ASPECTOS IMUNOPATOGÊNICOS, CLÍNICOS E FARMACOLÓGICOS DA HANSENÍASE: UMA REVISÃO DE LITERATURA

Hanseníase é uma infecção crônica causada pelo bacilo Mycobacterium lepraelevando a lesões de pele e nervos periféricos. O Brasil trata-se do único país que permanece acima do limite de prevalência de 1 caso/10.000 habitantes. O objetivo do presente artigo é abordar de forma interdisciplinar os principais aspectos imunopatogênicos, clínicos, laboratoriais e farmacológico desta doença, de modo a contribuir para a compreensão da doença. A pesquisa foi realizada através das bases de dado PubMed, Scielo, Lilacs. O diagnóstico da hanseníase, classicamente, é baseado na presença de anestesia em lesões cutâneas, espessamento de nervos periféricos e demonstração do agente etiológico na linfa ou cortes histológicos. Além da baciloscopia e histopatologia, o diagnóstico também pode ser feito pelos teste de Mitsuda e ML-Flow. A doença apresenta amplo espectro clínico, estando intimamente associado à resposta imunológica do hospedeiro. O diagnóstico precoce da hanseníase com o tratamento oportuno, ainda, é o principal ponto para cessar a transmissão e incapacidades. Assim, o reconhecimento precoce da doença é a parte que apresenta, ainda, maior deficiência dentro dos serviços de saúde

Liver accumulation of Plasmodium chabaudi-infected red blood cells and modulation of regulatory T Cell and dendritic cell responses

It is postulated that accumulation of malaria-infected Red Blood Cells (iRBCs) in the liver could be a parasitic escape mechanism against full destruction by the host immune system. Therefore, we evaluated the in vivo mechanism of this accumulation and its potential immunological consequences. A massive liver accumulation of P. c. chabaudi AS-iRBCs (PciRBCs) was observed by intravital microscopy along with an over expression of ICAM-1 on day 7 of the infection, as measured by qRT-PCR. Phenotypic changes were also observed in regulatory T cells (Tregs) and dendritic cells (DCs) that were isolated from infected livers, which indicate a functional role for Tregs in the regulation of the liver inflammatory immune response. In fact, the suppressive function of liver-Tregs was in vitro tested, which demonstrated the capacity of these cells to suppress naive T cell activation to the same extent as that observed for spleen-Tregs. On the other hand, it is already known that CD4+ T cells isolated from spleens of protozoan parasite-infected mice are refractory to proliferate in vivo. In our experiments, we observed a similar lack of in vitro proliferative capacity in liver CD4+ T cells that were isolated on day 7 of infection. It is also known that nitric oxide and IL-10 are partially involved in acute phase immunosuppression; we found high expression levels of IL-10 and iNOS mRNA in day 7-infected livers, which indicates a possible role for these\ud molecules in the observed immune suppression. Taken together, these results indicate that malaria parasite accumulation within the liver could be an escape mechanism to avoid sterile immunity sponsored by a tolerogenic environment.CAPES-FCT grant 258/2010CAPES-IGC grant 04/2012Fundação de Apoio à Pesquisa do Estado de São Paulo – FAPESP grant 2009/53.889-0CAPES-FCT grant 258/2010FCT grant PTDC/EBB-BIO/115514/200

Brazilian Green Propolis: Anti-Inflammatory Property by an Immunomodulatory Activity

The immunomodulatory and anti-inflammatory activities of green propolis extracts from Apis mellifera were investigated using acute and chronic inflammation models. Swiss mice were anesthetized and a cotton pellet granuloma was implanted in subcutaneous tissue. Then the mice were divided into six groups and received apyrogenic water or different propolis extracts by oral route (5 mg/kg). According to the treatment the groups were designated as E1A, E1B, E10, E11, and E12. The control group received apyrogenic water. The treatment was performed by six days when the mice were killed. The blood and the bronchoalveolar lavage (BAL) were collected to measure the leukocyte recruitment. In acute pulmonary inflammation, Balb/c mice received lipopolysaccharide (LPS) of Escherichia coli by intranasal route for three days. Concomitantly the mice received by oral route apyrogenic water (control) or E10 and E11 propolis extracts. BAL was performed to assess the inflammatory infiltrate and cytokine quantification. The results showed that the E11 extract has anti-inflammatory property in both models by the inhibition of proinflammatory cytokines and increase of anti-inflammatory cytokines suggesting an immunomodulatory activity

Role of the inflammasome in the immunopathogenesis of severe malaria.

A síndrome do desconforto respiratório agudo (SDRA) e a malária placentária (MP) são complicações da malária, cujos mecanismos imunopatogênicos pouco compreendidos. Neste trabalho, mostramos que camundongos MyD88-/- e Casp1/11-/- não desenvolveu SDRA, morrendo devido ao quadro de anemia severa associada à hiperparasitemia. Posteriormente, demonstrou-se que, embora a patogênese da doença dependa do inflamassoma AIM2, não depende dos inflamassomas NLRP3 e NLRC4 e do eixo IL1. Em uma segunda etapa do projeto foi mostrado que a progressão da PM são decorrentes da ativação das vias de sinalização TLR4/9/MyD88, mas não do TLR2. Ademais, evidenciou-se a participação dos inflamassomas NLRP3 e AIM2, porém não do NLRC4, nesse processo. Por fim, os dados obtidos sugerem que a ativação dessas vias culmina com a liberação de IL-1β que, ao agir em seu receptor, inibe a expressão de transportadores de aminoácidos e glicose, com consequente disfunção do desenvolvimento do feto em camundongos grávidas com MP. Em conclusão, este trabalho apresenta, pela primeira vez, uma associação entre a ativação da via MyD88 e dos inflamassomas pelo plasmódio e a progressão da SDRA e MP.Acute respiratory distress syndrome (ARDS) and placental malaria (PM) are complications of the malaria, whose the immunopathogenic mechanisms are poorly understood. In that study we showed that MyD88-/- and Casp 1/11-/- mice did not develop ARDS, dying due to severe anemia associated to hyperparasitemia. Subsequently, it was been shown that although such mechanism depends on the AIM2 inflammasome, it does not depend on the NLRP3 and NLRC4 inflammasomes and the IL-1 axis. In a second stage of the project, it should be noted that those complications are due to the activation of the TLR4/9/MyD88 signaling pathways, but not the TLR2. In addition, the participation of the NLRP3 and AIM2 inflammosomes, but not the NLRC4 was shown in that process. Finally, the data suggest that the activation of these pathways culminates with the release of the IL-1β which acts on its receptor inhibiting the amino acid expression and glucose transporters with a consequent dysfunction in the fetal development of pregnant mice with MP. In conclusion, this work makes for the first time an association between the MyD88 pathway activation and inflammasomes by plasmodium and the progression of the ARDS and MP

Leishmaniose visceral humana:: indicação terapêutica e fatores associados à letalidade em uma região endêmica do Nordeste brasileiro

Objetivo: Investigar a associação entre a conduta terapêutica, faixa etária e a letalidade por leishmaniose visceral humana (LVH), em uma região endêmica. Métodos: Foi realizado um estudo descritivo e retrospectivo dos casos autóctones confirmados de LVH em Imperatriz-MA no período de 2007 a 2016. Resultados: O município estudado apresentou uma letalidade 8,4%, para a doença, com aumento ao logo dos anos. A maioria dos pacientes (93,9%) usaram antimoniato de N-metil glucamina como medicamento de primeira escolha e 9,9% apresentavam coinfecção por HIV. Interessantemente, foi identificada uma importante inconformidade terapêutica, considerando os protocolos do Ministério da Saúde do Brasil, especialmente em faixas etárias e condições clínicas associadas a uma maior letalidade por LVH. Conclusão:  O alto índice de uso inadequado de fármacos específicos para LVH sugere a necessidade de reavaliação da abordagem terapêutica da LVH no município, e apontam indícios de sua relação com o aumento da letalidade em grupos específicos

MyD88 signaling is directly involved in the development of murine placental Malaria

Malaria is a widespread infectious disease caused by the parasite Plasmodium. During pregnancy, malaria infection leads to a range of complications that can affect both the mother and fetus, including stillbirth, infant mortality, and low birth weight. In this study, we utilized a mouse model of placental malaria (PM) infection to determine the importance of the protein MyD88 in the host immune response to Plasmodium during pregnancy. Initially, we demonstrated that Plasmodium berghei NK65GFP adhered to placental tissue via chondroitin sulfate A and induced PM in mice with a C57BL/6 genetic background. To evaluate the involvement of MyD88 in the pathology of PM, we performed a histopathological analysis of placentas obtained from MyD88(-/-) and wild-type (WT) mice following infection on the 19th gestational day. Our data demonstrated that the detrimental placental alterations observed in the infected mice were correlated with the expression of MyD88. Moreover, in the absence of this protein, production of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) was significantly reduced in the infected mice. More importantly, in contrast to fetuses from infected WT mice, which exhibited a reduction in body weight, the fetuses from infected MyD88(-/-) mice did not display significant weight loss compared to their noninfected littermates. In addition, we observed a decrement of maternal care associated with malaria infection, which was attenuated in the MyD88-deficient mice. Collectively, the results of this study illustrate the pivotal importance of the MyD88 signaling pathway in the pathogenesis of placental malaria, thus presenting new possibilities for targeting MyD88 in therapeutic interventions.Programa Estratégico de Ciência, Tecnologia & Inovação nas Fundações Estaduais de Saúde (PECTI/AM Saúde), FAPEAMSão Paulo Research Foundation (FAPESP), 2009/53889-0São Paulo Research Foundation (FAPESP), 2009/53256-7São Paulo Research Foundation (FAPESP), 2011/17880-8São Paulo Research Foundation (FAPESP), 2012/02270-2Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES, AUX-PE-PNPD 2751/2010Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES, AUX-PE-PNPD 258/2010Conselho Nacional do Desenvolvimento Científico e Tecnológico - CNPq, 475771/2009-5Conselho Nacional do Desenvolvimento Científico e Tecnológico - CNPq, 404213/201

Therapeutic Potential of Punica granatum and Isolated Compounds: Evidence-Based Advances to Treat Bacterial Infections

Punica granatum Linn has been known for its nutritional and medicinal value since ancient times and is used in the treatment of various pathologies owing to its antibacterial properties. This review reports the results of the most recent studies on the antibacterial effects of P. granatum and its isolated compounds on bacteria of clinical interest. A search in the PubMed, Scopus, Science Direct, and Science Citation Index Expanded (Web of Science) databases was performed, which included articles that evaluated the antibacterial activity of P. granatum extracts and excluded articles that analyzed other microorganisms or nonpathogenic bacteria, as well as theses, dissertations, duplicate articles, and those not fully available. The literature suggests that P. granatum extracts can act on bacteria, such as methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Streptococcus mutans, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. In addition, fruit peel was the most commonly used pharmacogen and methanol, ethanol, and water were the most common solvents for the extraction of bioactive compounds. The antibacterial potential of the methanolic extract of pomegranate peel could be attributed to the presence of active compounds, such as 5-hydroxymethylfurfural, punicic acid, gallic acid, and punicalagin. Thus, there is evidence that these plant extracts, having high polyphenol content, can disrupt the bacterial plasma membrane and inhibit the action of proteins related to antimicrobial resistance. P. granatum shows antibacterial activity against Gram-positive and Gram-negative bacteria, with great potential against multidrug-resistant strains. Further research is needed to clarify the mechanism of action related to this biological activity and investigate the isolated substances that may be responsible for the antibacterial effects