Validation of a yellow fever vaccine model using data from primary vaccination in children and adults, re-vaccination and dose-response in adults and studies with immunocompromised individuals

Background: An effective yellow fever (YF) vaccine has been available since 1937. Nevertheless, questions regarding its use remain poorly understood, such as the ideal dose to confer immunity against the disease, the need for a booster dose, the optimal immunisation schedule for immunocompetent, immunosuppressed, and pediatric populations, among other issues. This work aims to demonstrate that computational tools can be used to simulate different scenarios regarding YF vaccination and the immune response of individuals to this vaccine, thus assisting the response of some of these open questions. Results: This work presents the computational results obtained by a mathematical model of the human immune response to vaccination against YF. Five scenarios were simulated: primovaccination in adults and children, booster dose in adult individuals, vaccination of individuals with autoimmune diseases under immunomodulatory therapy, and the immune response to different vaccine doses. Where data were available, the model was able to quantitatively replicate the levels of antibodies obtained experimentally. In addition, for those scenarios where data were not available, it was possible to qualitatively reproduce the immune response behaviours described in the literature. Conclusions: Our simulations show that the minimum dose to confer immunity against YF is half of the reference dose. The results also suggest that immunological immaturity in children limits the induction and persistence of long-lived plasma cells are related to the antibody decay observed experimentally. Finally, the decay observed in the antibody level after ten years suggests that a booster dose is necessary to keep immunity against YF

Analysis of the immunological biomarker profile during acute zika virus infection reveals the overexpression of CXCL10, a chemokine linked to neuronal damage

BACKGROUND Infection with Zika virus (ZIKV) manifests in a broad spectrum of disease ranging from mild illness to severe neurological complications and little is known about Zika immunopathogenesis. OBJECTIVES To define the immunologic biomarkers that correlate with acute ZIKV infection. METHODS We characterized the levels of circulating cytokines, chemokines, and growth factors in 54 infected patients of both genders at five different time points after symptom onset using microbeads multiplex immunoassay; comparison to 100 age-matched controls was performed for statistical analysis and data mining. FINDINGS ZIKV-infected patients present a striking systemic inflammatory response with high levels of pro-inflammatory mediators. Despite the strong inflammatory pattern, IL-1Ra and IL-4 are also induced during the acute infection. Interestingly, the inflammatory cytokines IL-1β, IL-13, IL-17, TNF-α, and IFN-γ; chemokines CXCL8, CCL2, CCL5; and the growth factor G-CSF, displayed a bimodal distribution accompanying viremia. While this is the first manuscript to document bimodal distributions of viremia in ZIKV infection, this has been documented in other viral infections, with a primary viremia peak during mild systemic disease and a secondary peak associated with distribution of the virus to organs and tissues. MAIN CONCLUSIONS Biomarker network analysis demonstrated distinct dynamics in concurrence with the bimodal viremia profiles at different time points during ZIKV infection. Such a robust cytokine and chemokine response has been associated with blood-brain barrier permeability and neuroinvasiveness in other flaviviral infections. High-dimensional data analysis further identified CXCL10, a chemokine involved in foetal neuron apoptosis and Guillain-Barré syndrome, as the most promising biomarker of acute ZIKV infection for potential clinical application. © 2018, Fundacao Oswaldo Cruz. All rights reserved

Panoramic snapshot of serum soluble mediator interplay in pregnant women with convalescent COVID-19: an exploratory study

IntroductionSARS-CoV-2 infection during pregnancy can induce changes in the maternal immune response, with effects on pregnancy outcome and offspring. This is a cross-sectional observational study designed to characterize the immunological status of pregnant women with convalescent COVID-19 at distinct pregnancy trimesters. The study focused on providing a clear snapshot of the interplay among serum soluble mediators.MethodsA sample of 141 pregnant women from all prenatal periods (1st, 2nd and 3rd trimesters) comprised patients with convalescent SARS-CoV-2 infection at 3-20 weeks after symptoms onset (COVID, n=89) and a control group of pre-pandemic non-infected pregnant women (HC, n=52). Chemokine, pro-inflammatory/regulatory cytokine and growth factor levels were quantified by a high-throughput microbeads array.ResultsIn the HC group, most serum soluble mediators progressively decreased towards the 2nd and 3rd trimesters of pregnancy, while higher chemokine, cytokine and growth factor levels were observed in the COVID patient group. Serum soluble mediator signatures and heatmap analysis pointed out that the major increase observed in the COVID group related to pro-inflammatory cytokines (IL-6, TNF-α, IL-12, IFN-γ and IL-17). A larger set of biomarkers displayed an increased COVID/HC ratio towards the 2nd (3x increase) and the 3rd (3x to 15x increase) trimesters. Integrative network analysis demonstrated that HC pregnancy evolves with decreasing connectivity between pairs of serum soluble mediators towards the 3rd trimester. Although the COVID group exhibited a similar profile, the number of connections was remarkably lower throughout the pregnancy. Meanwhile, IL-1Ra, IL-10 and GM-CSF presented a preserved number of correlations (≥5 strong correlations in HC and COVID), IL-17, FGF-basic and VEGF lost connectivity throughout the pregnancy. IL-6 and CXCL8 were included in a set of acquired attributes, named COVID-selective (≥5 strong correlations in COVID and <5 in HC) observed at the 3rd pregnancy trimester.Discussion and conclusionFrom an overall perspective, a pronounced increase in serum levels of soluble mediators with decreased network interplay between them demonstrated an imbalanced immune response in convalescent COVID-19 infection during pregnancy that may contribute to the management of, or indeed recovery from, late complications in the post-symptomatic phase of the SARS-CoV-2 infection in pregnant women

Influência do antígeno solúvel de ovos de Schistosoma mansoni sobre a ativação e progressão do ciclo celular de linfócitos T de indivíduos infectados e não infectados por Schistosoma mansoni e/ou Necator americanus

Submitted by Nuzia Santos ([email protected]) on 2013-01-25T11:10:46Z No. of bitstreams: 1 Ana_Carolina_Campi_Azevedo.pdf: 1918315 bytes, checksum: a62cce824b234bbc8dcecd085f2c7908 (MD5)Made available in DSpace on 2013-01-25T11:10:46Z (GMT). No. of bitstreams: 1 Ana_Carolina_Campi_Azevedo.pdf: 1918315 bytes, checksum: a62cce824b234bbc8dcecd085f2c7908 (MD5) Previous issue date: 2007Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil.A infecção pelo S. mansoni é muito freqüente em regiões com condições precárias de saneamento básico, resultando em elevadas prevalências de esquistossomose nas populações entre 10 e 20 anos de idade. A patologia desta infecção é caracterizada pela formação de granulomas em torno dos ovos liberados pelos vermes adultos, no interior do sistema portahepático. Sabe-se que, os pacientes portadores da infecção crônica apresentam uma modulação da capacidade proliferativa em resposta ao antígeno solúvel de ovos de S. mansoni (SEA) e, este estado parece ser benéfico para o hospedeiro e tem sido considerada fundamental para o equilíbrio hospedeiro-parasito. Em contrapartida, indivíduos não infectados residentes em área endêmica para esquistossomose apresentam uma elevada reatividade celular em resposta a estes antígenos. Neste trabalho, comparamos a influência do SEA na progressão do ciclo celular de linfócitos T do sangue periférico de pacientes portadores de infecção crônica pelo S. mansoni (XTO), de indivíduos não infectados residentes em área endêmica (NEG) e de indivíduos não infectados, porém não residentes em área endêmica, denominados por DS. Nossos resultados mostraram que pacientes XTO apresentam uma modulação da resposta ao SEA e, sugerem que esta imunossupressão pode ser devido a participação das células T reguladoras, que secretam IL-10 em resposta ao SEA. A citocina IL-10 pode atuar inibindo a ativação celular de linfócitos T CD4+ e CD8+, por meio do bloqueio destas células nas fases G0/G1 do ciclo celular, promovendo a anergia nestas células. Este bloqueio da progressão do ciclo celular se dá por inibição da expressão da ciclina D1,2,3 nos linfócitos T. Por outro lado, nas culturas celulares dos indivíduos NEG estimuladas com SEA, foram detectados níveis elevados de TNF-α, ativação celular dos linfócitos T CD4+ e CD8+ e um aumento da expressão da ciclina D1,2,3, promovendo a progressão através do ciclo celular em resposta ao SEA. Em áreas endêmicas, existe uma alta prevalência de ancilostomídeos co-infectando pacientes portadores de S. mansoni. Neste contexto, avaliamos também a influência da presença da co-infecção pelo N. americanus na resposta imunológica ao SEA de pacientes infectados por S. mansoni. Nossos resultados mostraram que tanto as PBMC de pacientes mono-infectados (MONO) quanto as de co-infectados (CO) apresentaram anergia celular em resposta ao SEA, sugerindo que a presença da infecção por N. americanus não influencia na resposta imune ao SEA.S. mansoni infection is frequent in regions where factors such as poor sanitary conditions occur and may lead to high prevalence of the disease mainly in individuals of the age groups of 10 to 20 years. The pathology caused by the infection is characterized by granulomatous reactions around the eggs eliminated by the parasites that are trapped in the tissues and the hepatic-portal system. It is well known that during the chronic phase individuals that harbor the infection modulate their cellular immune response to soluble egg antigens (SEA) and this immune reactivity is highly accepted to be beneficial to the host and fundamental for the maintenance of equilibrium of the host-parasite interaction. In contrast to infected individual, those not infected but living in an endemic area for the disease show high cellular reactivity to the same antigens. In this thesis, we evaluate the effect of that the response to SEA has on the cell cycle progression of peripheral blood T lymphocyte from patients in the chronic phase of the disease (XTO), non-infected individuals living in endemic areas (NEG) and of non-infected individuals that do not reside in endemic areas (DS). Our results show that cells from XTO have a modulated response to SEA and suggest that this immunosuppression may be due to regulatory T cells that secret IL-10 in response to SEA. IL-10 may act via the inhibition of the activation of CD4+ and CD8+ T lymphocytes by blocking these cells in the G0/G1 phase of the cell cycle promoting anergy of these cells. The blockage of cell cycle progression occurs via the inhibition of the expression of cyclin D1,2,3 by the T lymphocytes. On the other hand, cells from NEG stimulated in vitro with SEA, high levels of TNF-α secretion was detected, together with the activation of both CD4+ and CD8+ cells and increase on the expression of cyclin D1,2,3 with consequent progression of these cell through the cell cycle. In endemic areas, there is a high prevalence of hookworms co-infecting individuals with S. mansoni. We therefore, evaluated the putative influence of the co-infection with N. americanus on the immune response of S. mansoni infected patients to in vitro SEA stimulation. Our results show that peripheral blood mononuclear cells (PBMC) from mono-infected patients (MONO) as well as of co-infected (CO) were anergic to SEA, suggesting that the presence of the infection by N. americanus does not influence the response to SEA

Divergent cytokine response following maximum progressiveswimming in hot water.

Exercise promotes transitory alterations in cytokine secretion, and these changes are affected by exercise duration and intensity. Consideringthat exercise responses also are affected by environmental factors, the goal of the present study was to investigate the effect of watertemperature on the cytokine response to maximum swimming. Swiss mice performed a maximum progressive swimming exercise at 31 or38C, and plasma cytokine levels were evaluated immediately or 1, 6 or 24 h after exercise. The cytokine profile after swimming at 31Cwas characterized by increased interleukin (IL)-6 and monocyte chemotactic protein-1 (MCP-1) levels, which peaked 1 h after exercise, sug-gesting an adequate inflammatory milieu to induce muscle regeneration. Transitory reductions in IL-10 and IL-12 levels also were observedafter swimming at 31C. The cytokine response to swimming was modified when the water temperature was increased to 38C. Althoughexercise at 38C also led to IL-6 secretion, the peak in IL-6 production occurred 6 h after exercise, and IL-6 levels were significantly lowerthan those observed after maximum swimming at 31C(p =0030). Furthermore, MCP-1 levels were lower and tumour necrosis factor-alevels were higher immediately after swimming at 38C, suggesting a dysregulated pro-inflammatory milieu. These alterations in the cyto-kine profile can be attributed in part to reduced exercise total work because exhaustion occurred sooner in mice swimming at 38C than inthose swimming at 31oC

The 17D-204 and 17DD yellow fever vaccines: an overview of major similarities and subtle differences

Introduction: The yellow fever vaccine is a live attenuated virus vaccine that is considered one of the most efficient vaccines produced to date. The original 17D strain generated the substrains 17D-204 and 17DD, which are used for the current production of vaccines against yellow fever. The 17D-204 and 17DD substrains present subtle differences in their nucleotide compositions, which can potentially lead to variations in immunogenicity and reactogenicity. We will address the main changes in the immune responses induced by the 17D-204 and 17DD yellow fever vaccines and report similarities and differences between these vaccines in cellular and humoral immunity . This is a relevant issue in view of the re-emergence of yellow fever in Uganda in 2016 and in Brazil in the beginning of 2017. Areas covered: This article will be divided into 8 sections that will analyze the innate immune response, adaptive immune response, humoral response, production of cytokines, immunity in children, immunity in the elderly, gene expression and adverse reactions. Expert commentary: The 17D-204 and 17DD yellow fever vaccines present similar immunogenicity, with strong activation of the cellular and humoral immune responses. Additionally, both vaccines have similar adverse effects, which are mostly mild and thus are considered safe

Swim training does not protect mice from skeletal muscle oxidative damage following a maximum exercise test.

We investigated whether swim training protects skeletal muscle from oxidative damage in response to a maximum progressive exercise. First, we investigated the effect of swim training on the activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), in the gastrocnemius muscle of C57Bl/6 mice, 48 h after the last training session. Mice swam for 90 min, twice a day, for 5 weeks at 31C (?1C). The activities of SOD and CAT were increased in trained mice (P\0.05) compared to untrained group. However, no effect of training was observed in the activity of GPx. In a second experiment, trained and untrained mice were submitted to a maximum progressive swim test. Compared to control mice (untrained, not acutely exercised), malondialdehyde (MDA) levels were increased in the skeletal muscle of both trained and untrained mice after maximum swim. The activity of GPx was increased in the skeletal muscle of both trained and untrained mice, while SOD activity was increased only in trained mice after maximum swimming. CAT activity was increased only in the untrained compared to the control group. Although the trained mice showed increased activity of citrate synthase in skeletal muscle, swim performance was not different compared to untrained mice. Our results show an imbalance in the activities of SOD, CAT and GPx in response to swim training, which could account for the oxidative damage observed in the skeletal muscle of trained mice in response to maximum swim, resulting in the absence of improved exercise performance

Distinct pattern of immunophenotypic features of innate and adaptive immunity as a putative signature of clinical and laboratorial status of patients with localized cutaneous leishmaniasis

Submitted by Nuzia Santos ([email protected]) on 2014-03-26T17:57:42Z No. of bitstreams: 1 Distinct pattern of immunophenotypic features of innate and adaptive immunity as a putative signature of clinical and laboratorial status of patients with localized cutaneous leishmaniasis.pdf: 363556 bytes, checksum: aa0f7007fe0304cc8325f473d2a830d9 (MD5)Made available in DSpace on 2014-03-26T17:57:42Z (GMT). No. of bitstreams: 1 Distinct pattern of immunophenotypic features of innate and adaptive immunity as a putative signature of clinical and laboratorial status of patients with localized cutaneous leishmaniasis.pdf: 363556 bytes, checksum: aa0f7007fe0304cc8325f473d2a830d9 (MD5) Previous issue date: 2012CNPq, FAPEMIG, PNPD/CAPES, CPqRR/FIOCRUZ-Minas.Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrazilUniversidade Federal de Ouro Preto. Núcleo de Pesquisas em Ciências Biológicas. Ouro Preto, MG, Brazil/Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Parasitologia. Belo Horizonte, MG, BrazilUniversidade Federal de Ouro Preto. Núcleo de Pesquisas em Ciências Biológicas. Ouro Preto, MG, Brazil/Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Parasitologia. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrazilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Morfologia. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrazilIn this study, we have analysed the phenotypic features of innate/adaptive immunity of patients with localized cutaneous leishmaniasis (LCL), categorized according to their clinical/laboratorial status, including number of lesion (L1; L2–4), days of illness duration (≤60;>60) and positivity in the Montenegro skin test (MT−;MT+). Our findings highlighted a range of phenotypic features observed in patients with LCL (↑%HLA-DR+ neutrophils; ↑CD8+ HLA-DR+/CD4+ HLA-DR+ T cell ratio; ↑HLA-DR in B lymphocytes, ↑%CD23+ neutrophils, monocytes and B cells; ↑α-Leishmania IgG and ↑serum + ). Selective changes were observed in L1 (↑%HLA-DR+ neutrophils, ↑CD8+ HLA-DR+/CD4+ HLA-DR+ T cell ratio and ↑serum + ) as compared to L2–4 (↑%CD5− B cells; ↑CD23+ B cells and ↑α-Leishmania IgG). Whilst ≤60 presented a mixed profile of innate/adaptive immunity (↓%CD28+ neutrophils and ↑%CD4+ T cells), >60 showed a well-known leishmanicidal events (↑CD8+ T cells; ↑serum + and ↑α-Leishmania IgG). MT+ patients showed increased putative leishmanicidal capacity (↑%HLA-DR+ neutrophils; ↑%CD23+ monocytes; ↑CD8+ HLA-DR+/CD4+ HLA-DR+ T cell ratio and ↑ serum + ). Overall, a range of immunological biomarkers illustrates the complex immunological network associated with distinct clinical/laboratorial features of LCL with applicability in clinical studies