Zinc/copper imbalance reflects immune dysfunction in human leishmaniasis: an ex vivo and in vitro study

BACKGROUND: The process of elimination of intracellular pathogens, such as Leishmania, requires a Th1 type immune response, whereas a dominant Th2 response leads to exacerbated disease. Experimental human zinc deficiency decreases Th1 but not Th2 immune response. We investigated if zinc and copper levels differ in different clinical forms of leishmaniasis, and if these trace metals might be involved in the immune response towards the parasite. METHODS: Blood was collected from 31 patients with either localized cutaneous (LCL), mucosal (ML) or visceral (VL) leishmaniasis, as well as from 25 controls from endemic and non-endemic areas. Anti-Leishmania humoral and cellular immune response were evaluated by quantifying specific plasma IgG, lymphoproliferation and cytokine production, respectively. Plasma levels of Cu and Zn were quantified by atomic absorption spectrophotometry. RESULTS: A significant decrease in plasma Zn was observed in all three patient groups (p < 0.01 for LCL and ML, p < 0.001 for VL), as compared to controls, but only VL (7/10) and ML (1/7) patients displayed overt Zn deficiency. Plasma Cu was increased in LCL and VL (p < 0.001) but not in ML, and was strongly correlated to anti-Leishmania IgG (Spearman r = 0.65, p = 0.0028). Cu/Zn ratios were highest in patients with deficient cellular (VL<<LCL<ML) and exacerbated humoral (VL>LCL>ML) immune response. Ex vivo production of parasite-induced IFN-γ was negatively correlated to plasma Cu levels in LCL (r = -0.57, p = 0.01). In vitro, increased Cu levels inhibited IFN-γ production. CONCLUSIONS: 1. Zn deficiency in VL and ML indicate possible therapeutic administration of Zn in these severe forms of leishmaniasis. 2. Plasma Cu positively correlates to humoral immune response across patient groups. 3. Environmentally or genetically determined increases in Cu levels might augment susceptibility to infection with intracellular pathogens, by causing a decrease in IFN-γ production

Genetic and Functional Role of TNF-alpha in the Development Trypanosoma cruzi Infection

TNF-alpha plays an important role in trypanocidal mechanisms and is related to tissue injury. This cytokine has been detected in the heart of human chagasic patients where it is associated with tissue damage. This study investigated whether TNF-alpha levels and the presence of genetic polymorphisms are associated with the presence of T. cruzi infection and/or with the development of the cardiac form in chronic chagasic patients. Genomic DNA of 300 subjects from an endemic area was extracted and analyzed by PCR using specific primers. TNF-alpha was assayed in culture supernatants by ELISA. An association was observed between the absence of the TNF-238A allele and negative serology. Furthermore, seropositive individuals carrying the TNF-238A allele produced significantly higher TNF-alpha levels without stimulation (p = 0.04) and after stimulation with LPS (p = 0.007) and T. cruzi antigens (p = 0.004). The present results suggest that the polymorphism at position -238 influences susceptibility to infection and that this allele is associated with higher TNF-alpha production in seropositive individuals

Relationship between functional fitness, medication costs and mood in elderly people

Objective: to verify if functional fitness (FF) is associated with the annual cost of medication consumption and mood states (MSt) in elderly people. Methods: a cross-sectional study with 229 elderly people aged 65 years or more at Santa Casa de Misericórdia de Coimbra, Portugal. Seniors with physical and psychological limitations were excluded, as well as those using medication that limits performance on the tests. The Senior Fitness Test was used to evaluate FF, and the Profile of Mood States - Short Form to evaluate the MSt. The statistical analysis was based on Mancova, with adjustment for age, for comparison between men and women, and adjustment for sex, for comparison between cardiorespiratory fitness quintiles. The association between the variables under study was made with partial correlation, controlling for the effects of age, sex and body mass index. Results: an inverse correlation between cardiorespiratory fitness and the annual cost of medication consumption was found (p < 0.01). FF is also inversely associated with MSt (p < 0.05). Comparisons between cardiorespiratory fitness quintiles showed higher medication consumption costs in seniors with lower aerobic endurance, as well as higher deterioration in MSt (p < 0.01). Conclusion: elderly people with better FF and, specifically, better cardiorespiratory fitness present lower medication consumption costs and a more positive MSt

Health-related factors correlate with behavior trends in physical activity level in old age: longitudinal results from a population in São Paulo, Brazil

<p>Abstract</p> <p>Background</p> <p>Physical inactivity in leisure time is common among elderly in Brazil and this finding is particularly alarming considering that this population is greatly affected by chronic diseases. The identification of health factors that influence physical activity level (PAL) will help in the development of strategies for increasing PAL older adults. The current research aimed to identify variables that independently affect behavior trends in PAL over the course of two years among elderly.</p> <p>Methods</p> <p>A survey entitled the Epidoso Project ("Epidemiology of aging") studied 1,667 community-based older individuals in São Paulo city, Brazil over the course of two years. Physical activity level was determined through questions about frequency and duration of physical activities. Body Mass Index was calculated; functional capacity was assessed through the ADL (activities of daily living) scale; cognition was assessed by Mini-Mental State Examination; and mental health was assessed through the Dysthymia Screening. Experiences of falls and fractures were also assessed. Subjects were divided into three groups according to their self-report of Physical Activity Level: a - Regularly Active; b - Insufficiently Active and c - Physically Inactive. Behavior trends in PAL were also measured after two years. Multivariate regression model methodology was used to test associations longitudinally.</p> <p>Results</p> <p>Results from the final model demonstrated that the risk of a not favorable behavior trend in PAL, which included the group who remained physically inactive and the group that displayed decreased PAL, in this cohort of older adults was significantly increased if the individual was female (OR = 2.50; 95% CI = 1.60-3.89; <it>P < 0.01</it>), older (80 y vs. 65 y, OR = 6.29, 95% CI = 2.69-14.67; <it>P < 0.01</it>), dependent on help from others for activities in the ADL scale (moderate-severe = 4-7+ vs. 0 ADLs) (OR = 2.25, 95% CI = 1.20-4.21; <it>P < 0.011</it>) or had experienced a history of falls with consequences (OR = 6.88, 95% CI = 0.91-52.01; <it>P < 0.062</it>).</p> <p>Conclusions</p> <p>Age, gender, ADL scores and falls were associated with a not favorable behavior trend in PAL. Promotion programs should target these factors, reducing barriers to achieve desired changes in PAL.</p

Lineage Analysis of Circulating Trypanosoma cruzi Parasites and Their Association with Clinical Forms of Chagas Disease in Bolivia

Around 30–50% of Trypanosoma cruzi infections in Latin America cause chronic Chagas disease 10–30 years after the primary infection due to lack of effective treatment. The major clinical complications associated with chronic Chagas disease are cardiac myositis (leading to cardiac failure), and autonomous neuroplexus degeneration of the digestive tract that can cause megacolon or megaesophagus. Therefore, there are three major clinical forms of Chagas disease; cardiac, digestive and indeterminate (asymptomatic). The parasites, which can infect humans as well as other mammals, are transmitted by species of triatomines commonly found in the Americas. The parasite is divided in at least six discrete typing units: TcI, TcIIa–e. In humans, the TcI is mainly observed in Central America and northern parts of South America while the TcIIb/d/e is confined mainly to the southern cone of Latin America. We determined which DTU were prevalent in chronic patients in Bolivia, where the three clinical forms and several DTUs of the parasites are present, in order to determine whether there was a link between a particular parasite DTU and a particular clinical outcome. We found a vast majority of TcIId but its kDNA polymorphism showed no association with any of the clinical manifestations of chronic Chagas

Coadministration of the Three Antigenic Leishmania infantum Poly (A) Binding Proteins as a DNA Vaccine Induces Protection against Leishmania major Infection in BALB/c Mice

Highly conserved intracellular proteins from Leishmania have been described as antigens in natural and experimental infected mammals. The present study aimed to evaluate the antigenicity and prophylactic properties of the Leishmania infantum Poly (A) binding proteins (LiPABPs). Three different members of the LiPABP family have been described. Recombinant tools based on these proteins were constructed: recombinant proteins and DNA vaccines. The three recombinant proteins were employed for coating ELISA plates. Sera from human and canine patients of visceral leishmaniasis and human patients of mucosal leishmaniasis recognized the three LiPABPs. In addition, the protective efficacy of a DNA vaccine based on the combination of the three Leishmania PABPs has been tested in a model of progressive murine leishmaniasis: BALB/c mice infected with Leishmania major. The induction of a Th1-like response against the LiPABP family by genetic vaccination was able to down-regulate the IL-10 predominant responses elicited by parasite LiPABPs after infection in this murine model. This modulation resulted in a partial protection against L. major infection. LiPABP vaccinated mice showed a reduction on the pathology that was accompanied by a decrease in parasite burdens, in antibody titers against Leishmania antigens and in the IL-4 and IL-10 parasite-specific mediated responses in comparison to control mice groups immunized with saline or with the non-recombinant plasmid. The results presented here demonstrate for the first time the prophylactic properties of a new family of Leishmania antigenic intracellular proteins, the LiPABPs. The redirection of the immune response elicited against the LiPABP family (from IL-10 towards IFN-γ mediated responses) by genetic vaccination was able to induce a partial protection against the development of the disease in a highly susceptible murine model of leishmaniasisThe study was supported in Spain by grants from Ministerio de Ciencia e Innovación FIS PI11/00095 and FISPI14/00366 from the Instituto de Salud Carlos III within the Network of TropicalDiseases Research (VI P I+D+I 2008-2011, ISCIII -Subdirección General de Redes y Centros de Investigación Cooperativa (RD12/0018/0009)). This work was also supported in Brazil by a grant from CNPq (Ciencia sem Fronteiras-PVE 300174/2014-4). A CBMSO institutional grant from Fundación Ramón Areces is also acknowledged. EAFC is a grant recipient of CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscrip

Profile of Central and Effector Memory T Cells in the Progression of Chronic Human Chagas Disease

Chagas disease is a parasitic infection caused by protozoan Trypanosoma cruzi that affects approximately 11 million people in Latin America. The involvement of the host's immune response on the development of severe forms of Chagas disease has not been fully elucidated. Studies on the immune response against T. cruzi infection show that the immunoregulatory mechanisms are necessary to prevent the deleterious effect of excessive immune response stimulation and consequently the fatal outcome of the disease. A recall response against parasite antigens observed in in vitro peripheral blood cell culture clearly demonstrates that memory response is generated during infection. Memory T cells are heterogeneous and differ in both the ability to migrate and exert their effector function. This heterogeneity is reflected in the definition of central (TCM) and effector memory (TEM) T cells. Our results suggest that a balance between regulatory and effectors T cells may be important for the progression and development of the disease. Furthermore, the high percentage of central memory CD4+ T cells in indeterminate patients after stimulation suggests that these cells may modulate host's inflammatory response by controlling cell migration to tissues and their effector role during chronic phase of the disease