Leishmania braziliensis Infection Enhances Toll-Like Receptors 2 and 4 Expression and Triggers TNF-α and IL-10 Production in Human Cutaneous Leishmaniasis

PARTICIPAÇÃO DOS RECEPTORES TOLL-LIKE NA RESPOSTA A INFECÇÃO in vitro POR Leishmania (Viannia) braziliensis: UMA REVISÃO DE LITERATURA

Revista Multidisciplinar em Saúde ◽

10.51161/rems/731 ◽

2021 ◽

Vol 2 (1) ◽

pp. 54

Author(s):

Anna Clara Silva Fonseca ◽

Nathália Brígida de Oliveira ◽

Daniela Camargos Costa

Keyword(s):

Cutaneous Leishmaniasis ◽

Natural Killer ◽

Leishmania Braziliensis ◽

Toll Like Receptors ◽

American Cutaneous Leishmaniasis ◽

Tnf Α ◽

Mucosal Leishmaniasis

Introdução: A Leishmania braziliensis é um protozoário da família Trypanosomatidae responsável pelo desenvolvimento de uma das formas dermotrópicas da doença denominada leishmaniose mucosa (LM). O parasito é intracelular obrigatório e se multiplica dentro dos macrófagos e monócitos de seus hospedeiros. Os receptores tolllike (TLR) são glicoproteínas transmembrana presentes nas células de defesa, principalmente Natural Killer, macrófagos e células dendríticas, que reconhecem estruturas microbianas e que promovem uma série de sinais que produzem citocinas próinflamatórias importantes para que a resposta imune inata seja efetiva, como por exemplo TNF-α, IL-10 e TGF-β. Objetivo: Realizar revisão da literatura a respeito do papel dos receptores Toll-like na resposta à infecção in vitro por L. braziliensis. Material e métodos: Realizado no formato de revisão integrativa, a pesquisa abrangeu artigos científicos das bases de dados SCIELO e PUBMED. Os descritores utilizados foram “American Cutaneous leishmaniasis”, “Leishmania braziliensis”, “mucosal leishmaniasis” e “Toll-like receptors”. Foram selecionados artigos acadêmicos originais, escritos na língua inglesa, que foram publicados no período de 2014 a 2020, obtendo -se 20 artigos. Após a leitura dos títulos e resumos e ao adotar os critérios de exclusão, foram selecionados 12 artigos originais para a presente revisão. Resultados: As pesquisas selecionadas avaliaram 147 pacientes com diagnóstico histopatológico de Leishmaniose Cutânea (LC). Os pacientes que apresentavam LM, concomitantemente possuíam uma maior expressão de células TCD4+, TCD8+, IL-10+ e TGF-β+ em comparação com aqueles que possuíam LC, que expressavam uma menor quantidades dessas citocinas. Em oposição, o TNF-α em pacientes com LC, encontrava-se aumentado se comparada a LM. Na análise relacionada a TLR-2 e TLR-4, houve uma maior expressão em monócitos nos pacientes com LC associadas a L. braziliensis e que o bloqueio dos TRL reduziu as respostas oxidativas das células de pacientes com LC. Conclusão: Diante dos resultados é possível concluir que a maior expressão de TLR-2 e TLR-4 promove a hiper-reatividade de citocinas pró-inflamatórias e consequente pré-disposição para desenvolvimento da doença. Portanto, seu bloqueio é eficaz para redução das lesões. Esse dado demonstra a relação e o papel dos TLR na infecção por L. braziliensis, trazendo importantes esclarecimentos para a resposta imune e desenho vacinal.

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Potential Use of Interleukin-10 Blockade as a Therapeutic Strategy in Human Cutaneous Leishmaniasis

Journal of Immunology Research ◽

10.1155/2015/152741 ◽

2015 ◽

Vol 2015 ◽

pp. 1-5 ◽

Cited By ~ 8

Author(s):

Lucio Roberto Castellano ◽

Laurent Argiro ◽

Helia Dessein ◽

Alain Dessein ◽

Marcos Vinícius da Silva ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Therapeutic Strategy ◽

Interleukin 10 ◽

Leishmania Braziliensis ◽

Soluble Antigen ◽

Innovative Strategies ◽

Host Protection ◽

Human Cutaneous Leishmaniasis ◽

Potential Use ◽

Worse Prognosis

Interleukin-10 overproduction has been associated with worse prognosis in human cutaneous leishmaniasis, while IFN-γ-dependent responses are associated with parasite killing and host protection. Innovative strategies are needed to overcome therapeutic failure observed in endemic areas. The use of monoclonal antibody-based immunotherapy targeting IL-10 cytokine was evaluated here. Partial IL-10 blockade inLeishmania braziliensiswhole soluble antigen-stimulated cells from endemic area CL patients with active or healed lesions and asymptomatic controls was evaluated. Overall decrease in IL-10, IL-4, and TNF-αproduction was observed in all groups of subjects. Only patients with active lesions still produced some levels of TNF-αafter anti-IL-10 stimulation in association withLeishmaniaantigens. Moreover, this strategy showed limited modulatory effects on IFN-γ-dependent chemokine CXCL10 production. Results suggest the potential immunotherapeutic use of partial IL-10 blockade in localized cutaneous leishmaniasis.

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Flow Cytometric Determination of Cellular Sources and Frequencies of Key Cytokine-Producing Lymphocytes Directed against Recombinant LACK and Soluble Leishmania Antigen in Human Cutaneous Leishmaniasis

Infection and Immunity ◽

10.1128/iai.69.5.3232-3239.2001 ◽

2001 ◽

Vol 69 (5) ◽

pp. 3232-3239 ◽

Cited By ~ 88

Author(s):

R. L. A. Bottrel ◽

W. O. Dutra ◽

F. A. Martins ◽

B. Gontijo ◽

E. Carvalho ◽

...

Keyword(s):

T Lymphocytes ◽

Cutaneous Leishmaniasis ◽

Ex Vivo ◽

Protozoan Parasite ◽

Recombinant Antigen ◽

Interleukin 4 ◽

Leishmania Braziliensis ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Ifn Γ

ABSTRACT Leishmaniasis, caused by infection with the protozoan parasiteLeishmania, affects millions of individuals worldwide, causing serious morbidity and mortality. This study directly determined the frequency of cells producing key immunoregulatory cytokines in response to the recombinant antigen Leishmania homolog of receptors for activated kinase C (LACK) and soluble leishmania antigen (SLA), and it determined relative contributions of these antigens to the overall cytokine profile in individuals infected for the first time with Leishmania braziliensis. All individuals presented with the cutaneous clinical form of leishmaniasis and were analyzed for proliferative responses to LACK antigen and SLA, frequency of lymphocyte subpopulations (analyzed ex vivo), and antigen-induced (LACK and SLA) cytokine production at the single-cell level (determined by flow cytometry). The following were determined. (i) The Th1-type response previously seen in patients with cutaneous leishmaniasis is due to gamma interferon (IFN-γ) production by several different sources, listed in order of contribution: CD4+ T lymphocytes, CD4−, CD8− lymphocytes, and CD8+ T lymphocytes. (ii) SLA induced a higher frequency of lymphocytes producing IFN-γ and tumor necrosis factor alpha (TNF-α) than did LACK. (iii) LACK induced an activation of monocyte populations as reflected by an increased percentage of CD14-positive cells. (iv) Neither SLA nor LACK induced detectable frequencies of cells producing interleukin-4 (IL-4) or IL-5. These data demonstrated a multifaceted immune response to SLA in human leishmaniasis involving Th1 CD4+ T lymphocytes (IFN-γ+ and IL-10−/IL-4−), Tc1 CD8+ T cells (IFN-γ+, and IL-10−/IL-4−), and a high frequency of TNF-α-producing lymphocytes. Moreover, it was determined that the recombinant antigen LACK acts as a weak inducer of Th1-type lymphocyte responses compared to SLA.

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Meglumine antimonate treatment enhances phagocytosis and TNF-α production by monocytes in human cutaneous leishmaniasis

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1016/j.trstmh.2012.07.001 ◽

2012 ◽

Vol 106 (10) ◽

pp. 596-603 ◽

Cited By ~ 10

Author(s):

Rosana Regina de Saldanha ◽

Marianna Carminatti Martins-Papa ◽

Raimunda Nonata Ribeiro Sampaio ◽

Maria Imaculada Muniz-Junqueira

Keyword(s):

Cutaneous Leishmaniasis ◽

Tnf Α ◽

Human Cutaneous Leishmaniasis

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Characterization of Neutrophil Function in Human Cutaneous Leishmaniasis Caused by Leishmania braziliensis

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0004715 ◽

2016 ◽

Vol 10 (5) ◽

pp. e0004715 ◽

Cited By ~ 16

Author(s):

Jacilara Conceição ◽

Richard Davis ◽

Pedro Paulo Carneiro ◽

Angela Giudice ◽

Aline C. Muniz ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Neutrophil Function ◽

Leishmania Braziliensis ◽

Human Cutaneous Leishmaniasis

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Blockade of TLR2 and TLR4 Attenuates Inflammatory Response and Parasite Load in Cutaneous Leishmaniasis

Frontiers in Immunology ◽

10.3389/fimmu.2021.706510 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pedro Paulo Carneiro ◽

Andreza S. Dórea ◽

Walker N. Oliveira ◽

Luiz Henrique Guimarães ◽

Claúdia Brodskyn ◽

...

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Cutaneous Leishmaniasis ◽

Parasite Load ◽

Skin Lesions ◽

Innate Immune ◽

Leishmania Braziliensis ◽

Infected Cells ◽

Host Inflammatory Response ◽

Human Cutaneous Leishmaniasis

Human cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by a pronounced inflammatory response associated with ulcer development. Monocytes/macrophages, the main cells harboring parasites, are largely responsible for parasite control. Toll-like receptor (TLR) signaling leads to the transcription of inflammatory mediators, such as IL-1β and TNF during innate immune response. TLR antagonists have been used in the treatment of inflammatory disease. The neutralization of these receptors may attenuate an exacerbated inflammatory response. We evaluated the ability of TLR2 and TLR4 antagonists to modulate host immune response in L. braziliensis-infected monocytes and cells from CL patient skin lesions. Following TLR2 and TLR4 neutralization, decreased numbers of infected cells and internalized parasites were detected in CL patient monocytes. In addition, reductions in oxidative burst, IL-1β, TNF and CXCL9 production were observed. TNF production by cells from CL lesions also decreased after TLR2 and TLR4 neutralization. The attenuation of host inflammatory response after neutralizing these receptors suggests the potential of TLR antagonists as immunomodulators in association with antimonial therapy in human cutaneous leishmaniasis.

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Identification of Potentially DiagnosticLeishmania braziliensis Antigens in Human Cutaneous Leishmaniasis by Immunoblot Analysis

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.7.2.318-321.2000 ◽

2000 ◽

Vol 7 (2) ◽

pp. 318-321 ◽

Cited By ~ 22

Author(s):

Maria Edileuza F. Brito ◽

Mitzi G. Mendonça ◽

Yara M. Gomes ◽

Márcio L. Jardim ◽

Frederico G. C. Abath

Keyword(s):

Antibody Response ◽

Cutaneous Leishmaniasis ◽

Immunosorbent Assay ◽

Indirect Immunofluorescence ◽

Immunoblot Analysis ◽

Enzyme Linked Immunosorbent Assay ◽

Leishmania Braziliensis ◽

American Cutaneous Leishmaniasis ◽

Human Cutaneous Leishmaniasis

ABSTRACT The antibody response in patients with American cutaneous leishmaniasis was analyzed by immunoblotting with soluble and insoluble antigens of Leishmania braziliensis. The recognition of the 27- and/or 30-kDa soluble antigens was considered relevant for the diagnosis of cutaneous leishmaniasis. Immunoblotting was found to be significantly more sensitive and specific than indirect immunofluorescence and enzyme-linked immunosorbent assay.

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Influence of Obesity on Clinical Manifestations and Response to Therapy in Cutaneous Leishmaniasis caused by Leishmania braziliensis

Clinical Infectious Diseases ◽

10.1093/cid/ciab236 ◽

2021 ◽

Author(s):

Tainã Lago ◽

Lucas Carvalho ◽

Mauricio Nascimento ◽

Luiz H Guimarães ◽

Jamile Lago ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Clinical Presentation ◽

Clinical Manifestations ◽

Healing Time ◽

Response To Therapy ◽

Leishmania Braziliensis ◽

Cutaneous Lesions ◽

Cytokine Levels ◽

Cure Rates ◽

The Impact

Abstract Background Cutaneous leishmaniasis (CL) caused by L. braziliensis is characterized by a single ulcer or multiple cutaneous lesions with raised borders. Cure rates below 60% are observed in response to meglumine antimoniate therapy. We investigated the impact of obesity on CL clinical presentation and therapeutic response. Methods A total of 90 age-matched CL patients were included (30 obese, 30 overweight and 30 with normal BMI). CL was diagnosed through documentation of L. braziliensis DNA by PCR or identification of amastigotes in biopsied skin lesion samples. Serum cytokine levels were determined by chemiluminescence. Antimony therapy with Glucantime (20mg/kg/day) was administered for 20 days. Results Obese CL patients may present hypertrophic ulcers rather than typical oval, ulcerated lesions. A direct correlation between BMI and healing time was noted. After one course of Antimony, cure was achieved in 73% of patients with normal BMI, 37% of overweight subjects, yet just 18% of obese CL patients (p<0.01). Obese CL cases additionally presented higher leptin levels than overweight patients or those with normal BMI (p<0.05). Conclusions Obesity modifies the clinical presentation of CL and host immune response, and is associated with greater failure to therapy.

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