A First Natural Infection Induces Increased Activity of the Interferon Gamma-Driven Tryptophan Catabolism Pathway.

The human immune response that controls infection in the liver and blood stages of the parasite life cycle is composed by both pro- and anti-inflammatory programs. Pro-inflammatory responses primarily mediated by IFN-γ controls the infection, but also induce tolerogenic mechanisms to limit host damage, including the tryptophan (TRP) catabolism pathway mediated by the enzyme Indoleamine 2,3-Dioxygenase (IDO1), an enzyme that catalyzes the degradation of TRP to kynurenines (KYN). Here we assessed total serum kynurenines and cytokine dynamics in a cohort of natural human infection and compared them to those of endemic healthy controls and other febrile diseases.

Protective Immunity in Mice Immunized With MSP1-Based Formulations and Challenged With Expressing MSP1.

The lack of continuous cultures has been an obstacle delaying pre-clinical testing of vaccine formulations based on known antigens. In this study, we generated a model to test available formulations based on the MSP1 antigen. The strains ANKA and NK65 were modified to express MSP1 instead of the endogenous MSP1.

Novel Insights into Plasmodium vivax Therapeutic Failure: CYP2D6 Activity and Time of Exposure to Malaria Modulate the Risk of Recurrence.

relapse is one of the major causes of sustained global malaria transmission. Primaquine (PQ) is the only commercial drug available to prevent relapses, and its efficacy is dependent on metabolic activation by cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 function, caused by allelic polymorphisms, leads to the therapeutic failure of PQ as a radical cure for malaria.

Apical membrane protein 1-specific antibody profile and temporal changes in peripheral blood B-cell populations in Plasmodium vivax malaria.

Plasmodium falciparum-specific antibodies tend to be short-lived, but their cognate memory B cells (MBCs) circulate in the peripheral blood of exposed subjects for several months or years after the last infection. However, the time course of antigen-specific antibodies and B-cell responses to the relatively neglected parasite Plasmodium vivax remains largely unexplored. Here, we showed that uncomplicated vivax malaria elicits short-lived antibodies but long-lived MBC responses to a major blood-stage P vivax antigen, apical membrane protein 1 (PvAMA-1), in subjects exposed to declining malaria transmission in the Amazon Basin of Brazil.

Susceptibility to Plasmodium vivax malaria associated with DARC (Duffy antigen) polymorphisms is influenced by the time of exposure to malaria.

Malaria has provided a major selective pressure and has modulated the genetic diversity of the human genome. The variants of the Duffy Antigen/Receptor for Chemokines (DARC) gene have probably been selected by malaria parasites, particularly the FY*O allele, which is fixed in sub-Saharan Africa and confers resistance to Plasmodium vivax infection. Here, we showed the influence of genomic ancestry on the distribution of DARC genotypes in a highly admixed Brazilian population and confirmed the decreased susceptibility of the FY*A/FY*O genotype to clinical P.

CpG Oligodeoxinucleotides and Flagellin Modulate the Immune Response to Antigens Targeted to CD8α and CD8α Conventional Dendritic Cell Subsets.

Dendritic cells (DCs) are antigen-presenting cells essential for the induction of adaptive immune responses. Their unprecedented ability to present antigens to T cells has made them excellent targets for vaccine development. In the last years, a new technology based on antigen delivery directly to different DC subsets through the use of hybrid monoclonal antibodies (mAbs) to DC surface receptors fused to antigens of interest opened new perspectives for the induction of robust immune responses.

T follicular helper cells regulate the activation of B lymphocytes and antibody production during Plasmodium vivax infection.

Although the importance of humoral immunity to malaria has been established, factors that control antibody production are poorly understood. Follicular helper T cells (Tfh cells) are pivotal for generating high-affinity, long-lived antibody responses. While it has been proposed that expansion of antigen-specific Tfh cells, interleukin (IL) 21 production and robust germinal center formation are associated with protection against malaria in mice, whether Tfh cells are found during Plasmodium vivax (P.

The influence of intestinal parasites on Plasmodium vivax-specific antibody responses to MSP-119 and AMA-1 in rural populations of the Brazilian Amazon.

Background: Polyparasitism is a common condition in humans but its impact on the host immune system and clinical diseases is still poorly understood. There are few studies of the prevalence and the effect of malaria-intestinal parasite co-infections in the immune response to malaria vaccine candidates. The present study determines whether the presence of malaria and intestinal parasites co-infection is associated with impaired IgG responses to Plasmodium vivax AMA-1 and MSP-119 in a rural population of the Brazilian Amazon.

Immunogenicity of recombinant proteins consisting of Plasmodium vivax circumsporozoite protein allelic variant-derived epitopes fused with Salmonella enterica Serovar Typhimurium flagellin.

A Plasmodium falciparum circumsporozoite protein (CSP)-based recombinant fusion vaccine is the first malaria vaccine to reach phase III clinical trials. Resistance to infection correlated with the production of antibodies to the immunodominant central repeat region of the CSP. In contrast to P.

Tryptamine and dimethyltryptamine inhibit indoleamine 2,3 dioxygenase and increase the tumor-reactive effect of peripheral blood mononuclear cells.

Indoleamine 2,3-dioxygenase (IDO) is an interferon-γ (IFN-γ)-induced tryptophan-degrading enzyme, producing kynurenine (KYN) that participates in the mechanism of tumor immune tolerance. Thus, IDO inhibition has been considered a strategy for anticancer therapy. The aim of this study was to identify whether the metabolites originated from the competitive routes of tryptophan metabolism, such as the serotonergic or N, N-dimethyltryptamine (DMT) pathways, have inhibitory effects on recombinant human IDO (rhIDO) activity.

Naturally acquired antibodies to Plasmodium vivax blood-stage vaccine candidates (PvMSP-1₁₉ and PvMSP-3α₃₅₉₋₇₉₈ and their relationship with hematological features in malaria patients from the Brazilian Amazon.

An important step when designing a vaccine is identifying the antigens that function as targets of naturally acquired antibodies. We investigated specific antibody responses against two Plasmodium vivax vaccine candidates, PvMSP-1₁₉ and PvMSP-3α₃₅₉₋₇₉₈. Moreover, we assessed the relationship between these antibodies and morbidity parameters.

Identification of a highly antigenic linear B cell epitope within Plasmodium vivax apical membrane antigen 1 (AMA-1).

Apical membrane antigen 1 (AMA-1) is considered to be a major candidate antigen for a malaria vaccine. Previous immunoepidemiological studies of naturally acquired immunity to Plasmodium vivax AMA-1 (PvAMA-1) have shown a higher prevalence of specific antibodies to domain II (DII) of AMA-1. In the present study, we confirmed that specific antibody responses from naturally infected individuals were highly reactive to both full-length AMA-1 and DII.

Plasmodium vivax: induction of CD4+CD25+FoxP3+ regulatory T cells during infection are directly associated with level of circulating parasites.

Circulation CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) have been associated with the delicate balancing between control of overwhelming acute malaria infection and prevention of immune pathology due to disproportionate inflammatory responses to erythrocytic stage of the parasite. While the role of Tregs has been well-documented in murine models and P. falciparum infection, the phenotype and function of Tregs in P.

Direct effect of Plasmodium vivax recombinant vaccine candidates AMA-1 and MSP-119 on the innate immune response.

The recombinant apical membrane antigen 1 (AMA-1) and 19-kDa fragment of merozoite surface protein (MSP-1(19)) are the lead candidates for inclusion in a vaccine against blood stages of malaria due to encouraging protective studies in humans and animals. Despite the importance of an efficacious malaria vaccine, vaccine-related research has focused on identifying antigens that result in protective immunity rather than determining the nature of anti-malarial immune effector mechanisms. Moreover, emphasis has been placed on adaptive rather than innate immune responses.

A multianalyte Dot-ELISA for simultaneous detection of malaria, Chagas disease, and syphilis-specific IgG antibodies.

A multianalyte Dot-enzyme-linked immunosorbent assay (Dot-ELISA-Multi) with Trypanosoma cruzi epimastigote alkaline extract (EAE), trypomastigote excreted-secreted antigen (TESA), recombinant protein derived from 19-kDa C-terminal region of the Plasmodium vivax merozoite surface protein 1 (PvMSP1(19)), Plasmodium falciparum Zwittergent extract (Pf-Zw), and Treponema pallidum Zwittergent extract (Tp-Zw) was standardized and evaluated as a method for surveying IgG-specific antibodies in Chagas disease, malaria, and syphilis in a single test. The study was carried out on serum samples from 52 patients with chronic Chagas disease, 103 individuals with current (parasitemic) or past malaria (aparasitemic), 43 patients with syphilis, 21 individuals with heterologous antibodies, and 100 blood donors. Dot-ELISA-Multi yielded 99% specificity for Chagas disease and 100% for malaria and syphilis.