RESUMEN
Visceral leishmaniasis, caused by Leishmania infantum in New World countries, is the most serious and potentially fatal form of leishmaniasis, if left untreated. There are currently no effective prophylactic measures, and therapeutic options are limited. Therefore, we investigated whether the aromatase inhibitor letrozole (LET), which is already used to treat breast cancer, has an antileishmanial activity and/or immunomodulatory potential and therefore may be used to treat L. infantum infection. LET was active against L. infantum promastigote and amastigote life cycle stages in an in vitro infection model using human THP-1 cell-derived macrophages. In human peripheral blood leukocytes ex vivo, LET reduced the internalized forms of L. infantum by classical monocytes and activated neutrophils. Concomitantly, LET stimulated the production of IL-12/TNF-α and decreased the production of IL-10/TGF-ß by peripheral blood phagocytes, while in T and B cells, it promoted the production of TNF-α/IFN-γ and decreased that of IL-10. In a murine infection model, LET significantly reduced the parasite load in the liver after just 5 days and in the spleen after 15 days. During in vivo treatment with LET, the production of TNF-α/IFN-γ also increased. In addition, the proportion of developing granulomas decreased and that of mature granulomas increased in the liver, while there was no significant change in organ architecture in the spleen. Based on these data, repositioning of LET may be promising for the treatment of visceral leishmaniasis in humans.
Asunto(s)
Reposicionamiento de Medicamentos , Interleucina-10 , Leishmania infantum , Leishmaniasis Visceral , Letrozol , Factor de Necrosis Tumoral alfa , Leishmaniasis Visceral/tratamiento farmacológico , Leishmaniasis Visceral/parasitología , Animales , Leishmania infantum/efectos de los fármacos , Humanos , Ratones , Letrozol/uso terapéutico , Letrozol/farmacología , Interleucina-10/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Femenino , Células THP-1 , Ratones Endogámicos BALB C , Interferón gamma , Interleucina-12/metabolismo , Monocitos/efectos de los fármacos , Monocitos/parasitología , Carga de Parásitos , Bazo/parasitología , Bazo/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The present study aimed to verify the impact of etiological treatment on the genotype-specific serological diagnosis of chronic Chagas disease patients (CH), using the Chagas-Flow ATE IgG1 methodology. For this purpose, a total of 92 serum samples from CH, categorized as Not Treated (NT, n = 32) and Benznidazole-Treated (Bz-T, n = 60), were tested at Study Baseline and 5Years Follow-up. At Study Baseline, all patients have the diagnosis of Chagas disease confirmed by Chagas-Flow ATE IgG1, using the set of attributes ("antigen/serum dilution/cut-off"; "EVI/250/30%"). The genotype-specific serodiagnosis at Study Baseline demonstrated that 96% of patients (44/46) presented a serological profile compatible with TcII genotype infection. At 5Years Follow-up monitoring, NT and Bz-T presented no changes in anti-EVI IgG1 reactivity. However, significant differences were detected in the genotype-specific IgG1 reactivity for Bz-T. The most outstanding shift comprised the anti-amastigote TcVI/(AVI), anti-amastigote TcII/(AII) and anti-epimastigote TcVI/(EVI) reactivities. Regardless no changes in the genotype-specific serology of NT (TcI = 6%; TcII = 94%), distinct T. cruzi genotype-specific sero-classification was detected for Bz-T samples at 5Years Follow-up (TcII = 100%) as compared to Baseline (TcII = 97%; TcVI = 3%). The anti-trypomastigote TcI/(TI) was the attribute accountable for the change in genotype-specific sero-classification. In conclusion, our findings of dissimilar T. cruzi genotype-specific serology upon Bz-treatment re-emphasize the relevance of accomplishing the genotype-specific serodiagnosis during clinical pos-therapeutic management of chronic Chagas disease patients.
Asunto(s)
Anticuerpos Antiprotozoarios , Enfermedad de Chagas , Genotipo , Inmunoglobulina G , Nitroimidazoles , Tripanocidas , Trypanosoma cruzi , Humanos , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Nitroimidazoles/uso terapéutico , Trypanosoma cruzi/genética , Trypanosoma cruzi/inmunología , Inmunoglobulina G/sangre , Anticuerpos Antiprotozoarios/sangre , Masculino , Femenino , Persona de Mediana Edad , Adulto , Tripanocidas/uso terapéutico , Pruebas Serológicas , Enfermedad Crónica , Anciano , Adulto JovenRESUMEN
SARS-CoV-2 caused the pandemic situation experienced since the beginning of 2020, and many countries faced the rapid spread and severe form of the disease. Mechanisms of interaction between the virus and the host were observed during acute phase, but few data are available when related to immunity dynamics in convalescents. We conducted a longitudinal study, with 51 healthy donors and 62 COVID-19 convalescent patients, which these had a 2-month follow-up after symptoms recovery. Venous blood sample was obtained from all participants to measure blood count, subpopulations of monocytes, lymphocytes, natural killer cells and dendritic cells. Serum was used to measure cytokines, chemokines, growth factors, anti-N IgG and anti-S IgG/IgM antibodies. Statistic was performed by Kruskal-Wallis test, and linear regression with days post symptoms and antibody titers. All analysis had confidence interval of 95%. Less than 35% of convalescents were anti-S IgM+, while more than 80% were IgG+ in D30. Anti-N IgG decreased along time, with loss of seroreactivity of 13%. Eosinophil count played a distinct role on both antibodies during all study, and the convalescence was orchestrated by higher neutrophil-to-lymphocyte ratio and IL-15, but initial stages were marked by increase in myeloid DCs, B1 lymphocytes, inflammatory and patrolling monocytes, G-CSF and IL-2. Later convalescence seemed to change to cytotoxicity mediated by T lymphocytes, plasmacytoid DCs, VEGF, IL-9 and CXCL10. Anti-S IgG antibodies showed the longest perseverance and may be a better option for diagnosis. The inflammatory pattern is yet present on initial stage of convalescence, but quickly shifts to a reparative dynamic. Meanwhile eosinophils seem to play a role on anti-N levels in convalescence, although may not be the major causative agent. We must highlight the importance of immunological markers on acute clinical outcomes, but their comprehension to potentialize adaptive system must be explored to improve immunizations and further preventive policies.
Asunto(s)
Anticuerpos Antivirales , COVID-19 , Convalecencia , Citocinas , Inmunoglobulina G , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/sangre , Masculino , Femenino , Adulto , Persona de Mediana Edad , SARS-CoV-2/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Citocinas/sangre , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Estudios Longitudinales , Anciano , Eosinófilos/inmunología , Eosinófilos/metabolismoRESUMEN
Extracellular vesicles (EVs) are heterogeneous, phospholipid membrane enclosed particles that are secreted by healthy and cancerous cells. EVs are present in diverse biological fluids and have been associated with the severity of diseases, which indicates their potential as biomarkers for diagnosis, prognosis and as therapeutic targets. This study investigated the phenotypic characteristics of EVs derived from peripheral blood (PB) and bone marrow (BM) in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) during different treatment stages. PB and BM plasma were collected from 20 B-ALL patients at three time points during induction therapy, referred to as: diagnosis baseline (D0), day 15 of induction therapy (D15) and the end of the induction therapy (D35). In addition, PB samples were collected from 10 healthy children at a single time point. The EVs were measured using CytoFLEX S flow cytometer. Calibration beads were employed to ensure accurate size analysis. The following, fluorescent-labeled specific cellular markers were used to label the EVs: Annexin V (phosphatidylserine), CD235a (erythrocyte), CD41a (platelet), CD51 (endothelial cell), CD45 (leukocyte), CD66b (neutrophil), CD14 (monocyte), CD3 (T lymphocyte), CD19, CD34 and CD10 (B lymphoblast/leukemic blast). Our results demonstrate that B-ALL patients had a marked production of EV-CD51/61+, EV-CD10+, EV-CD19+ and EV-CD10+CD19+ (double-positive) with a decrease in EV-CD41a+ on D0. However, the kinetics and signature of production during induction therapy revealed a clear decline in EV-CD10+ and EV-CD19+, with an increase of EV-CD41a+ on D35. Furthermore, B-ALL patients showed a complex biological network, exhibiting distinct profiles on D0 and D35. Interestingly, fold change and ROC curve analysis demonstrated that EV-CD10+CD19+ were associated with B-ALL patients, exhibited excellent clinical performance and standing out as a potential diagnostic biomarker. In conclusion, our data indicate that EVs represent a promising field of investigation in B-ALL, offering the possibility of identifying potential biomarkers and therapeutic targets.
Asunto(s)
Médula Ósea , Vesículas Extracelulares , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Niño , Vesículas Extracelulares/metabolismo , Femenino , Masculino , Preescolar , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Médula Ósea/metabolismo , Adolescente , Prueba de Estudio Conceptual , Biomarcadores de Tumor , LactanteRESUMEN
Breakthrough COVID-19 (occurring in fully vaccinated people) has been described. Data on its characteristics among immune-mediated rheumatic disease (IMRD) patients are scarce. This study describes breakthrough COVID-19 occurring in IMRD patients participating in the SAFER-study, a Brazilian multicentric cohort evaluating the safety, effectiveness, and immunogenicity of SARS-CoV-2 vaccines in patients with autoimmune diseases. A descriptive analysis of the population and a binary logistic regression model were performed to evaluate the predictors of COVID-19-related hospitalization. A p-value < 0.05 was significant. The included 160 patients were predominantly females (83.1%), with a mean (SD) age of 40.23 (13.19) years. The patients received two (19%), three (70%), or four (11%) vaccine doses. The initial two-dose series was mainly with ChAdOx1 (Oxford/AstraZeneca) (58%) or BBIBP-CorV (Sinopharm-Beijing) (34%). The first booster (n = 150) was with BNT162b2 (BioNtech/Fosun Pharma/Pfizer) (63%) or ChAdOx1 (29%). The second booster (n = 112) was with BNT162b2 (40%) or ChAdOx1 (26%). The COVID-19 hospitalization rate was 17.5%. IMRD moderate/high activity (OR: 5.84; CI: 1.9-18.5; p = 0.002) and treatment with corticosteroids (OR: 2.94; CI: 1.02-8.49; p = 0.0043) were associated with higher odds of hospitalization, while increasing the number of vaccine doses was protective (OR: 0.37; CI: 0.15-0.9; p = 0.032). These findings, along with previous reassuring results about the safety of the COVID-19 vaccines, argue in favor of booster vaccination in IMRD patients.
RESUMEN
Introduction: Visceral leishmaniasis (VL) is an important tropical and neglected disease and represents a serious global health problem. The initial interaction between the phagocytes and the parasite is crucial to determine the pathogen's capacity to initiate infection and it shapes the subsequent immune response that will develop. While type-1 T-cells induce IL-6, IL-1ß, TNF-α, and IL-12 production by monocytes/macrophages to fight the infection, type-2 T-cells are associated with a regulatory phenotype (IL-10 and TGF-ß) and successful infection establishment. Recently, our group demonstrated the role of an important Th1/Th17 T-cell population, the mucosal-associated invariant T (MAIT) cells, in VL. MAIT cells can respond to L. infantum by producing TNF-α and IFN-γ upon MR1-dependent activation. Objective and methods: Here, we describe the impact of the MR1-blockage on L. infantum internalization on the functional profile of circulating neutrophils and monocytes as well as the impact of the MR1-blockage on the soluble mediator signatures of in vitro whole blood cultures. Results: Overall, our data showed that VL patients presents higher percentage of activated neutrophils than asymptomatic and non-infected controls. In addition, MR1 blockade led to lower TNF-α and TGF-ß production by non-activated neutrophils from asymptomatic individuals. Moreover, TNF-α and IL-10 production by monocytes was higher in VL patients. In the analysis of soluble mediators produced in vitro, MR1-blockade induced a decrease of IFN-γ and an increase of IL-10, IL-27 and IL-33 in the cell cultures of AS group, a cytokine pattern associated with type 2 deleterious response. Discussion and conclusion: These data corroborate the hypothesis that MR1-restricted responses are associated to a protective role during Leishmania infection.
Asunto(s)
Citocinas , Leishmaniasis Visceral , Monocitos , Leishmaniasis Visceral/inmunología , Humanos , Citocinas/metabolismo , Adulto , Femenino , Masculino , Monocitos/inmunología , Monocitos/metabolismo , Leishmania infantum/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Células T Invariantes Asociadas a Mucosa/inmunología , Células T Invariantes Asociadas a Mucosa/metabolismo , Persona de Mediana Edad , Adulto Joven , AdolescenteRESUMEN
The present study compares the ability of distinct immunological assays (chemiluminescence immunoassay-CLIA, western blot-WB and flow cytometry-FC-Simplex and Duplex) to detect anti-HTLV (human T-lymphotropic virus) antibodies in candidates for blood donations at the Amazonas State Blood Center (Brazil) between January 2018 and December 2022. Overall, 257,942 samples from candidates for blood donations were screened using CLIA, which led to 0.15% seropositivity for HTLV (409 samples). A total of 151 candidates for blood donations were enrolled for retesting with CLIA followed by additional testing using WB and FC-Simplex and Duplex analysis. Our results demonstrated that 62% (93/151), 20% (30/151) and 17% (26/151) of the samples presented positive results with retesting using CLIA, WB and FC-Simplex analysis, respectively. Additional analysis of the CLIA, WB and FC-Simplex results revealed an overall agreement of 56% for CLIA and WB (22 co-negative; 30 co-positive samples), 48% for CLIA and FC-Simplex (21 co-negative; 24 co-positive samples) and 80% for WB and FC-Simplex (51 co-negative; 23 co-positive samples). Considering the WB as the reference standard for the diagnosis of infection with HTLV-1/2, we observed that the CLIA results of ≤3.0 RLU and >10.0 RLU in the retest can be used define a negative or positive result, respectively, and could be used as new specific cut-off values. The overall agreement between WB and FC-Duplex for accomplishing the differential diagnosis was evaluated and demonstrated 100% correspondence for the diagnosis of HTLV-1 (15/15) and HTLV-2 (7/7). Our findings demonstrate that gaps in the diagnosis of infection with HTLV-1/2 could be overcome by the simultaneous use of distinct immunological assays during retesting of candidates for blood donations.
Asunto(s)
Donantes de Sangre , Infecciones por HTLV-I , Infecciones por HTLV-II , Virus Linfotrópico T Tipo 1 Humano , Virus Linfotrópico T Tipo 2 Humano , Humanos , Brasil , Infecciones por HTLV-I/diagnóstico , Infecciones por HTLV-I/sangre , Infecciones por HTLV-I/inmunología , Infecciones por HTLV-II/diagnóstico , Infecciones por HTLV-II/sangre , Virus Linfotrópico T Tipo 1 Humano/inmunología , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Virus Linfotrópico T Tipo 2 Humano/inmunología , Masculino , Femenino , Adulto , Diagnóstico Diferencial , Persona de Mediana Edad , Western Blotting , Citometría de Flujo/métodos , Donación de SangreRESUMEN
We enrolled 21 patients with laboratory-confirmed yellow fever (YF), hospitalized at Eduardo de Menezes Hospital, Brazil, to be treated with sofosbuvir, a drug approved for hepatitis C. Given the absence of specific YF antiviral treatments, the off-label nonrandomized sofosbuvir treatment aimed to address high disease severity and the risk of fatal outcomes. Patients received a daily dose of 400â mg sofosbuvir from 4 to 10 days post-symptom onset. YF viral load (VL) comparisons were made between treated and nontreated patients who either survived or died. The genomic VL for the treated group steadily decreased after day 7 post-symptom onset, suggesting that sofosbuvir might reduce YF VL. This study underscores the urgent need for YF antiviral therapies, advocating for randomized clinical trials to further explore sofosbuvir's role in YF treatment.
RESUMEN
Neurological complications are frequent during the active course of infective endocarditis (IE), and they are associated with high in-hospital mortality rates. However, limited data exist on the prognostic value of these complications for late outcomes. This study aimed to assess the long-term impact of neurological complications in patients surviving an IE episode. A total of 263 consecutive IE patients admitted to a tertiary care center between 2007 and 2022 were prospectively included. Neurological complications at admission included transient ischemic attack (TIA), ischemic stroke, hemorrhagic stroke, intracerebral abscess, and meningitis. The primary outcome was a composite of overall mortality or heart valve surgery. Of the patients, 34.2% died in the hospital, leaving 173 survivors for long-term follow-up. Over a median of 3.5 years, 29 patients died, and 13 (9%) underwent cardiac surgery, resulting in an overall adverse event rate of 30%. Neurological complications independently predicted long-term adverse outcomes (hazard ratio (HR) 2.237; 95% CI 1.006-4.976), after adjusting for age, chronic kidney disease (CKD), and heart failure (HF) development. In an IE patient cohort, neurological complications at admission, which is a complication directly related to the IE process, were independent predictors of long-term outcomes.
RESUMEN
Introduction: Chagas disease is a neglected parasitic disease caused by Trypanosoma cruzi. While most patients are asymptomatic, around 30% develop Chronic Chagasic Cardiomyopathy (CCC). Methods: Here, we employed high-dimensional flow cytometry to analyze CD4+ T and B cell compartments in patients during the chronic phase of Chagas disease, presenting the asymptomatic and mild or moderate/severe cardiac clinical forms. Results: Effector CD27-CD4+ T cells were expanded in both CCC groups, and only mild CCC patients showed higher frequencies of effector memory and T follicular helper (Tfh) cells than healthy donors (CTL) and asymptomatic patients. Unsupervised analysis confirmed these findings and further revealed the expansion of a specific subpopulation composed of Tfh, transitional, and central memory CD4+ T cells bearing a phenotype associated with strong activation, differentiation, and exhaustion in patients with mild but not moderate/severe CCC. In contrast, patients with mild and moderate/severe CCC had lower frequencies of CD4+ T cells expressing lower levels of activation markers, suggesting resting status, than CTL. Regarding the B cell compartment, no alterations were found in naïve CD21-, memory cells expressing IgM or IgD, marginal zone, and plasma cells in patients with Chagas disease. However, expansion of class-switched activated and atypical memory B cells was observed in all clinical forms, and more substantially in mild CCC patients. Discussion: Taken together, our results showed that T. cruzi infection triggers changes in CD4+ T and B cell compartments that are more pronounced in the mild CCC clinical form, suggesting an orchestrated cellular communication during Chagas disease. Conclusion: Overall, these findings reinforce the heterogeneity and complexity of the immune response in patients with chronic Chagas disease and may provide new insights into disease pathology and potential markers to guide clinical decisions.
Asunto(s)
Linfocitos T CD4-Positivos , Cardiomiopatía Chagásica , Humanos , Cardiomiopatía Chagásica/inmunología , Masculino , Persona de Mediana Edad , Femenino , Linfocitos T CD4-Positivos/inmunología , Adulto , Linfocitos B/inmunología , Trypanosoma cruzi/inmunología , Enfermedad Crónica , Anciano , Activación de Linfocitos/inmunologíaRESUMEN
The present study aimed at evaluating the YF-specific neutralizing antibody profile besides a multiparametric analysis of phenotypic/functional features of cell-mediated response elicited by the 1/5 fractional dose of 17DD-YF vaccine, administered as a single subcutaneous injection. The immunological parameters of each volunteer was monitored at two time points, referred as: before (Day 0) [Non-Vaccinated, NV(D0)] and after vaccination (Day 30-45) [Primary Vaccinees, PV(D30-45)]. Data demonstrated high levels of neutralizing antibodies for PV(D30-45) leading to a seropositivity rate of 93%. A broad increase of systemic soluble mediators with a mixed profile was also observed for PV(D30-45), with IFN-γ and TNF-α presenting the highest baseline fold changes. Integrative network mapping of soluble mediators showed increased correlation numbers in PV(D30-45) as compared to NV(D0) (532vs398). Moreover, PV(D30-45) exhibited increased levels of Terminal Effector (CD45RA+CCR7-) CD4+ and CD8+ T-cells and Non-Classical memory B-cells (IgD+CD27+). Dimensionality reduction of Mass Cytometry data further support these findings. A polyfunctional cytokine profile (TNF-α/IFN-γ/IL-10/IL-17/IL-2) of T and B-cells was observed upon in vitro antigen recall. Mapping and kinetics timeline of soluble mediator signatures for PV(D30-45) further confirmed the polyfunctional profile upon long-term in vitro culture, mediated by increased levels of IFN-γ and TNF-α along with decreased production of IL-10. These findings suggest novel insights of correlates of protection elicited by the 1/5 fractional dose of 17DD-YF vaccine.
Asunto(s)
Vacuna contra la Fiebre Amarilla , Fiebre Amarilla , Humanos , Adulto , Anticuerpos Neutralizantes , Interleucina-10 , Anticuerpos Antivirales , Factor de Necrosis Tumoral alfa , Linfocitos T CD8-positivos , VacunaciónRESUMEN
Chagas disease, caused by Trypanosoma cruzi, remains a serious public health problem worldwide. The parasite was subdivided into six distinct genetic groups, called "discrete typing units" (DTUs), from TcI to TcVI. Several studies have indicated that the heterogeneity of T. cruzi species directly affects the diversity of clinical manifestations of Chagas disease, control, diagnosis performance, and susceptibility to treatment. Thus, this review aims to describe how T. cruzi genetic diversity influences the biology of the parasite and/or clinical parameters in humans. Regarding the geographic dispersion of T. cruzi, evident differences were observed in the distribution of DTUs in distinct areas. For example, TcII is the main DTU detected in Brazilian patients from the central and southeastern regions, where there are also registers of TcVI as a secondary T. cruzi DTU. An important aspect observed in previous studies is that the genetic variability of T. cruzi can impact parasite infectivity, reproduction, and differentiation in the vectors. It has been proposed that T. cruzi DTU influences the host immune response and affects disease progression. Genetic aspects of the parasite play an important role in determining which host tissues will be infected, thus heavily influencing Chagas disease's pathogenesis. Several teams have investigated the correlation between T. cruzi DTU and the reactivation of Chagas disease. In agreement with these data, it is reasonable to suppose that the immunological condition of the patient, whether or not associated with the reactivation of the T. cruzi infection and the parasite strain, may have an important role in the pathogenesis of Chagas disease. In this context, understanding the genetics of T. cruzi and its biological and clinical implications will provide new knowledge that may contribute to additional strategies in the diagnosis and clinical outcome follow-up of patients with Chagas disease, in addition to the reactivation of immunocompromised patients infected with T. cruzi.
Asunto(s)
Enfermedad de Chagas , Variación Genética , Trypanosoma cruzi , Trypanosoma cruzi/genética , Humanos , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Animales , Interacciones Huésped-Parásitos/genética , Interacciones Huésped-Parásitos/inmunologíaRESUMEN
Immunosenescence is a phenomenon caused by changes in the immune system, and part of these changes involves an increase in circulating immunological biomarkers, a process known as "Inflammaging." Inflammaging can be associated with many diseases related to older people. As the older population continues to grow, understanding changes in the immune system becomes essential. While prior studies assessing these alterations have been conducted in countries with Caucasian populations, this investigation marks a pioneering effort. The object of the study is to describe for the first time that the distribution of cytokines, chemokines, and growth factors serum levels, assessed by Luminex platform, has been examined in a Brazilian population-based study of older adult females and males by age. Blood samples from 2111 participants (≥50 years old) were analyzed at the baseline (2015/2016) of the ELSI-Brazil study. The exploratory variables considered in the study were age, sex, educational level, residence area, geographic region, alcohol and smoking consumption, physical activity, and self-reported medical diagnoses of hypertension, diabetes, asthma, arthritis, and cancer. The association between serum biomarker levels and age was assessed by a quantile regression model adjusted in the total population and stratified by sex. The significance level considered in the analysis was 0.05. The mean age of the participants was 62.9 years, with a slight majority of female (52.7 %). Differences were found between the sexes in the median circulating levels of the CCL11, CXCL10, and FGF biomarkers. Eight biomarkers showed significant associations with age, including the pro-inflammatory CXCL10, TNF-α, IL-6, IL-17, and IL-2; and type 2/regulatory CCL11 and IL-4, showing positive associations, and anti-inflammatory IL-1Ra showing a negative association. The results suggest similar associations between the sexes, revealing an inflammatory profile characterized by types 1 and 2. Remarkably, these findings reinforce the concept of the Inflammaging process in Brazilian population. These findings add novel insights to about the immunosenescence aspects in middle-income countries and help define biomarkers capable of monitoring inflammation in older adults.
Asunto(s)
Biomarcadores , Citocinas , Inmunosenescencia , Humanos , Masculino , Femenino , Brasil/epidemiología , Biomarcadores/sangre , Anciano , Persona de Mediana Edad , Citocinas/sangre , Envejecimiento/inmunología , Envejecimiento/sangre , Anciano de 80 o más Años , Inflamación/sangre , Quimiocinas/sangreRESUMEN
OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator. It is not known whether the pro-resolving effects of Ang-(1-7) are sustained and protect the lung from a subsequent inflammatory challenge. This study sought to investigate the impact of treatment in face of a second allergic or lipopolysaccharide (LPS) challenge. METHODS: Mice, sensitized and challenged with ovalbumin (OVA), received a single Ang-(1-7) dose at the peak of eosinophilic inflammation, 24 h after the final OVA challenge. Subsequently, mice were euthanized at 48, 72, 96, and 120 h following the OVA challenge, and cellular infiltrate, inflammatory mediators, lung histopathology, and macrophage-mediated efferocytic activity were evaluated. The secondary inflammatory stimulus (OVA or LPS) was administered 120 h after the last OVA challenge, and subsequent inflammatory analyses were performed. RESULTS: Treatment with Ang-(1-7) resulted in elevated levels of IL-10, CD4+Foxp3+, Mres in the lungs and enhanced macrophage-mediated efferocytic capacity. Moreover, in allergic mice treated with Ang-(1-7) and then subjected to a secondary OVA challenge, inflammation was also reduced. Similarly, in mice exposed to LPS, Ang-(1-7) effectively prevented the lung inflammation. CONCLUSION: A single dose of Ang-(1-7) resolves lung inflammation and protect the lung from a subsequent inflammatory challenge highlighting its potential therapeutic for individuals with asthma.
Asunto(s)
Angiotensina I , Lipopolisacáridos , Pulmón , Ovalbúmina , Fragmentos de Péptidos , Animales , Angiotensina I/uso terapéutico , Angiotensina I/farmacología , Angiotensina I/administración & dosificación , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/uso terapéutico , Fragmentos de Péptidos/administración & dosificación , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/inmunología , Ovalbúmina/inmunología , Ratones , Masculino , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Ratones Endogámicos BALB C , Inflamación/tratamiento farmacológico , Eosinofilia/tratamiento farmacológico , Eosinofilia/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/citologíaRESUMEN
The re-emergence of yellow fever (YF) urged new mass vaccination campaigns and, in 2017, the World Health Organization approved the use of the fractional dose (FD) of the YF vaccine due to stock shortage. In an observational cross-sectional investigation, we have assessed viremia, antibodies, soluble mediators and effector and memory T and B-cells induced by primary vaccination of volunteers with FD and standard dose (SD). Similar viremia and levels of antibodies and soluble markers were induced early after immunization. However, a faster decrease in the latter was observed after SD. The FD led to a sustained expansion of helper T-cells and an increased expression of activation markers on T-cells early after vaccination. Although with different kinetics, expansion of plasma cells was induced upon SD and FD immunization. Integrative analysis reveals that FD induces a more complex network involving follicular helper T cells and B-cells than SD. Our findings substantiate that FD can replace SD inducing robust correlates of protective immune response against YF.
RESUMEN
Between 2016 and 2018, Brazil experienced major sylvatic yellow fever (YF) outbreaks that caused hundreds of casualties, with Minas Gerais (MG) being the most affected state. These outbreaks provided a unique opportunity to assess the immune response triggered by the wild-type (WT) yellow fever virus (YFV) in humans. The plaque reduction neutralization test (PRNT) is currently the standard method to assess the humoral immune response to YFV by measuring neutralizing antibodies (nAbs). The present study aimed to evaluate the humoral immune response of patients from the 2017-2018 sylvatic YF outbreak in MG with different disease outcomes by using PRNTs with a WT YFV strain, isolated from the 2017-2018 outbreak, and a vaccine YFV strain. Samples from naturally infected YF patients were tested, in comparison with healthy vaccinees. Results showed that both groups presented different levels of nAb against the WT and vaccine strains, and the levels of neutralization against the strains varied homotypically and heterotypically. Results based on the geometric mean titers (GMTs) suggest that the humoral immune response after a natural infection of YFV can reach higher levels than that induced by vaccination (GMT of patients against WT YFV compared to GMT of vaccinees, P < 0.0001). These findings suggest that the humoral immune responses triggered by the vaccine and WT strains of YFV are different, possibly due to genetic and antigenic differences between these viruses. Therefore, current means of assessing the immune response in naturally infected YF individuals and immunological surveillance methods in areas with intense viral circulation may need to be updated.IMPORTANCEYellow fever is a deadly febrile disease caused by the YFV. Despite the existence of effective vaccines, this disease still represents a public health concern worldwide. Much is known about the immune response against the vaccine strains of the YFV, but recent studies have shown that it differs from that induced by WT strains. The extent of this difference and the mechanisms behind it are still unclear. Thus, studies aimed to better understand the immune response against this virus are relevant and necessary. The present study evaluated levels of neutralizing antibodies of yellow fever patients from recent outbreaks in Brazil, in comparison with healthy vaccinees, using plaque reduction neutralization tests with WT and vaccine YFV strains. Results showed that the humoral immune response in naturally infected patients was higher than that induced by vaccination, thus providing new insights into the immune response triggered against these viruses.
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Brotes de Enfermedades , Inmunidad Humoral , Vacuna contra la Fiebre Amarilla , Fiebre Amarilla , Virus de la Fiebre Amarilla , Fiebre Amarilla/inmunología , Fiebre Amarilla/epidemiología , Fiebre Amarilla/virología , Humanos , Brasil/epidemiología , Virus de la Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/genética , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Masculino , Vacuna contra la Fiebre Amarilla/inmunología , Femenino , Adulto , Persona de Mediana Edad , Vacunación , Pruebas de Neutralización , Adulto Joven , Anciano , AdolescenteRESUMEN
Introduction: Understanding compartmentalized immune responses in target organs is crucial for elucidating the pathogenesis of various diseases. However, obtaining samples from affected vital organs often poses safety challenges. In this study, we aimed to investigate potential correlations between the levels of disease-associated immune molecules in the bloodstream with their gene expression profiles in the hearts of patients suffering from Chagas Cardiomyopathy (CCC). This debilitating and often fatal condition is caused by infection with the protozoan Trypanosoma cruzi. Methods: Blood samples were analyzed using the Bio-Plex platform. Gene Expression Omnibus (GEO) database was used to determine gene expression profile in heart tissue from CCC and non-Chagas controls (CTRL). Results: Elevated levels of inflammatory cytokines were detected in the plasma of CCC patients, and these levels correlated with clinical indicators of deteriorating cardiac function. Notably, 75% of the soluble factors assessed in the plasma exhibited a consistent relationship with their gene expression levels in the cardiac tissue of CCC patients. Analysis of interactions and signaling pathways related to these molecules revealed an overrepresentation of inflammatory pathways in both blood and heart compartments. Moreover, we identified that differentially expressed genes in CCC cardiac tissue were primarily associated with T-cell signaling pathways and correlated with the presence of CD8+ T cells in the myocardium. Discussion: Our findings establish a strong correlation between relevant immune molecules and their signaling pathways in both the blood and heart tissue in CCC. This validates the use of blood as a non-invasive medium for understanding immunopathology and identifying markers for cardiac dysfunction in Chagas disease.
Asunto(s)
Cardiomiopatía Chagásica , Trypanosoma cruzi , Humanos , Transcriptoma , Corazón , Miocardio/patologíaRESUMEN
BACKGROUND: Leprosy is a highly neglected disease that is considered a serious public health problem in many countries. This illness is characterised by a variety of clinical and histopathological manifestations that are related to the patient immune response. OBJECTIVES: This work aimed evaluate the profile of circulating immune mediators in the plasma from patients classified clinically as paucibacillary (PB), multibacillary (MB), households contacts (HHC), type1 leprosy reaction (T1R), type2 leprosy reaction (T2R) and control individuals without medical history of leprosy (CTL). METHODS: To assessment of the plasma immune mediators was used multiplex microbeads immunoassay "Luminex". FINDINGS: The results showed that patients (PB) had a regulatory-biased profile, while MB revealed a pro-inflammatory trend of highly expressed biomarkers. HHC display conspicuously increased levels in the plasma of the chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8), pro-inflammatory cytokines (IFN-γ,TNF and IL-1ß), modulating cytokines (IL-9 and IL-1Ra) and growth factors (PDGF, G-CSF and IL-2). Interestingly, HHC displayed superior production of IFN-γ as compared to other leprosy groups, indicating a putative protective role for this cytokine during chronic Mycobacterium leprae exposure. MAIN CONCLUSION: Further investigations are currently underway to elucidate the potential of these mediators as biomarkers applicable to the diagnosis/prognosis of leprosy and also T1R and T2R leprosy reactions.
Asunto(s)
Citocinas , Lepra , Humanos , Mycobacterium leprae , Quimiocinas , BiomarcadoresRESUMEN
Massive vaccination positively impacted the SARS-CoV-2 pandemic, being a strategy to increase the titers of neutralizing antibodies (NAbs) in the population. Assessing NAb levels and understanding the kinetics of NAb responses is critical for evaluating immune protection. In this study, we optimized and validated a PRNT50 assay to assess 50% virus neutralization and evaluated its accuracy to measure NAbs to the original strain or variant of SARS-CoV-2. The optimal settings were selected, such as the cell (2 × 105 cells/well) and CMC (1.5%) concentrations and the viral input (~60 PFU/well) for PRNT-SARS-CoV-2 with cut-off point = 1.64 log5 based on the ROC curve (AUC = 0.999). The validated PRNT-SARS-CoV-2 assay presented high accuracy with an intraassay precision of 100% for testing samples with different NAb levels (low, medium, and high titers). The method displays high selectivity without cross-reactivity with dengue (DENV), measles (MV), zika (ZIKV), and yellow fever (YFV) viruses. In addition, the standardized PRNT-SARS-CoV-2 assay presented robustness when submitted to controlled variations. The validated PRNT assay was employed to test over 1000 specimens from subjects with positive or negative diagnoses for SARS-CoV-2 infection. Patients with severe COVID-19 exhibited higher levels of NAbs than those presenting mild symptoms for both the Wuhan strain and Omicron. In conclusion, this study provides a detailed description of an optimized and validated PRNT50 assay to monitor immune protection and to subsidize surveillance policies applied to epidemiologic studies of COVID-19.
RESUMEN
A safe and effective vaccine with long-term protection against SARS-CoV-2 variants of concern (VOCs) is a global health priority. Here, we develop lipid nanoparticles (LNPs) to provide safe and effective delivery of plasmid DNA (pDNA) and show protection against VOCs in female small animal models. Using a library of LNPs encapsulating unique barcoded DNA (b-DNA), we screen for b-DNA delivery after intramuscular administration. The top-performing LNPs are further tested for their capacity of pDNA uptake in antigen-presenting cells in vitro. The lead LNP is used to encapsulate pDNA encoding the HexaPro version of SARS-CoV-2 spike (LNP-HPS) and immunogenicity and protection is tested in vivo. LNP-HPS elicit a robust protective effect against SARS-CoV-2 Gamma (P.1), correlating with reduced lethality, decreased viral load in the lungs and reduced lung damage. LNP-HPS induce potent humoral and T cell responses against P.1, and generate high levels of neutralizing antibodies against P.1 and Omicron (B.1.1.529). Our findings indicate that the protective efficacy and immunogenicity elicited by LNP-HPS are comparable to those achieved by the approved COVID-19 vaccine from Biontech/Pfizer in animal models. Together, these findings suggest that LNP-HPS hold great promise as a vaccine candidate against VOCs.