, Leonardo Gomes; Paiva, Nívia Carolina Nogueira de; Carneiro, Cláudia Martins; Vieira, Leda Quercia; Faria, Ana Maria Caetano de; Maioli, Tatiani UceliAn association between increased susceptibility to infectious diseases and obesity has been described as a result of impaired immunity in obese individuals. It is not clear whether a similar linkage can be drawn between obesity and parasitic diseases. To evaluate the effect of obesity in the immune response to cutaneous Leishmania major infection, we studied the ability of C57BL/6 mice fed a hypercaloric diet (HSB) to control leishmaniasis. Mice with diet-induced obesity presented thicker lesions with higher parasite burden and a more intense inflammatory infiltrate in the infected ear after infection with L. major. There was no difference between control and obese mice in IFN-gamma or IL-4 production by auricular draining lymph node cells, but obese mice produced higher levels of IgG1 and IL-17. Peritoneal macrophages from obese mice were less efficient to kill L. major when infected in vitro than macrophages from control mice. In vitro stimulation of macrophages with IL-17 decreased their capacity to kill the parasite. Moreover, macrophages from obese mice presented higher arginase activity. To confirm the role of IL-17 in the context of obesity and infection, we studied lesion development in obese IL-17R-/- mice infected with L. major and found no difference in skin lesions and the leukocyte accumulation in the draining lymph node is redcuced in knockout mice compared between obese and lean animals. Our results indicate that diet-induced obesity impairs resistance to L. major in C57BL/6 mice and that IL-17 is involved in lesion development.Item Regulation of macrophage subsets and cytokine production in leishmaniasis.(2021) Carneiro, Matheus Batista; Vaz, Leonardo Gomes; Afonso, Luís Carlos Crocco; Horta, Maria de Fátima Martins; Vieira, Leda QuerciaMacrophages are host cells for parasites of the genus Leishmania where they multiply inside parasitophorous vacuoles. Paradoxically, macrophages are also the cells responsible for killing or controlling parasite growth, if appropriately activated. In this review, we will cover the patterns of macrophage activation and the mechanisms used by the parasite to circumvent being killed. We will highlight the impacts of the vector bite on macrophage activation. Finally, we will discuss the ontogeny of macrophages that are infected by Leishmania spp.Item Short-term protection conferred by Leishvacin® against experimental Leishmania amazonensis infection in C57BL/6 mice.(2014) Carneiro, Matheus Batista Heitor; Sousa, Louisa Maria de Andrade e; Vaz, Leonardo Gomes; Santos, Liliane Martins dos; Vilela, Luciano; Souza, Carolina Carvalho de; Gonçalves, Ricardo; Tafuri, Wagner Luiz; Afonso, Luís Carlos Crocco; Côrtes, Denise Fonseca; Vieira, Leda QuerciaTo date, there is no vaccine available against human leishmaniasis. Although some vaccination protocols can induce immunity in murine models, they fail to induce protection in humans. The reasons for that remain unclear. The aimof the present study was to characterize the changes in the pattern of the immune response during subcutaneous vaccination with Leishvacin® in mice. We also investigated whether IFN-γ and nitric oxide synthase are indispensable for the protection elicited by the vaccine. C57BL/6 WT vaccinated mice showed smaller lesions and fewer numbers of parasites in footpads until 8 weeks post-infection. Up to this time, they produced higher levels of IFN-γ, IL-2, IL-4, IL-17A and IL-10 and higher specific antibody response than control non-vaccinated mice. Moreover, we showed that IFN-γ, most likely by induction of iNOS expression, is essential for immunity. However, after 12 weeks of infection, we observed loss of difference in lesion size and parasite burden between the groups. Loss of resistancewas associatedwith the disappearance of differences in cytokine patterns between vaccinated and control mice, but not of antibody response, which remained different until a later time of infection. The reversal of resistance to L. amazonensis could not be explained by upregulation of regulatory cytokines. Our data point to a subversion of the host immune response by L. amazonensis even when a protective response was previously induced.Item The effect of iron nutritional status on Trypanosoma cruzi infection in germfree and conventional mice.(1993) Pedrosa, Maria Lúcia; Nicoli, Jacques Robert; Silva, Marcelo Eustáquio; Silva, Marcio Eustáquio; Silva, Marcílio Eustáquio de Castro; Vieira, Leda Quercia; Bambirra, Eduardo Alves; Vieira, Enio Carlos1. Conventional (CV) and gnotobiotic (GN) female CFW mice were infected with the Y strain of Trypanosoma cruzi. 2. After infection, both CV and GN groups received injections of iron-dextran or desferrioxamine. Non-injected mice served as controls. 3. The parasitemia was more intense in iron-dextran-treated mice. 4. The iron levels in serum, liver, and spleen were: (a) not decreased by desferrioxamine and (b) increased by iron-dextran treatments. 5. An increase in leukocyte numbers was observed in all GN and CV groups after infection. 6. There was no difference in total iron binding capacity (TIBC) and iron saturation transferrin (IST) between GN and CV mice before infection. 7. In CV groups, after infection, TIBC was decreased whereas the levels of IST were increased; in GN the opposite occurred. 8. Trypanosome-specific IgG and IgM antibody levels were raised in the GN group but not in the CV group.Item The endogenous cytokine profile and nerve fibre density in mouse ear Leishmania major-induced lesions related to nociceptive thresholds.(2013) Cangussú, Silvia Dantas; Souza, Carolina Carvalho de; Castro, Maria Salete de Abreu; Vieira, Leda Quercia; Cunha, Fernando de Queiroz; Afonso, Luís Carlos Crocco; Arantes, Rosa Maria EstevesSeveral reports have shown that cutaneous leishmaniasis lesions are painless, suggesting that Leishmania infection interferes with pain perception. Comparisons of inflammation-induced hyperalgesia between BALB/c and C57BL/6 mice have been little explored in the literature, and comparative data regarding nociception in leishmaniasis are non-existent. In susceptible BALB/c mice and resistant C57BL/6 mice that were intradermally inoculated with a low dose of Leishmania major in the ear, we investigated the variation in nociception over a 12-wk period post-infection and this variation’s association with the structure of nerve fibres and the presence of endogenous cytokines that are classically considered hyper- or hyponociceptive. Infected BALB/c mice presented susceptibility and severe lesions. Infected C57BL/6 mice exhibited resistance and healing lesions. The immune response involved pro- and anti-inflammatory cytokine secretion, respectively. The infection-induced hypoalgesia in BALB/c mice after wks 9 was accompanied by decreased levels of IL-6 and IL-10 in ear tissue with intact nerves. C57BL/6 mice showed short-lived hyperalgesia in wks 2, which was related to increased local levels of IL-6, KC/CXCL-1, TNF-a and IL-10 and a decrease in nerve density. The increase in pro-inflammatory cytokine IL-6, KC/CXCL-1 and TNF-a levels during hyperalgesia suggested a role for these mediators in afferent nerve sensitisation, which was secondary to the inflammatory damage of nerve fibres stained by PGP 9.5. In contrast, the mechanisms of hypoalgesia may include the downregulation of cytokines, the preservation of the structure of nerve endings, and as yet uninvestigated unidentified differences in neurotransmitter release or a direct role of the parasites in the context of the progressive and permissive inflammatory response of BALB/c mice.