Kárita Cláudia Freitas Lidani

The Complement System: A Prey of Trypanosoma cruzi

Trypanosoma cruzi is a protozoan parasite known to cause Chagas disease (CD), a neglected sickness that affects around 6–8 million people worldwide. Originally, CD was mainly found in Latin America but more recently, it has been spread to countries in North America, Asia, and Europe due the international migration from endemic areas. Thus, at present CD represents an important concern of global public health. Most of individuals that are infected by T. cruzi may remain in asymptomatic form all lifelong, but up to 40% of them will develop cardiomyopathy, digestive mega syndromes, or both. The interaction between the T. cruzi infective forms and host-related immune factors represents a key point for a better understanding of the physiopathology of CD. In this context, the complement, as one of the first line of host defense against infection was shown to play an important role in recognizing T. cruzi metacyclic trypomastigotes and in controlling parasite invasion. The complement consists of at least 35 or more plasma proteins and cell surface receptors/regulators, which can be activated by three pathways: classical (CP), lectin (LP), and alternative (AP). The CP and LP are mainly initiated by immune complexes or pathogen-associated molecular patterns (PAMPs), respectively, whereas AP is spontaneously activated by hydrolysis of C3. Once activated, several relevant complement functions are generated which include opsonization and phagocytosis of particles or microorganisms and cell lysis. An important step during T. cruzi infection is when intracellular trypomastigotes are release to bloodstream where they may be target by complement. Nevertheless, the parasite uses a sequence of events in order to escape from complement-mediated lysis. In fact, several T. cruzi molecules are known to interfere in the initiation of all three pathways and in the assembly of C3 convertase, a key step in the activation of complement. Moreover, T. cruzi promotes secretion of plasma membrane-derived vesicles from host cells, which prevent the activity of C3 convertase C4b2a and thereby may hinder complement. In this review, we aim to present an overview on the strategies used by T. cruzi in order to circumvent the activation of complement and, consequently, its biological effects.

Genotipificação de isolados de Staphylococcus epidermidis provenientes de casos de mastite caprina

To verify the dynamics of antimicrobial resistance in a property in Santa Maria da Boa Vista city - Pernambuco were evaluated 14 Staphylococcus epidermidis isolates from goats with subclinical mastitis. The profile of antimicrobial resistance was determined by disk diffusion test. The genotyping was performed using the marker REP (Repetitive Extragenic Palindromic) - PCR, using RW3A primer, where the degrees of similarity and clustering phenogram were established by means of the Sorensen-Dice coefficient (SD) algorithm UPGMA, program NTSYS-pc, which allowed the identification of 4 patterns of 14 S. epidermidis isolates, being eight in the profile A, four in a profile B, one in profile C and one in profile D. For all groups to penicillin resistance was observed, while for groups A and C this was associated with lincomycin, for group B this was associated with tetracycline.

Plasma levels of pentraxin 3 in patients with spondyloarthritis

Abstract Context: Determining the disease’s inflammatory activity in spondyloarthritis (SpA) is difficult although very important as it is this that drives treatment. Objective: To investigate if plasma pentraxin-3 (PTX3) could act as an inflammatory marker in SpA. Methods: Eighty one SpA patients (11 with psoriatic arthritis (PsoA) and 70 with ankylosing spondylitis (AS)) and 90 gender and age paired controls were studied for plasma PTX3 levels by ELISA. Patients had determinations of disease activity through C reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP. Epidemiological, clinical and treatment data were collected through chart review. Results: SpA patients had lower concentrations of plasma PTX3 than controls (median of 0.95 ng/mL vs 1.64 ng/mL; p < 0.0001). Correlation of PTX3 levels and BASDAI, ASDAS-CPR, CRP levels and ESR could not be found. No differences in PTX3 levels were detected between PSoA and AS patients (p = 0.42). Uveitis, presence of HLA B27, tobacco exposure, age and disease duration did not influence PTX3 levels. Conclusions: PTX3 plasma levels do not reflect disease activity in SpA. However, it probably participates in the ethiopathogenetic process, as it is consumed in these patients.

Human complement receptor type 1 (CR1) protein levels and genetic variants in chronic Chagas Disease

Complement is an essential element in both innate and acquired immunity contributing to the immunopathogenesis of many disorders, including Chagas Disease (CD). Human complement receptor 1 (CR1) plays a role in the clearance of complement opsonized molecules and may facilitate the entry of pathogens into host cells. Distinct CR1 exon 29 variants have been found associated with CR1 expression levels, increased susceptibility and pathophysiology of several diseases. In this study, CR1 plasma levels were assessed by ELISA and CR1 variants in exon 29 by sequencing in a Brazilian cohort of 232 chronic CD patients and 104 healthy controls. CR1 levels were significantly decreased in CD patients compared to controls (p < 0.0001). The CR1 rs1704660G, rs17047661G and rs6691117G variants were significantly associated with CD and in high linkage disequilibrium. The CR1*AGAGTG haplotype was associated with T. cruzi infection (p = 0.035, OR 3.99, CI 1.1-14.15) whereas CR1*AGGGTG was related to the risk of chagasic cardiomyopathy (p = 0.028, OR 12.15, CI 1.13-113). This is the first study that provides insights on the role of CR1 in development and clinical presentation of chronic CD.

Complement Factor H as a potential atherogenic marker in chronic Chagas’ disease

We aimed to investigate the association between plasma levels of complement Factor H (FH) with cardiac involvement, inflammatory and cardiometabolic parameters in patients with chronic Chagas’ disease (CD). FH plasmatic levels were determined in 80 chronic CD patients. Glycaemic index, lipidogram (high‐density lipoprotein cholesterol HDL‐C, low‐density lipoprotein cholesterol LDL‐C, triglycerides and total cholesterol) and Ultrasensitive C‐Reactive Protein (uCRP) values were obtained from medical records. Height, weight, body mass index (BMI) blood pressure and left ventricular ejection fraction (LVEF) were obtained from echocardiography examinations. Comparisons between chronic CD clinical forms were performed using Mann‐Whitney test and correlation Spearman’s test. FH levels were correlated positively with triglycerides (P = .001, r = .39), LDL‐C (P = .009, r = .3), cholesterol (P = .02, r = .28), uCRP (P = .029, r = .31) and BMI (P = .008, r = .34); and negatively with HDL‐C (P = .03, r = −.25) levels. Dyslipidemic patients showed higher FH levels compared to normolipidemic, although no difference for FH levels was observed between chronic CD clinical forms. Alternative pathway of complement may be a link between immune response and metabolic disorders, with important immunoregulatory role in chronic CD.

Complement activation in acute myocardial infarction: An early marker of inflammation and tissue injury?

BACKGROUND Acute myocardial infarction (AMI) is a potentially fatal condition, being a major cause of death worldwide. Ischemia suffered during AMI causes tissue damage, leading to an inflammatory process. Moreover, myocardial injury can generate damage-associated molecular patterns that activate pattern recognition molecules including some complement proteins. METHODS Here we investigated products of complement activation, C3d and soluble C5b9 (sC5b9), as potential biomarkers for myocardial injury and inflammation, as well as serum cytokines (IL-6 and TNF-alpha), alpha-1-acid glycoprotein (AGP), and classical markers of myocardial necrosis (creatine kinase, creatine kinase-MB isoform, myoglobin and troponin-I) in a longitudinal study of patients with AMI (from admission, 6 h and 12 h post admission, and at discharge from hospital). Individuals undergoing cardiac catheterization (CC) with normal coronary arteries and asymptomatics with no history of cardiovascular disease or invasive procedures were included as controls. RESULTS Plasma C3d was higher in AMI at admission, 6 h, 12 h, and discharge vs CC (p < 0.0001; p = 0.0061; p = 0.0081; p = 0.044) and asymptomatic (p = 0.0001 for admission, 6 h and 12 h; p = 0.0002 for discharge). Moreover, sC5b9 was higher only at admission and 6 h vs asymptomatic (p = 0.0031 and p = 0.0019). Additionally, AGP levels were elevated at admission, 6 h, 12 h, and discharge vs asymptomatic (p = 0.0003; p = 0.0289; p = 0.0009, p = 0.0017). IL-6 concentration was low at admission and 6 h and reached a peak at 12 h (p < 0.0001 for all groups). All classical markers of myocardial necrosis presented higher concentration at 6 h. CONCLUSIONS Our results showed that complement activation is an early event in AMI occurring before the elevation of classical markers of myocardial necrosis such as creatine kinase, creatine kinase-MB isoform, myoglobin and troponin-I. These findings indicated C3d and sC5b9 as possible biomarkers for inflammation and tissue damage in AMI.

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 < 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 < 0.0001, medians 18,240 vs. 44,030 ng/ml, respectively) and HIV/HCV coinfected (p < 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.

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.

Serine Proteases in the Lectin Pathway of the Complement System

The complement system plays a crucial role in host defense against pathogen infections and in the recognition and removal of damaged or altered self-components. Complement system activation can be initiated by three different pathways—classical, alternative, and lectin pathways—resulting in a proteolytic cascade, which culminates in multiple biological processes including opsonization and phagocytosis of intruders, inflammation, cell lysis, and removal of immune complexes and apoptotic cells. Furthermore, it also functions as a link between the innate and adaptive immune responses. The lectin pathway (LP) activation is mediated by serine proteases, termed mannan-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with the pattern recognition molecules (PRMs) that recognize carbohydrates or acetylated compounds on surfaces of pathogens or apoptotic cells. These result in the proteolysis of complement C2 and C4 generating C3 convertase (C4b2a), which carries forward the activation cascade of complements, culminating in the elimination of foreign molecules. This chapter presents an overview of the complement system focusing on the characterization of MASPs and its genes, as well as its functions in the immune response.

Visceral Leishmaniasis and Natural Infection Rates of Leishmania in Lutzomyia longipalpis in Latin America

Leishmaniasis, a neglected disease caused by protozoans of the Leishmania genus, is still present in 98 countries with about two million new cases yearly worldwide. It is trans‐ mitted by female phlebotomine sandflies and presents itself as cutaneous, mucocutane‐ ous and visceral clinical forms, depending on the Leishmania species and the parasite‐host relationship. Visceral leishmaniasis (VL) is caused by Leishmania (Leishmania) infantum chagasi, endemic in 12 countries of Latin America, with 90% of the cases reported in Brazil. VL is characterized by irregular bouts of fever, weight loss, hepatosplenomegaly and pancytopenia, being highly fatal with no treatment. The main strategy in limiting the expansion of VL, besides the treatment of human cases, is the control of the vector Lutzomyia longipalpis and its reservoirs. There are only few studies on the natural infection of Leishmania species, especially in relation to its endemic distribution. Epidemiological studies of leishmaniasis may indicate the infection rate of parasites in sandflies in order to assess the populations at risk and to direct public health control strategies. In this con‐ text, we aimed to review the main features of VL with regard the distribution of disease cases and natural infection rates of Leishmania in Lu. longipalpis in Latin America.