Aspectos evolutivos dos fenômenos imunopatológicos com ênfase na COVID-19 / Evolutionary aspects of immunopathological phenomena with emphasis on COVID-19

A seleção natural é o principal mecanismo da evolução das espécies, e favorece fenótipos com defesas imunes efetivas contra patógenos. Entretanto, há uma grande variação das respostas imunes entre os indivíduos da espécie humana e a ocorrência de fenômenos imunopatológicos. A infecção com o vírus da família Coronaviridae, SARS-CoV-2, responsável pela doença conhecida como COVID-19, induz a respostas imunes inflamatórias exacerbadas e à tempestade de citocinas, nos casos graves. Nesta revisão discutiremos, à luz da Evolução, esse aparente paradoxo entre as respostas imunes, e os três principais fatores que contribuem para a manutenção dos fenótipos hiperativos: o custo-benefício das respostas imunes, a coevolução e a história de vida da espécie.

Natural selection is the main mechanism by which species evolve, and it favors phenotypes associated with an effective immune defense against pathogens. However, human immune responses and the occurrence of immunopathological phenomena vary considerably from individual to individual. Infection with SARSCoV- 2, a virus of the Coronaviridae family causing the disease known as COVID-19, induces exacerbated inflammatory immune responses and cytokine storm in severe cases. In this review, we discuss, in the light of Evolution, this apparent paradox between the immune responses and the 3 main factors contributing to the maintenance of hyperactive phenotypes: the cost-effectiveness of immune responses, coevolution, and the life history of the species.

A cell-culturing system for the study of interaction between macrophages infected with leishmania amazonensis

The cell culture insert system is a culturing system for the study of contact-independent cellular communication. Leishmaniasis is a neglect tropical disease with no vaccines and the available drugs present toxic side effects. Studies on Leishmania interaction with host macrophages aim to develop strategies for parasite control and drug development. The purpose of this study was to evaluate the effects of interaction between non-infected and L. amazonensis-infected human macrophages, by using the cell culture system. The results showed that the infection index was reduced by 56.2% as compared to controls only when infected macrophages were inserted on both sides of the Transwell membranes. An improvement in macrophage viability was also observed in this cell culture. The levels of interleukin-1ß, an inflammatory cytokine, and nitric oxide, a microbicidal molecule, did not increase in L. amazonensis-infected macrophage cultures in the Transwell system; thus other soluble factors were responsible for parasite control

HSP70 of Leishmania amazonensis alters resistance to different stresses and mitochondrial bioenergetics

The 70 kDa heat shock protein (HSP70) is a molecular chaperone that assists the parasite Leishmania in returning to homeostasis after being subjected to different types of stress during its life cycle. In the present study, we evaluated the effects of HSP70 transfection of L. amazonensis promastigotes (pTEX-HSP70) in terms of morphology, resistance, infectivity and mitochondrial bioenergetics. The pTEX-HSP70 promastigotes showed no ultrastructural morphological changes compared to control parasites. Interestingly, the pTEX-HSP70 promastigotes are resistant to heat shock, H2O2-induced oxidative stress and hyperbaric environments. Regarding the bioenergetics parameters, the pTEX-HSP70 parasites had higher respiratory rates and released less H2O2 than the control parasites. Nevertheless, the infectivity capacity of the parasites did not change, as verified by the infection of murine peritoneal macrophages and human macrophages, as well as the infection of BALB/c mice. Together, these results indicate that the overexpression of HSP70 protects L. amazonensis from stress, but does not interfere with its infective capacity.

Potential utility of hyperbaric oxygen therapy and propolis in enhancing the leishmanicidal activity of glucantime / A utilidade da terapia de oxigenação hiperbárica e própolis em potencializar a atividade leishmanicida do glucantime

In this study we investigated the efficacy of hyperbaric oxygen (HBO) therapy, alone or combined with the pentavalent antimonial glucantime on Leishmania amazonensis infection. In parallel, the effect of Brazilian red propolis gel (propain) alone or combined with glucantime on L. amazonensis infection was evaluated. The inhibition of the infection in macrophages treated with glucantime in combination with HBO exposition was greater than that of macrophages treated with glucantime alone or HBO alone. The susceptible mouse strain BALB/c infected in the shaved rump with L. amazonensis treated with glucantime and exposed to HBO showed: time points in the course of the disease in which lesions were smaller than those of mice treated with glucantime alone and revascularization of the skin in the lesion site; interferon-gamma (IFN-g) levels were not elevated in lymph node cells from these animals. Propain alone was not efficient against lesions, although less exudative lesions were observed in animals treated with propain alone or combined with glucantime. These results reveal the potential value of HBO and red propolis in combination with glucantime for treating cutaneous leishmaniasis and encourage further studies on the effect of more aggressive HBO, propolis and glucantime therapies on different mouse models of leishmaniasis.

Nesse trabalho foi avaliada a eficácia da terapia da oxigenação hiperbárica (HBO), aplicada em combinação ou não com o tratamento com glucantime, durante a infecção com Leishmania amazonensis. O efeito de gel da própolis vermelha de origem brasileira (propaina) aplicado em combinação ou não com o tratamento com glucantime, também foi avaliado durante infecção com esse parasita. A inibição da infecção de macrófagos tratados com glucantime em combinação com HBO foi maior que a de macrófagos tratados apenas com glucantime ou HBO. A linhagem murina susceptível, BALB/c, infectada no dorso com L. amazonensis, tratada com glucantime e exposta a HBO, mostrou durante o curso da doença, fases em que as lesões eram menores do que a de camundongos apenas tratados com glucantime; observou-se revascularização da pele da lesão e baixa produção de interferon-gama em células de linfonodos desses animais. O tratamento com propaina não foi eficiente na cura das lesões, apesar de lesões menos exsudativas serem observadas em animais tratados com propaina ou propaina combinada ao tratamento com glucantime. Os resultados demonstram que tanto HBO como a própolis vermelha em combinação com glucantime, são promissoras no tratamento da leishmaniose cutânea. Novos estudos devem ser realizados para avaliar tratamentos e outros protocolos em diferentes modelos murinos da leishmaniose.

Effects of Brazilian propolis on Leishmania amazonensis

Leishmaniasis, an endemic parasitosis that leads to chronic cutaneous, mucocutaneous or visceral lesions, is part of those diseases, which still requires improved control tools. Propolis has shown activities against different bacteria, fungi, and parasites. In this study we investigated the effect of four ethanolic extracts of typified propolis collected in different Brazilian states, on Leishmania amazonensis performing assays with promastigote forms, extracellular amastigotes, and on infected peritoneal macrophages. Ethanolic extracts of all propolis samples (BRG, BRPG, BRP-1, and BRV) were capable to reduce parasite load as monitored by the percentage of infected macrophages and the number of intracellular parasites. BRV sample called red propolis, collected in the state of Alagoas, and containing high concentration of prenylated and benzophenones compounds, was the most active extract against L. amazonensis. The anti-Leishmania effect of BRV sample was increased in a concentration and time dependent manner. BRV treatment proved to be non-toxic to macrophage cultures. Since BRV extract at the concentration of 25 æg/ml reduced the parasite load of macrophages while presented no direct toxic to promastigotes and extracellular amastigotes, it was suggested that constituents of propolis intensify the mechanism of macrophage activation leading to killing of L. amazonensis. Our results demonstrate, for the first time, that ethanolic extracts of Brazilian propolis reduce L. amazonensis infection in macrophages, and encourage further studies of this natural compound in animal models of leishmaniasis.

Intracellular Leishmania amazonensis killing induced by the guanine nucleoside 8-bromoguanosine

Neste trabalho, nos investigamos o efeito da 8-Bromoguanosina, um composto imunoestimulador, na citotoxicidade de macrofagos infectados com Leishmania amazonensis em um sistema in vitro. Os resultados mostraram que macrofagos tratados com 8-Bromoguanosina pre- ou pos-infeccao foram capazes de reduzir a carga parasitaria, monitorada pelo numero de amastigotas por macrofago e a percentagem de celulas infectadas (i.e. indice fagocitico). Sendo a 8-Bromoguanosina inocua para promastigotas, concluimos que o composto induz ativacao celular. Os macrofagos produziriam interferon alfa e beta e teriam seus mecanismos leishmanicidas estimulados. Esses resultados sugerem que compostos como a 8-Bromoguanosina (ribonucleosideos de guanina) podem auxiliar no tratamento contra patogenos intracelulares

Imunoestimuladores: potencial para o tratamento de imunodepressões e doenças infecciosas / Immunostimulants: potential for immunodepression and treatment of infectious diseases

No presente trabalho, revisamos os agentes que restauram e ampliam a habilidade do sistema imunológico de reagir contra uma gama de patógenos e tumores, e que também aumentam a imunogenicidade das vacinas. As várias condições patológicas causadas pelo inadequado funcionamento do sistema imune, tais como as imunodeficiencias congênitas e adquiridas (exemplificadas pela AIDS), aumentaram a importância de pesquisas na área de imunoestimulantes. Moléculas de origem endógena e compostos naturais e sintéticos são descritos nesta revisão. Enfase especial é dada à origem, à estrutura química e às principals atividades imunológicas de dois imunoestimuladores: produtos de origem bacteriana e derivados de ácidos nucléicos. As perspectives de uso desses compostos na clínica são também discutidos

Casos de leishmaniose tegumentar americana por Leishmania (Viannia) braziliensis nos Municípios de Cosmópolis e Indaiatuba-regiäo de Campinas, Estado de Säo Paulo, Brasil / Cases of mucocutaneous leishmaniasis due to Leishmania (Viannia) braziliensis from Cosmópolis and Indaituba municipalities - Campinas region, State of Säo Paulo, Brazil

A study was carried out to identify Leishmania species involved in skin lesions of patients from Cosmópolis and Indaiatuba, State of Säo Paulo, Brazil. The epidemiological data of cutaneous leishmaniasis in two cities suggested a epidemic situation in 1994. The lesions were clinically characteristic of cutaneous leishmaniasis and five out six patients responded positively to Montenegro's intradermal test. The histopathology of skin lesions were characterized by two patterns: exudative-cellular reaction and exudative granulomatous reaction. The clinical and histopathological parameters suggested Leishmania (Viannia) braziliensis as the possible etiologic agent. In agreement, it was difficult to isolate and maintain the parasite in the laboratory. Characterization by in situ hybridization with kDNA amastigotes from lesions fragments confirmed that Leishmania (Viannia) braziliensis was the parasite responsible for the studied cutaneous lesions.

Moderna visäo da evoluçäo da virulência / A modern view of the evolution of virulence

Atualmente considera-se que parasitas devem evoluir em direçäo à virulência reduzida, pois patógenos virulentos apresentam maiores probabilidades de levarem seus hospedeiros e eles próprios à extinçäo. A virulência é assim considerada estágio primitivo da associaçäo parasita-hospedeiro. A validade dessas idéias tem sido questionada. Portanto, fez-se revisäo dos estudos recentes que sugerem que parasitas näo evoluem necessariamente em direçäo à reduzida virulência. Do ponto de vista da medicina darwinista, na evoluçäo da virulência podem haver muitas trajetórias coevolutivas possíveis, que dependeräo da história natural do parasita, do comportamento do hospedeiro e da via de transmissäo