Immunity to Protozoan Parasites

Protozoan parasites cause several diseases, such as Malaria, Leishmaniasis, and Trypanosomiasis, hampering human development worldwide. Many protozoa cause infections that often follow chronic courses, owing to coevolution between parasites and host immune system. The survival and transmission of pathogenic protozoa depends on their ability to evade or subvert host’s innate and adaptive immune responses. A great challenge to research in immunology and parasitology is the development of strategies that favor immunity against protozoan parasites and prevent their evasion, chronic, or recurrent infections and associated pathologies. This special issue includes original papers and reviews that summarize current advances in our understanding on the mechanisms of immunity to protozoan parasites in humans and experimental animal models.Fil: Lopes, Marcela F. Universidade Federal do Rio de Janeiro; BrazilFil: Zamboni, Dario S. Faculdade de Medicina de Ribeirao Preto. Universidade de Sao Paulo; BrazilFil: Luján, Hugo Daniel. Universidad Católica de Córdoba. Facultad de Ciencias de la Salud; ArgentinaFil: Rodrigues, Mauricio M. , Escola Paulista de Medicina; Brazi

Shifting Macrophage Phenotypes in Leishmaniasis

Macrophage phenotypes, such as macrophage (M) 1 (classically activated macrophage) and M2 (alternatively activated macrophage), determine the macrophage role as an effector immune cell or as a permissive host for the intracellular pathogenic protozoan Leishmania spp. Leishmania parasites and the host immune system shape macrophage phenotypes, which in turn can help parasite control or promote infection. Here, we discussed how shifting macrophage phenotypes might change disease outcome in leishmaniasis, by addressing: (1) macrophage phenotypes in leishmaniasis; (2) the functional phenotypes of resident and inflammatory macrophages; (3) the interplay with neutrophils modulates macrophage function; (4) the crosstalk with T cells shapes macrophage phenotypes; and (5) potential therapeutic tools to skew macrophage phenotypes and disease outcomes

Immunopathogenesis in Trypanosoma cruzi infection: a role for suppressed macrophages and apoptotic cells

During Trypanosoma cruzi infection, macrophages phagocytose parasites and remove apoptotic cells through efferocytosis. While macrophage 1 (M1) produces proinflammatory cytokines and NO and fights infection, M2 macrophages are permissive host cells that express arginase 1 and play a role in tissue repair. The regulation of M1 and M2 phenotypes might either induce or impair macrophage-mediated immunity towards parasite control or persistence in chronic Chagas disease. Here, we highlight a key role of macrophage activation in early immune responses to T. cruzi that prevent escalating parasitemia, heart parasitism, and mortality during acute infection. We will discuss the mechanisms of macrophage activation and deactivation, such as T cell cytokines and efferocytosis, and how to improve macrophage-mediated immunity to prevent parasite persistence, inflammation, and the development of chagasic cardiomyopathy. Potential vaccines or therapy must enhance early T cell-macrophage crosstalk and parasite control to restrain the pathogenic outcomes of parasite-induced inflammation in the heart

Sapropterin dihydrochloride therapy in dihydropteridine reductase deficiency: Insight from the first case with molecular diagnosis in Brazil

Tetrahydrobiopterin (BH$_{4}$) is a cofactor that participates in the biogenesis reactions of a variety of biomolecules, including l-tyrosine, l-3,4-dihydroxyphenylalanine, 5-hydroxytryptophan, nitric oxide, and glycerol. Dihydropteridine reductase (DHPR, EC 1.5.1.34) is an enzyme involved in the BH$_{4}$ regeneration. DHPR deficiency (DHPRD) is an autosomal recessive disorder, leading to severe and progressive neurological manifestations, which cannot be exclusively controlled by l-phenylalanine (l-Phe) restricted diet. In fact, the supplementation of neurotransmitter precursors is more decisive in the disease management, and the administration of sapropterin dihydrochloride may also provide positive effects. From the best of our knowledge, there is limited information regarding DHPRD in the past 5 years in the literature. Here, we describe the medical journey of the first patient to have DHPRD confirmed by molecular diagnostic methods in Brazil. The patient presented with two pathogenic variants of the quinoid dihydropteridine reductase (QDPR) gene-which codes for the DHPR protein, one containing the in trans missense mutation c.515C>T (pPro172Leu) in exon 5 and the other containing the same type of mutation in the exon 7 (c.635T>C [p.Phe212Ser]). The authors discuss their experience with sapropterin dihydrochloride for the treatment of DHPRD in this case report

CARACTERÍSTICAS FÍSICO-QUÍMICAS E CITOLÓGICAS DO LÍQUOR DE OVINOS SADIOS DA RAÇA SANTA INÊS

A ocorrência de doenças neurológicas é elevada na clínica médica dos animais, porém poucos estudos documentam a composição normal do líquor de ovinos, em especial o da raça Santa Inês. O objetivo deste estudo foi o de estabelecer parâmetros de normalidade para as características físico-químicas e citológicas do líquor de ovinos desta raça. Para isso, foram utilizados 40 ovinos, com idades entre seis a dezoito meses, para a realização da punção lombossacral de líquor. Foi observado um padrão límpido e incolor, e a média para densidade foi de 1,006 ± 0,0064, a concentração de proteínas foi de 25,27 ± 6,64 mg/dL e a de glicose de 46,89 ± 10,99 mg/dL. Quanto às atividades enzimáticas, foram observadas médias de 80,79 ± 116,72 U/L para creatina quinase (CK); 17,43 ± 11,91 U/L para lactato desidrogenase (LDH) e 17,08 ± 3,85 U/L para aspartato aminotransferase (AST). Os achados obtidos para contagem global de leucócitos foram de 4,61 ± 4,96 células/µL (0 a 15 linfócitos, 0 a 10 monócitos, 1 a 14 neutrófilos). Diante da carência de dados de referência para parâmetros do líquor de ovinos Santa Inês, sugere-se que os resultados obtidos nesta pesquisa sejam considerados valores normais na clínica de ovinos e, assim, contribuam no diagnóstico de doenças neurológicas nesta raça. PALAVRAS-CHAVE: bioquímica; citologia; LCR; parâmetros fisiológicos; pequenos ruminantes

Cardiovascular abnormalities in patients with oral cleft: a clinical-electrocardiographic-echocardiographic study

OBJECTIVES: The present study aims to describe the clinical, electrocardiographic, and echocardiographic cardiological findings in a group of patients with oral clefts. METHODS: This is a prospective cross-sectional study on 70 children (age range from 13 days to 19 years) with oral clefts who attended the multidisciplinary program of a university hospital from March 2013 to September 2014. The patients were evaluated by a pediatric cardiologist and underwent detailed anamnesis, physical examination, electrocardiogram, and echocardiogram. RESULTS: Sixty percent of the patients were male; 55.7% presented with cleft lip and palate, and 40.0% presented with health complaints. Comorbidities were found in 44.3%. Relevant pregnancy, neonatal, family and personal antecedents were present in 55.7%, 27.1%, 67.2%, and 24.3% of the patients, respectively. Regarding the antecedents, 15.2% of the patients presented with a cardiac murmur, 49.0% with a familial risk of developing plurimetabolic syndrome, and 6% with family antecedents of rheumatic fever. Electrocardiographic evaluation showed one case of atrioventricular block. Echocardiograms were abnormal in 35.7% of the exams, including 5 cases of mitral valve prolapse — one of which was diagnosed with rheumatic heart disease. CONCLUSION: The finding of a family risk of developing plurimetabolic syndrome and a diagnosis of rheumatic heart disease indicates that patients with oral clefts may be more prone to developing acquired heart disease. Thus, our findings highlight the importance of anamnesis and methodological triangulation (clinical-electrocardiographic-echocardiographic) in the investigation of patients with oral clefts and emphasize that cardiological follow-up to evaluate acquired and/or rhythm heart diseases is necessary. This strategy permits comorbidity prevention and individualized planned treatment

Vaccinia Virus Infection in Monkeys, Brazilian Amazon

To detect orthopoxvirus in the Brazilian Amazon, we conducted a serosurvey of 344 wild animals. Neutralizing antibodies against orthopoxvirus were detected by plaque-reduction neutralizing tests in 84 serum samples. Amplicons from 6 monkey samples were sequenced. These amplicons identified vaccinia virus genetically similar to strains from bovine vaccinia outbreaks in Brazil

Trypanosoma cruzi Infection Induces Cellular Stress Response and Senescence-Like Phenotype in Murine Fibroblasts

Trypanosoma cruzi infects and replicates within a wide variety of immune and non-immune cells. Here, we investigated early cellular responses induced in NIH-3T3 fibroblasts upon infection with trypomastigote forms of T. cruzi. We show that fibroblasts were susceptible to T. cruzi infection and started to release trypomastigotes to the culture medium after 4 days of infection. Also, we found that T. cruzi infection reduced the number of fibroblasts in 3-day cell cultures, by altering fibroblast proliferation. Infected fibroblasts displayed distinctive phenotypic alterations, including enlarged and flattened morphology with a nuclei accumulation of senescence-associated heterochromatin foci. In addition, infection induced an overexpression of the enzyme senescence-associated β-galactosidase (SA-β-gal), an activation marker of the cellular senescence program, as well as the production of cytokines and chemokines involved with the senescence-associated secretory phenotype (SASP) such as IL-6, TNF-α, IL-1β, and MCP-1. Infected fibroblasts released increased amounts of stress-associated factors nitric oxide (NO) and reactive oxygen species (ROS), and the treatment with antioxidants deferoxamine (DFO) and N-acetylcysteine reduced ROS generation, secretion of SASP-related cytokine IL-6, SA-β-gal activity, and parasite load by infected fibroblasts. Taken together, our data suggest that T. cruzi infection triggers a rapid cellular stress response followed by induction of a senescent-like phenotype in NIH-3T3 fibroblasts, enabling them to act as reservoirs of parasites during the early stages of the Chagas disease

Pathogen-Induced Proapoptotic Phenotype and High CD95 (Fas) Expression Accompany a Suboptimal CD8+ T-Cell Response: Reversal by Adenoviral Vaccine

MHC class Ia-restricted CD8+ T cells are important mediators of the adaptive immune response against infections caused by intracellular microorganisms. Whereas antigen-specific effector CD8+ T cells can clear infection caused by intracellular pathogens, in some circumstances, the immune response is suboptimal and the microorganisms survive, causing host death or chronic infection. Here, we explored the cellular and molecular mechanisms that could explain why CD8+ T cell-mediated immunity during infection with the human protozoan parasite Trypanosoma cruzi is not optimal. For that purpose, we compared the CD8+ T-cell mediated immune responses in mice infected with T. cruzi or vaccinated with a recombinant adenovirus expressing an immunodominant parasite antigen. Several functional and phenotypic characteristics of specific CD8+ T cells overlapped. Among few exceptions was an accelerated expansion of the immune response in adenoviral vaccinated mice when compared to infected ones. Also, there was an upregulated expression of the apoptotic-signaling receptor CD95 on the surface of specific T cells from infected mice, which was not observed in the case of adenoviral-vaccinated mice. Most importantly, adenoviral vaccine provided at the time of infection significantly reduced the upregulation of CD95 expression and the proapoptotic phenotype of pathogen-specific CD8+ cells expanded during infection. In parallel, infected adenovirus-vaccinated mice had a stronger CD8 T-cell mediated immune response and survived an otherwise lethal infection. We concluded that a suboptimal CD8+ T-cell response is associated with an upregulation of CD95 expression and a proapoptotic phenotype. Both can be blocked by adenoviral vaccination