The Emerging Role of Complement Lectin Pathway in Trypanosomatids: Molecular Bases in Activation, Genetic Deficiencies, Susceptibility to Infection, and Complement System-Based Therapeutics

The innate immune system is evolutionary and ancient and is the pivotal line of the host defense system to protect against invading pathogens and abnormal self-derived components. Cellular and molecular components are involved in recognition and effector mechanisms for a successful innate immune response. The complement lectin pathway (CLP) was discovered in 1990. These new components at the complement world are very efficient. Mannan-binding lectin (MBL) and ficolin not only recognize many molecular patterns of pathogens rapidly to activate complement but also display several strategies to evade innate immunity. Many studies have shown a relation between the deficit of complement factors and susceptibility to infection. The recently discovered CLP was shown to be important in host defense against protozoan microbes. Although the recognition of pathogen-associated molecular patterns by MBL and Ficolins reveal efficient complement activations, an increase in deficiency of complement factors and diversity of parasite strategies of immune evasion demonstrate the unsuccessful effort to control the infection. In the present paper, we will discuss basic aspects of complement activation, the structure of the lectin pathway components, genetic deficiency of complement factors, and new therapeutic opportunities to target the complement system to control infection

A globally occurring indel polymorphism in the promoter of the IFNA2 gene is not associated with severity of malaria but with the positivity rate of HCV

<p>Abstract</p> <p>Background</p> <p>Type I Interferons (IFNs) are well known cytokines which exert antiviral activity, antitumor activity and immunomodulatory effects. Single-nucleotide polymorphisms (SNP) and deletions in the gene coding for <it>IFNA2 </it>have been shown to influence the level of expression <it>in vitro</it>. The indel polymorphism -305_-300delAACTTT showed the strongest effect <it>in vitro</it>. To analyse the worldwide distribution of this polymorphism we analyzed five different populations (586 Vietnamese, 199 Central Africans, 265 Brazilians, 108 Kaingang and 98 Guarani). To investigate a possible association with susceptibility to infectious diseases we determined the polymorphism in malaria patients suffering either mild or severe malaria and in a cohort of hepatitis C virus infected individuals.</p> <p>Results</p> <p>We could detect the indel polymorphism in all populations analysed. There was no association with this polymorphism and the outcome of malaria but we found an increase of this indel polymorphism in hepatitis C virus positive individuals compared to healthy controls (p = 0.014).</p> <p>Conclusion</p> <p>Polymorphisms in genes involved in the interferon pathway have been implicated in the resistance or susceptibility against cerebral malaria and HBV. Here we show that an indel polymorphism, which mediates a disadvantageous effect in HBV patients, may also play a disadvantageous role in HCV infections stressing the importance of a fully functional interferon pathway.</p

Autoimmunity in Chronic Chagas Disease: A Road of Multiple Pathways to Cardiomyopathy?

Chagas disease (CD), a neglected tropical disease caused by the protozoan Trypanosoma cruzi, affects around six million individuals in Latin America. Currently, CD occurs worldwide, becoming a significant public health concern due to its silent aspect and high morbimortality rate. T. cruzi presents different escape strategies which allow its evasion from the host immune system, enabling its persistence and the establishment of chronic infection which leads to the development of chronic Chagas cardiomyopathy (CCC). The potent immune stimuli generated by T. cruzi persistence may result in tissue damage and inflammatory response. In addition, molecular mimicry between parasites molecules and host proteins may result in cross-reaction with self-molecules and consequently in autoimmune features including autoantibodies and autoreactive cells. Although controversial, there is evidence demonstrating a role for autoimmunity in the clinical progression of CCC. Nevertheless, the exact mechanism underlying the generation of an autoimmune response in human CD progression is unknown. In this review, we summarize the recent findings and hypotheses related to the autoimmune mechanisms involved in the development and progression of CCC

MASP-1 and MASP-2 Serum Levels Are Associated With Worse Prognostic in Cervical Cancer Progression

Background: MBL-associated serine proteases (MASP-1, MASP-2, MASP-3, MAp-44, and MAp-19) are key factors in the activation of the lectin pathway of complement. Serum levels of these components have been associated with recurrence and poor survival of some types of cancer, such as colorectal and ovarian cancer. In this investigation, we determined the serum levels of MASP-1, MASP-2, MASP-3, MAp-44, and MAp-19 in patients with cervical cancer and cervical intraepithelial neoplasia (CIN).Methods:A total of 351 women who underwent screening for cervical cancer or treatment at the Erasto Gaertner Cancer Hospital in Curitiba-Brazil, were enrolled in the study. Based on their latest cervical colposcopy-guided biopsy results, they were divided into four groups: CIN-I: n = 52; CIN-II: n = 73; CIN-III: n = 141; and invasive cancer: n = 78. All the serum protein levels were determined by time-resolved immunofluorometric assay (TRIFMA).Results:Patients with invasive cancer presented significantly higher MASP-2, MASP-1, and MAp-19 serum levels than other groups (p &lt; 0.0001; p = 0.012; p = 0.025 respectively). No statistically significant differences in MASP-3 and MAp-44 serum levels were found between the four studied groups. In addition, high MASP-2, MASP-1, and MAp-19 serum levels were significantly associated with poor survival in patients with invasive cancer and relapse (p = 0.002, p = 0.0035 and p = 0.025, respectively).Conclusion:High MASP-2, MASP-1, and MAp-19 serum levels were associated with cervical cancer progression and worse disease prognosis. These novel findings demonstrate the involvement of the serine proteases of the lectin pathway in the pathogenesis of cervical cancer and future investigations should clarify their role in the disease process

Ficolin-1 and Ficolin-3 Plasma Levels Are Altered in HIV and HIV/HCV Coinfected Patients From Southern Brazil

The complement system is a key component of the innate immune system, participating in the surveillance against infectious agents. Once activated by one of the three different pathways, complement mediates cell lysis, opsonization, signalizes pathogens for phagocytosis and induces the adaptive immune response. The lectin pathway is constituted by several soluble and membrane bound proteins, called pattern recognition molecules (PRM), including mannose binding lectin (MBL), Ficolins-1, -2, and -3, and Collectin 11. These PRMs act on complement activation as recognition molecules of pathogen-associated molecular patterns (PAMPs) such as N-acetylated, found in glycoproteins of viral envelopes. In this study, Ficolin-1 and Ficolin-3 plasma levels were evaluated in 178 HIV patients (93 HIV; 85 HIV/HCV) and 85 controls from southern Brazil. Demographic and clinical-laboratory findings were obtained during medical interview and from medical records. All parameters were assessed by logistic regression, adjusted for age, ancestry, and sex. Significantly lower levels of Ficolin-1 were observed in HIV/HCV coinfected when compared to HIV patients (p = 0.005, median = 516 vs. 667 ng/ul, respectively) and to controls (p &lt; 0.0001, 1186 ng/ul). Ficolin-1 levels were lower in males than in females among HIV patients (p = 0.03) and controls (p = 0.0003), but no association of Ficolin-1 levels with AIDS was observed. On the other hand, Ficolin-3 levels were significantly lower in controls when compared to HIV (p &lt; 0.0001, medians 18,240 vs. 44,030 ng/ml, respectively) and HIV/HCV coinfected (p &lt; 0.0001, 40,351 ng/ml) patients. There was no correlation between Ficolin-1 and Ficolin-3 levels and age, HIV viral load or opportunistic infections. However, Ficolin-3 showed a positive correlation with T CD4 cell counts in HIV monoinfected patients (p = 0.007). We provide here the first assessment of Ficolin-1 and−3 levels in HIV and HIV/HCV coinfected patients, which indicates a distinct role for these pattern recognition molecules in both viral infections

Teor de compostos fenólicos e capacidade antioxidante encontrados na casca do maná-cubiu (Solanum sessiliflorum Dunal), cultivado na Mata Atlântica Brasileira / Content of phenolic compounds and antioxidant capacity found in cocona peel (Solanum sessiliflorum Dunal), cultived from Brazilian Atlantic Forest

Solanum sessiliflorum Dunal (maná-cubiu) é um fruto da biodiversidade brasileira cultivado na Mata Atlântica do litoral paranaense, cujo suco é utilizado pela medicina tradicional para redução glicêmica. Embora os estudos com frutos tropicais sejam incentivados para caracterização de compostos bioativos, até o momento não foram encontrados relatos acerca do potencial antioxidante desta etnovariedade cultivada no bioma da Mata Atlântica. Esse trabalho teve como objetivo determinar o teor de compostos fenólicos biodisponíveis e a atividade antioxidante nas partes comestíveis: polpa com sementes (P) e casca (C). Extratos metanólicos do maná-cubiu foram utilizados para determinar o teor fenólico total (TFT), atividade antioxidante pelos métodos de 2,2-difenil-1-picryl-hidrazil (DPPH) com inibição de EC50, redução de ferro (FRAP) e captura radical livre de 2,2'-azinobis (3-etilbenzothiazolina-6-sulfônica) (ABTS). A casca do fruto apresentou maior TFT (p = 0,0001). Entretanto, a capacidade antioxidante das frações avaliadas foi similar pelos métodos DPPH (p = 0,0001) e FRAP (p = 0,0662).   A capacidade antioxidante do fruto se apresentou elevada, sendo necessário uma pequena concentração (19,84 g/ L), para redução de 50% do radical DPPH (IC50). O destaque da fração C no elevado conteúdo de fenólicos e na capacidade antioxidante detectada por ABTS comprovam a importância do consumo do fruto com casca, com ingestão de sua porção comestível integral. Além desse achado, os resultados obtidos apontam para um potencial promissor de utilização do maná-cubiu na prevenção ou remoção de danos oxidativos, justificando parcialmente seu uso tradicional no controle glicêmico