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1.
Wien Klin Wochenschr ; 132(1-2): 47-49, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31912288

RESUMO

Leishmaniasis is a severe vector-borne disease with two main clinical forms, visceral leishmaniasis and cutaneous leishmaniasis. Both forms of leishmaniasis are also endemic in Mediterranean countries including the Balkan region from where mainly visceral leishmaniasis is reported. Austrian soldiers returning from Kosovo were screened for anti-Leishmania antibodies to assess the risk of infection during operations. Anti-Leishmania antibodies were detected in more than 20% of the soldiers investigated, which indicates a considerable risk of infection during missions in this area and thus suggests the application of protective measures.


Assuntos
Leishmania , Leishmaniose , Militares , Animais , Áustria , Humanos , Insetos Vetores , Kosovo , Leishmania/imunologia , Leishmaniose/diagnóstico , Leishmaniose/imunologia , Testes Sorológicos
2.
Parasitol Int ; 74: 101997, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31626986

RESUMO

B-cell activating factor (BAFF) is known as a cytokine responsible for survival and activation of B cells. However, involvement of the molecule in IgG antibody production during infection remains elusive. In this study, dependency of antibody production in Leishmania infection on BAFF was examined by using BAFF-knockout (BAFF-KO) mice. When BAFF-KO mice were infected with L. major, there was no significant difference in lesion development or parasite burden from those in infected wildtype mice. In contrast, levels of IgG antibodies to Leishmania crude antigen were lower in BAFF-KO mice, suggesting that antibody production during L. major infection is BAFF-dependent. ELISA using defined leishmanial antigens demonstrated that the influence of BAFF on antibody production during L. major varies depending on antigens; IgG production to tandem repeat proteins were more affected by BAFF than non-repeat antigens. On the contrary, all of the defined antigens tested were strongly affected by BAFF for IgG antibody production during L. donovani infection. These results suggest degree of BAFF contribution to antibody production during infection is variable depending on the type of infection and even on the type of antigen in a given infection. These results may explain contradictory roles of BAFF in antibody production in previous works.


Assuntos
Anticorpos Antiprotozoários/imunologia , Fator Ativador de Células B/imunologia , Imunoglobulina G/imunologia , Leishmaniose/imunologia , Animais , Antígenos de Protozoários/imunologia , Fator Ativador de Células B/genética , Feminino , Leishmania donovani/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
3.
Vet Parasitol ; 274: 108921, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31536867

RESUMO

Dogs are the main domestic reservoir of Leishmania infantum, and in cases of uncontrolled infection, a strong humoral immune response is elicited, which is inefficient against the parasites. Previous studies have suggested that an adequate antigen/antibody ratio, with a moderate prevalence of antigens with respect to the antibodies, could result in the formation of circulating immune complexes (CIC) in canine leishmaniosis (CanL). Deposition of these complexes in tissues has been associated with vasculitis, uveitis, arthritis, dermatitis and especially glomerulonephritis and renal failure. However, little is known about the relationship between the presence of CIC and disease progression. The aim of this study was to evaluate serum CIC level and its correlation with disease severity in infected dogs with different stages of disease and non-infected animals as a control. A total of 60 dogs were included in the study, classified according to the proposed LeishVet classification criteria: healthy non-infected (n = 13); healthy infected (n = 12); sick stage I (n = 9); sick stage II (n = 17); sick stage III (n = 8); and sick stage IV (n = 1). CIC were isolated from serum samples using a modified polyethylene glycol precipitation method, and their levels measured by ELISA and bicinchoninic acid protein assay. A nanoparticle tracking analysis was performed to investigate the relationship between the molecular size distribution of the CIC and disease progression. In conclusion, the results confirmed a positive association between CIC levels, their molecular size and disease progression that suggests a potential use of CIC as biomarkers of CanL.


Assuntos
Complexo Antígeno-Anticorpo/sangue , Doenças do Cão/sangue , Imunofluorescência/veterinária , Leishmaniose/veterinária , Animais , Anticorpos Antiprotozoários/sangue , Biomarcadores/sangue , Doenças do Cão/diagnóstico , Doenças do Cão/imunologia , Doenças do Cão/parasitologia , Cães , Leishmaniose/imunologia , Leishmaniose/patologia
4.
PLoS Negl Trop Dis ; 13(6): e0007500, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31216268

RESUMO

BACKGROUND: Leishmania parasites are transmitted to vertebrate hosts by phlebotomine sandflies and, in humans, may cause tegumentary or visceral leishmaniasis. The role of PKR (dsRNA activated kinase) and Toll-like receptor 3 (TLR3) activation in the control of Leishmania infection highlights the importance of the engagement of RNA sensors, which are usually involved in the antiviral cell response, in the fate of parasitism by Leishmania. We tested the hypothesis that Phlebovirus, a subgroup of the Bunyaviridae, transmitted by sandflies, would interfere with Leishmania infection. METHODOLOGY/PRINCIPAL FINDINGS: We tested two Phlebovirus isolates, Icoaraci and Pacui, from the rodents Nectomys sp. and Oryzomys sp., respectively, both natural sylvatic reservoir of Leishmania (Leishmania) amazonensis from the Amazon region. Phlebovirus coinfection with L. (L.) amazonensis in murine macrophages led to increased intracellular growth of L. (L.) amazonensis. Further studies with Icoaraci coinfection revealed the requirement of the PKR/IFN1 axis on the exacerbation of the parasite infection. L. (L.) amazonensis and Phlebovirus coinfection potentiated PKR activation and synergistically induced the expression of IFNß and IL-10. Importantly, in vivo coinfection of C57BL/6 mice corroborated the in vitro data. The exacerbation effect of RNA virus on parasite infection may be specific because coinfection with dengue virus (DENV2) exerted the opposite effect on parasite load. CONCLUSIONS: Altogether, our data suggest that coinfections with specific RNA viruses shared by vectors or reservoirs of Leishmania may enhance and sustain the activation of host cellular RNA sensors, resulting in aggravation of the parasite infection. The present work highlights new perspectives for the investigation of antiviral pathways as important modulators of protozoan infections.


Assuntos
Infecções por Bunyaviridae/complicações , Coinfecção/imunologia , Suscetibilidade a Doenças , Interferon beta/metabolismo , Interleucina-10/metabolismo , Leishmaniose/imunologia , eIF-2 Quinase/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Leishmania/imunologia , Camundongos Endogâmicos C57BL , Modelos Teóricos , Phlebovirus/imunologia
5.
PLoS Pathog ; 15(6): e1007887, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31233552

RESUMO

Leishmaniasis is a neglected tropical disease affecting millions of individuals worldwide. P2X7 receptor has been linked to the elimination of Leishmania amazonensis. Biological responses evoked by P2X7 receptor activation have been well-documented, including apoptosis, phagocytosis, cytokine release, such as IL-1ß. It was demonstrated that NLRP3 inflammasome activation and IL-1ß signaling participated in resistance against L. amazonensis. Furthermore, our group has shown that L. amazonensis elimination through P2X7 receptor activation depended on leukotriene B4 (LTB4) production and release. Therefore, we investigated whether L. amazonensis elimination by P2X7 receptor and LTB4 involved NLRP3 inflammasome activation and IL-1ß signaling. We showed that macrophages from NLRP3-/-, ASC-/-, Casp-1/11-/-, gp91phox-/- , and IL-1R-/- mice treated with ATP or LTB4 did not decrease parasitic load as was observed in WT mice. When ASC-/- macrophages were treated with exogenous IL-1ß, parasite killing was noted, however, we did not see parasitic load reduction in IL-1R-/- macrophages. Similarly, macrophages from P2X7 receptor-deficient mice treated with IL-1ß also showed decreased parasitic load. In addition, when we infected Casp-11-/- macrophages, neither ATP nor LTB4 were able to reduce parasitic load, and Casp-11-/- mice were more susceptible to L. amazonensis infection than were WT mice. Furthermore, P2X7-/- L. amazonensis-infected mice locally treated with exogenous LTB4 showed resistance to infection, characterized by lower parasite load and smaller lesions compared to untreated P2X7-/- mice. A similar observation was noted when infected P2X7-/- mice were treated with IL-1ß, i.e., lower parasite load and smaller lesions compared to P2X7-/- mice. These data suggested that L. amazonensis elimination mediated by P2X7 receptor and LTB4 was dependent on non-canonical NLRP3 inflammasome activation, ROS production, and IL-1ß signaling.


Assuntos
Inflamassomos/imunologia , Interleucina-1beta/imunologia , Leishmania/imunologia , Leishmaniose/imunologia , Leucotrieno B4/imunologia , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Receptores Purinérgicos P2X7/imunologia , Transdução de Sinais/imunologia , Animais , Inflamassomos/genética , Interleucina-1beta/genética , Leishmaniose/genética , Leishmaniose/patologia , Leucotrieno B4/genética , Macrófagos/parasitologia , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Receptores Purinérgicos P2X7/genética , Transdução de Sinais/genética
6.
Parasite Immunol ; 41(9): e12659, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31173374

RESUMO

AIMS: CD8+ T cells are important in mediating protective responses to intracellular pathogens. However, an uncontrolled response may lead to pathology. The role of CD8+ T cells in different clinical manifestations of human leishmaniasis is controversial and poorly understood. We aim to study the response of CD8+ T cells to the first exposure to different strains of Leishmania, seeking to correlate these findings with clinical manifestations of disease. METHODS AND RESULTS: We have evaluated the expression of granzyme A, inflammatory and anti-inflammatory cytokines, as well as CTLA-4 by human naïve CD8+ T cells exposed to Leishmania braziliensis and two different strains of Leishmania infantum in vitro. We observed that while exposure to L braziliensis induced an inflammatory profile, as measured by the expression of granzyme A, IFN-gamma and IL-17, as well as a higher IFN/IL-10 ratio, exposure to L infantum led to a regulatory profile, as measured by lower IFN/IL-10 ratio and higher expression of CTLA-4. CONCLUSION: These results may help explain why patients with the visceral clinical form present a weaker cellular response and, consequently, a worse outcome of the disease. The use of CTLA-4 checkpoint inhibitors may emerge as a potential immunotherapy to ameliorate the immune response in visceral leishmaniasis patients.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/genética , Leishmania braziliensis/fisiologia , Leishmania infantum/fisiologia , Leishmaniose/imunologia , Leishmaniose/parasitologia , Adulto , Citocinas/imunologia , Feminino , Granzimas/imunologia , Humanos , Interleucina-10/imunologia , Leishmaniose Visceral/imunologia , Masculino , Análise de Componente Principal
7.
Ars pharm ; 60(2): 65-78, abr.-jun. 2019. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-186009

RESUMO

Two of the most important neglected tropical diseases, Chagas disease and leishmaniasis, are caused by protozoan intracellular parasites of the Trypanosomatida order. These infections provoke a high social burden and lead to the death of a large number of patients. The host triggers several immune mechanisms, but in the absence of adequate treatment, the infection becomes chronic and in many cases causes the appearance of serious alterations. T lymphocytes are fundamental cells of the adaptive system and are the main immune elements that orchestrate the cell-to-cell response in the context of intracellular infections. Furthermore, it has been described that continuous and persistent stimulation in response to pathogenic antigens causes loss of antigen-specific functional capacities in the T cell subsets. This process is known as exhaustion. This review explores the results to date of the exhaustion process during chronic infections caused by the trypanosomatid parasites Leishmania spp. and Trypanosoma cruzi. A large amount of evidence shows upregulation of the markers of the exhaustion process, namely, the inhibitory receptors, during these chronic infections. This increased expression is observed in both the CD4+ and CD8+ T cell populations. In parallel, with this increased expression of inhibitory receptors, the loss of antigen-specific functional capacity of these T cells is detected, reducing the lymphoproliferative potential and the ability to produce protective molecules against these parasitic infections, such as Th1-like cytokines, among others. Additionally, a positive correlation between the high coexpression of these inhibitory molecules and the severity of the pathology is demonstrated. Furthermore, T cell populations experience a phenotypic fluctuation in the course of these infections toward the predominance of effector memory subsets with a late or terminal differentiation state


La enfermedad de Chagas y la leishmaniasis, causadas por parásitos protozoarios intracelulares del orden Trypanosomatida, son consideradas dos de las enfermedades tropicales desatendidas más importantes. Estas infecciones conllevan un alto desgaste social, provocando el deterioro de la salud de un gran número de pacientes e incluso su muerte. Los linfocitos T son células fundamentales del sistema adaptativo y son los principales elementos inmunitarios para el control de estas infecciones intracelulares. La presente revisión explora los estudios y resultados obtenidos hasta la fecha del proceso de agotamiento celular durante las infecciones causadas por los parásitos Leishmania spp. y Trypanosoma cruzi. Así, se recoge que la persistente estimulación celular en respuesta a antígenos de estos patógenos conduce a un proceso de pérdida de la capacidad funcional antígeno-específica en las poblaciones de células T CD4+ y CD8+. Numerosos estudios muestran la existencia de una correlación directa entre el nivel de la co-expresión de receptores inhibitorios y la gravedad de estas patologías. Paralelamente, se detecta la pérdida de la capacidad funcional específica de antígeno de estas células T, lo que reduce su potencial linfoproliferativo y su capacidad de producir moléculas protectoras contra estas infecciones. Además, durante el curso de estas infecciones se observa un incremento de la frecuencia de células T de memoria efectora con un grado de diferenciación tardía o terminal


Assuntos
Humanos , Doença de Chagas/imunologia , Leishmaniose/imunologia , Linfócitos T/imunologia , Linfócitos T/parasitologia , Doença Crônica
8.
Vet Parasitol ; 269: 34-41, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31079826

RESUMO

The outcome of infection with Leishmania infantum in dogs is variable, which is thought to be due to the nature of the immune response mounted by the host. As a consequence, the clinical signs and severity of canine leishmaniosis vary between individual dogs. Host immunogenetic factors might play an important role in determining the outcome of infection. The aim of this study was to examine polymorphisms in innate and adaptive immune response genes, to determine whether any of these were associated with susceptibility or resistance to L. infantum infection. Genomic DNA was obtained from two groups: pet dogs in endemic regions of Europe and a group of Beagles exposed to sand fly infection as part of a vaccine study. Genotyping was performed using a SNP (single nucleotide polymorphism) array for selected immune response genes. The first part of the study compared 62 clinical cases with 101 clinically unaffected dogs that were seronegative for Leishmania antibodies. One SNP in the CIITA gene demonstrated a significantly higher minor allele frequency in the case group, compared with the control group at the individual SNP level after permutation, but was not significant after correction for multiple testing. The second part of the study examined 48 Beagle dogs exposed to L. infantum over two transmission seasons. Twenty-seven dogs with a resistant phenotype (no evidence of clinical disease, seronegative at the end of the study period, negative on lymph node culture and only transiently PCR positive in bone marrow) were compared with 21 dogs demonstrating a susceptible phenotype (clinical disease, seropositive, positive lymph node culture and consistently PCR positive in bone marrow). Three SNPs in TLR3, two SNPs in PTPN22 and one SNP in TLR4 and IL1A were associated with the susceptible phenotype in the Beagle group at the individual SNP level after permutation analysis, but were not significant after correction for multiple testing. Further validation of these SNPs is required in a larger cohort of dogs, ideally with extreme phenotypes to confirm an association with the outcome of L. infantum infection.


Assuntos
Resistência à Doença/genética , Doenças do Cão/imunologia , Leishmania infantum/imunologia , Leishmaniose/veterinária , Polimorfismo de Nucleotídeo Único/genética , Psychodidae/parasitologia , Imunidade Adaptativa/genética , Animais , Doenças do Cão/epidemiologia , Doenças do Cão/parasitologia , Cães , Doenças Endêmicas/veterinária , Europa (Continente)/epidemiologia , Imunidade Inata/genética , Leishmania infantum/genética , Leishmaniose/epidemiologia , Leishmaniose/imunologia , Leishmaniose/parasitologia , Reação em Cadeia da Polimerase/veterinária
9.
Acta Parasitol ; 64(3): 645-651, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31111360

RESUMO

PURPOSE: Leishmaniasis, as one of the most important vector-borne and zoonotic diseases, can be seen in different forms and is more prevalent in developing countries worldwide. Due to the absence of effective strategies in its prevention, treatment, and control, investigation of effective control strategies against the disease is necessary. In this research, we evaluated the immunogenicity of a cold-adapted laboratory strain of Leishmania major (LMC) in the mouse model. METHODS: Twenty BALB/c mice were divided into two groups. LMC group received 4 × 106 of LMC strain in 0.5 ml DMEM, and VLM group, as the control group, received 0.5 ml Dulbecco's modified Eagle's medium. Both groups were challenged with virulent L. major 3 weeks after inoculation. RESULTS: The data obtained from the analysis of immune responses and histopathological changes interestingly revealed protection against L. major in immunized mice. Compared with the VLM group, the mice immunized with LMC strain of L. major in the LMC group showed a significant increase in IFN-γ and IgG2a levels (P < 0.05) which are important indexes for Th1-related immune responses. Additionally, significant differences in concentration of IgG1 and IgG total before and after the challenge was observed in LMC group (P < 0.05). Furthermore, the immunized mice showed a significant reduction in mean sizes of skin lesion and liver damage compared to the VLM group. CONCLUSION: Based on the present findings on immunogenicity of LMC strain, it seems this strain is able to induce both humoral and cellular immunity and a significant protection against L. major in the mouse model.


Assuntos
Leishmania major/imunologia , Leishmaniose/imunologia , Leishmaniose/prevenção & controle , Animais , Anticorpos Antiprotozoários/imunologia , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Imunização , Leishmania major/genética , Leishmaniose/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Protozoários/administração & dosagem , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Células Th1/imunologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-31024859

RESUMO

The leishmaniases are a group of diseases caused by Leishmania parasites, which have different clinical manifestations. Leishmania (Leishmania) amazonensis is endemic in South America and causes cutaneous leishmaniasis (CL), which can evolve into a diffuse form, characterized by an anergic immune response. Since the leishmaniases mainly affect poor populations, it is important to understand the involvement of immunonutrition, how the immune system is modulated by dietary nutrients and the effect this has on Leishmania infection. Vitamin D3 (VitD) is an immunonutrient obtained from diet or endogenously synthesized, which suppresses Th1 and Th17 responses by favoring T helper (Th) 2 and regulatory T cell (Treg) generation. Based on these findings, this study aims to evaluate dietary VitD influence on L. (L.) amazonensis experimental infection in C57BL/6 and BALB/c mice. Thus, C57BL/6 and BALB/c VitD deficient (VDD) mice were generated through dietary VitD restriction 45 days prior to infection. Both strains of VDD mice showed a more controlled lesion development compared to mice on a regular diet (Ctrl). There were no differences in serum levels of anti-Leishmania IgG1 and IgG2a, but there was a decrease in IgE levels in BALB/c VDD mice. Although CD4+ T cell number was not changed, the CD4+ IFN-y+ T cell population was increased in both absolute number and percentage in C57BL/6 and BALB/c VDD mice compared to Ctrl mice. There was also no difference in IL-4 and IL-17 production, however, there was reduction of IL-10 production in VDD mice. Together, our data indicate that VitD contributes to murine cutaneous leishmaniasis susceptibility and that the Th1 cell population may be related to the resistance of VDD mice to L. (L.) amazonensis infection.


Assuntos
Hormônios e Agentes Reguladores de Cálcio/deficiência , Colecalciferol/deficiência , Dieta/métodos , Resistência à Doença , Leishmania mexicana/imunologia , Leishmaniose/imunologia , Animais , Modelos Animais de Doenças , Fatores Imunológicos/sangue , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia
11.
Adv Parasitol ; 104: 1-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31030767

RESUMO

Leishmania tropica causes different forms of leishmaniasis in many parts of the world. Animal models can help to clarify the issues of pathology and immune response in L. tropica infections and can be applied to the control, prevention and treatment of the disease. The aim of this article is to summarize published data related to experimental models of this parasite, presenting an overview of the subject. We also present in brief the epidemiology, transmission and human manifestation of L. tropica infection. Mice, rats and hamsters have been used for experimental models of L. tropica infection. Main findings of the published studies show that: (1) Hamsters are the best animal model for L. tropica infection, with the drawback of being outbred hence not suitable for many studies. (2) L. tropica infection causes a non-ulcerative and chronic pathology as cutaneous form in mice and usually visceral form in hamsters. (3) L. tropica infection in mice results in a weaker immune response in comparison to Leishmania major. (4) While the Th1 responses are evoked against L. tropica, Th2 responses do not explain the outcomes of this infection, and IL-10 and TGF-ß are two main suppressive cytokines. (5) The host genotype affects the immune response and disease outcome of L. tropica infection and the dose, strain, routes of inoculation, and sex of the host are among the factors affecting disease outcome of this species.


Assuntos
Interações Hospedeiro-Parasita , Leishmania tropica , Leishmaniose , Animais , Modelos Animais de Doenças , Genótipo , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Leishmaniose/imunologia , Leishmaniose/prevenção & controle , Leishmaniose/terapia , Leishmaniose/transmissão , Fatores Sexuais
12.
Artigo em Inglês | MEDLINE | ID: mdl-30949455

RESUMO

Leishmaniases are neglected diseases that cause a large spectrum of clinical manifestations, from cutaneous to visceral lesions. The initial steps of the inflammatory response involve the phagocytosis of Leishmania and the parasite replication inside the macrophage phagolysosome. Melatonin, the darkness-signaling hormone, is involved in modulation of macrophage activation during infectious diseases, controlling the inflammatory response against parasites. In this work, we showed that exogenous melatonin treatment of BALB/c macrophages reduced Leishmania amazonensis infection and modulated host microRNA (miRNA) expression profile, as well as cytokine production such as IL-6, MCP-1/CCL2, and, RANTES/CCL9. The role of one of the regulated miRNA (miR-294-3p) in L. amazonensis BALB/c infection was confirmed with miRNA inhibition assays, which led to increased expression levels of Tnf and Mcp-1/Ccl2 and diminished infectivity. Additionally, melatonin treatment or miR-30e-5p and miR-302d-3p inhibition increased nitric oxide synthase 2 (Nos2) mRNA expression levels and nitric oxide (NO) production, altering the macrophage activation state and reducing infection. Altogether, these data demonstrated the impact of melatonin treatment on the miRNA profile of BALB/c macrophage infected with L. amazonensis defining the infection outcome.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/metabolismo , Leishmaniose/imunologia , Macrófagos/imunologia , Melatonina/metabolismo , Animais , Células Cultivadas , Quimiocina CCL2/biossíntese , Modelos Animais de Doenças , Feminino , Leishmania/imunologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , MicroRNAs/biossíntese , Óxido Nítrico Sintase Tipo II/biossíntese , Fator de Necrose Tumoral alfa/biossíntese
13.
Artigo em Inglês | MEDLINE | ID: mdl-31032234

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interações Hospedeiro-Patógeno , Leishmania mexicana/imunologia , Leishmania mexicana/metabolismo , Leishmaniose/imunologia , Ativação de Macrófagos , Fosfatidilserinas/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Leishmaniose/patologia , Camundongos , Camundongos Nus , Células Th1/imunologia , Células Th2/imunologia
14.
Mol Biochem Parasitol ; 229: 6-14, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30772424

RESUMO

Leishmaniasis is one of the most significant of the neglected tropical diseases, with 350 million people in 98 countries worldwide living at risk of developing one of the many forms of the disease. During the transmission of the parasite from its vector to the vertebrate host, neutrophils are rapidly recruited to the site of the sandfly bite. Using different strategies, neutrophils can often kill a large number of parasites. However, some parasites can resist neutrophil-killing mechanisms and survive until macrophage arrival at the infection site. One of the strategies for neutrophil-mediated killing is the production of neutrophil extracellular traps (NETs). Because of its ecto-localized nuclease activity, the enzyme 3'-nucleotidase/nuclease (3'NT/NU), present in different Leishmania species, was recently identified as part of a possible parasite escape mechanism from NET-mediated death. Previous studies showed that 3'NT/NU also plays an important role in the establishment of Leishmania infection by generating extracellular adenosine that favors the parasite and macrophage interaction. This study aims to deepen the knowledge about 3'NT/NU, mainly with respect to its nuclease activity that is little studied in the current literature. For this, we cloned, expressed and purified the recombinant La3'NT/NU and have confirmed its contribution to the parasite escape from NET-mediated killing.


Assuntos
Desoxirribonucleases/imunologia , Armadilhas Extracelulares/imunologia , Leishmania/enzimologia , Leishmaniose/imunologia , Neutrófilos/imunologia , Nucleotidases/imunologia , Proteínas de Protozoários/imunologia , Clonagem Molecular , Desoxirribonucleases/genética , Armadilhas Extracelulares/parasitologia , Humanos , Leishmania/genética , Leishmania/imunologia , Leishmaniose/parasitologia , Nucleotidases/genética , Proteínas de Protozoários/genética
15.
J Immunol ; 202(4): 1163-1175, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30635391

RESUMO

Neutrophils, the essential components of the innate immune system, are recruited in large numbers to the pathogen site of entry. Several pathogens induce neutrophil autophagy; however, function of autophagic events during Leishmania parasite infection remain unknown. In this article, we report a finding that is new, to our knowledge, of how Leishmania-induced human polymorphonuclear neutrophil (hPMN) autophagy regulates the silent mode of parasite transfer to macrophages by influencing the engulfment of infected cells. Leishmania infection induced a time-dependent autophagy increase responsive to block by 3-methyladenine but sensitive to ULK1/2 inhibition only after 3 h. This suggested the prevalence of canonical autophagy during later hours, ULK1/2 inhibition being able to block only canonical autophagy. Interaction of Rubicon and Beclin-1 at 1 h postinfection affirmed the prevalence of noncanonical autophagy during early infection. There was a reduction in macrophage uptake of parasite-exposed hPMNs treated with 3-methyladenine or ULK1/2 inhibitor, suggesting the involvement of both noncanonical and canonical autophagy in neutrophil engulfment. Autophagy inducer rapamycin augmented neutrophil engulfment by macrophages. Redistribution of hPMN surface CD47 encouraged neutrophil uptake. Activation of ERK, phosphoinositide 3-kinase, and NADPH oxidase-mediated reactive oxygen species generation were induced after parasite binding. The lpg1-knockout parasites expressing defective lipophosphoglycan did not induce autophagy, indicating that lipophosphoglycan is necessary for interaction with the neutrophils. Autophagy induction was TLR2/4 independent because the receptor blockade did not interfere with infection-induced autophagy. In summary, the engulfment of neutrophils by the macrophages was influenced by the escalation of hPMN autophagy, which is an important event during Leishmania infection.


Assuntos
Autofagia/imunologia , Leishmania donovani/imunologia , Leishmaniose/imunologia , Neutrófilos/imunologia , Antibacterianos/farmacologia , Autofagia/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Neutrófilos/efeitos dos fármacos , Sirolimo/farmacologia
16.
Parasite Immunol ; 41(3): e12540, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29888463

RESUMO

Congenital transmission of leishmaniasis is recognized in cases detected by passive surveillance. Most cases are from low-resource countries, limiting the study of several important aspects of this route of infection, including the offspring's immune response. Studies on natural and experimentally infected animals suggest that parasites might be transmitted to the embryo or foetus at any time during pregnancy. As immune system undergoes sequential stages of development, an infection before the time of self-recognition could lead to central tolerance, making an individual specifically tolerant and susceptible to infection. In the alternative scenario, infection after self-recognition would allow the proper development of T-lymphocyte clones in response to Leishmania antigens, providing resistance to the disease. Newborns undergo a transient period of low expression of several immune surface molecules and a naïve adaptive immune response with no memory, which together might contribute to slow elimination of the parasite over several months. This insight is a proposed independent mechanism of the previously proven T-cell exhaustion and must be investigated. Analyses of infected placenta, cord blood and infant immunity are required for a better understanding of immunity in congenital leishmaniasis infection.


Assuntos
Tolerância Imunológica/imunologia , Transmissão Vertical de Doença Infecciosa , Leishmania/imunologia , Leishmaniose/imunologia , Linfócitos T/imunologia , Feminino , Sangue Fetal/parasitologia , Humanos , Recém-Nascido , Placenta/parasitologia , Gravidez
17.
Acta Trop ; 197: 104855, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30529443

RESUMO

Given the prevalence of cancer and leishmaniasis worldwide, the presence of these two pathologies in the same tissue sample may be merely fortuitous. The clinical outcome of both diseases is under the control of innate and adaptive immunity, and in both cases these progressive diseases are characterized by an impaired host Th1 response. As a consequence, the Th2 cytokine microenvironment occurring in progressive leishmaniasis may potentially promote tumor cell proliferation and vice versa. On the other hand, clinical aspects of subclinical cutaneous or visceral leishmaniasis sometimes closely resemble those observed in various neoplasms thus leading to misdiagnosis. In this review, we present recent findings on the association between leishmaniasis and malignant disorders. Our review includes HIV positive, HIV negative subjects and patients whose HIV status has not been established. Leishmaniasis mimicking a malignant disorder was confirmed and extended to unreported neoplastic disorders including squamous cell carcinoma, T-cell and B-cell lymphoma, oral and intranasal tumors and granulomas. Thus, leishmaniasis should be considered in the differential diagnosis and course of various cancers in Leishmania endemic areas or in patients with travel history to these areas. We also listed recent reports showing that Leishmania can promote cancer development in immunocompromised as well as in immunocompetent patients. The potential mechanisms supporting this promoting effect are discussed.


Assuntos
Leishmaniose/diagnóstico , Neoplasias/diagnóstico , Animais , Carcinógenos , Diagnóstico Diferencial , Erros de Diagnóstico , Doenças do Cão/diagnóstico , Doenças do Cão/imunologia , Doenças do Cão/parasitologia , Cães , Feminino , Infecções por HIV/complicações , Humanos , Hospedeiro Imunocomprometido , Leishmania/imunologia , Leishmaniose/complicações , Leishmaniose/imunologia , Masculino , Neoplasias/complicações , Neoplasias/imunologia , Prevalência , Microambiente Tumoral
18.
Cell Immunol ; 335: 76-84, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30424873

RESUMO

Neutrophils are short-lived phagocytic cells equipped with several receptors for pathogen recognition and phagocytosis and have intracellular and extracellular effector mechanisms that can inactivate pathogens. Leishmaniases are diseases caused by different species of Leishmania that mainly afflicts poorer populations of tropical and subtropical regions and immunocompromised individuals. Thus, the present study aims to investigate the effector response of murine neutrophils to species of Leishmania causing American cutaneous leishmaniasis and zoonotic visceral leishmaniasis by evaluating pattern recognition receptors (PRR) and intracellular and extracellular effector microbicide activity. When exposed to Leishmania parasites, mouse neutrophils produced superoxide, released enzymes in the extracellular space and generated neutrophil extracellular traps, although PRR gene expression is negatively regulated. L. infantum, L. guyanensis, and L. shawi inhibited enzymatic activity, whereas L. amazonensis reduced the emission of extracellular structures. These findings indicate that although neutrophils trigger several microbicide mechanisms, Leishmania parasites can manipulate extracellular effector mechanisms. The present study also provides evidence that neutrophils can internalize parasites by coiling phagocytosis.


Assuntos
Leishmaniose/imunologia , Neutrófilos/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Animais , Linhagem Celular , Citoplasma , Imunidade Inata/imunologia , Leishmania/imunologia , Leishmania/patogenicidade , Leishmaniose/metabolismo , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/metabolismo , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/metabolismo , Camundongos , Neutrófilos/metabolismo , Parasitos , Fagocitose
19.
Int J Biol Macromol ; 126: 392-401, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30584943

RESUMO

Significant advances have been made in understanding the regulation of inflammasomes and its involvement in innate immunity during pathogenic infections. Inflammasome activation is a tightly regulated process that provides defense against pathogenic infection and important for inflammatory response. Very few studies on the involvement of NLRP3 inflammasome protein complex have been reported in leishmanial infections with contradictory results and without much mechanistic insights. However, the role of NLRP3 inflammasome and its components has not been well deciphered in Leishmania donovani infection. Here we report for the first time a detailed mechanism and plausible impairment of caspase 1 activation during L. donovani infection leading to the survival of these parasites inside the host cells. Low mRNA expression of pro-caspase 1 and lack of caspase 1 maturation were observed after infection, hindering the processing of pro-IL-1ß and pro-IL-18 into their mature counter parts. Further, siRNA mediated knock-down of caspase 1 in macrophage cells (THP-1) resulted in significantly higher parasitic burden validating the importance of caspase 1 in the host defense mechanism. Taken together, our data suggests that the parasite inhibits caspase 1 activation to evade the inflammatory nature of pyroptosis.


Assuntos
Caspase 1/metabolismo , Interações Hospedeiro-Parasita , Evasão da Resposta Imune , Leishmania donovani/imunologia , Leishmaniose/imunologia , Humanos , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Espécies Reativas de Oxigênio/metabolismo , Células THP-1 , Células U937
20.
Iran J Immunol ; 15(4): 281-293, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593742

RESUMO

BACKGROUND: Although there have been numerous attempts to develop vaccines for Leishmaniasis, no vaccine can be found against Leishmania in routine use for an effective global vaccination. It seems that one of the reasons for the low efficacy of such vaccines is the lack of a suitable adjuvant. OBJECTIVE: To evaluate the effects of chitosan nanoparticles containing whole Leishmania lysate antigen (WLL) and soluble leishmania antigens (SLA), a first generation Leishmania vaccine, on the type of immune response generated in BALB/c in a murine model of leishmaniasis. METHODS: The optimum coating ratio between the polymer and antigens was determined according to their physico-chemical properties such as particle size and zeta potential. Chitosan nanoparticles were loaded with antigens via ionic gelation method. BALB/c mice were immunized subcutaneously three times with various nanoparticulate and free antigens with 2-week intervals. RESULTS: There was no significant (P > 0.05) difference concerning the footpad thickness of mice immunized with nanoparticulate formulations containing either SLA or WLL during the experiment period; these formulations induced a strong mixed Th1/Th2 type immune response characterized by the production of IFN-γ and IL-4, and high levels of IgG2a IgG1 anti-Leishmania antibody. CONCLUSION: Nanoparticulate formulations (CHT: SLA and CHT: WLL) are not suitable candidates for preferential induction of a pure Th1-type immune response and immunization against Leishmania infection. However, it might be a good strategy in other infectious diseases where a mixed Th1/Th2 immune response is required.


Assuntos
Antígenos de Protozoários/imunologia , Leishmania/imunologia , Vacinas contra Leishmaniose/imunologia , Leishmaniose/imunologia , Células Th1/imunologia , Equilíbrio Th1-Th2 , Células Th2/imunologia , Animais , Anticorpos Antiprotozoários/metabolismo , Células Cultivadas , Quitosana/química , Quitosana/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-4/metabolismo , Vacinas contra Leishmaniose/química , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Vacinação
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