The development of an effective immune response can help decrease mortality from malaria and its clinical symptoms. However, this mechanism is complex and has significant inter-individual variation, ...most likely owing to the genetic contribution of the human host. Therefore, this study aimed to investigate the influence of polymorphisms in genes involved in the costimulation of B-lymphocytes in the naturally acquired humoral immune response against proteins of the asexual stage of Plasmodium vivax. A total of 319 individuals living in an area of malaria transmission in the Brazilian Amazon were genotyped for four SNPs in the genes CD40, CD40L, BLYS and CD86. In addition, IgG antibodies against P. vivax apical membrane antigen 1 (PvAMA-1), Duffy binding protein (PvDBP) and merozoite surface protein 1 (PvMSP-119) were detected by ELISA. The SNP BLYS -871C>T was associated with the frequency of IgG responders to PvAMA-1 and PvMSP-119. The SNP CD40 -1C>T was associated with the IgG response against PvDBP, whereas IgG antibody titers against PvMSP-119 were influenced by the polymorphism CD86 +1057G>A. These data may help to elucidate the immunological aspects of vivax malaria and consequently assist in the design of malaria vaccines.
Highlights • A novel chimeric recombinant protein was produced as a malaria immunogen. • This vaccine candidate was highly immunogenic in mice. • The protein potentially offers benefits over the use ...of each antigen alone or mixed.
Studies of Plasmodium falciparum invasion pathways in field isolates have been limited. Red blood cell (RBC) invasion is a complex process involving two invasion protein families; Erythrocyte ...Binding-Like (EBL) and the Reticulocyte Binding-Like (PfRh) proteins, which are polymorphic and not fully characterized in field isolates. To determine the various P. falciparum invasion pathways used by parasite isolates from South America, we studied the invasion phenotypes in three regions: Colombia, Peru and Brazil. Additionally, polymorphisms in three members of the EBL (EBA-181, EBA-175 and EBL-1) and five members of the PfRh (PfRh1, PfRh2a, PfRh2b, PfRh4, PfRh5) families were determined. We found that most P. falciparum field isolates from Colombia and Peru invade RBCs through an atypical invasion pathway phenotypically characterized as resistant to all enzyme treatments (NrTrCr). Moreover, the invasion pathways and the ligand polymorphisms differed substantially among the Colombian and Brazilian isolates while the Peruvian isolates represent an amalgam of those present in the Colombian and Brazilian field isolates. The NrTrCr invasion profile was associated with the presence of the PfRh2a pepC variant, the PfRh5 variant 1 and EBA-181 RVNKN variant. The ebl and Pfrh expression levels in a field isolate displaying the NrTrCr profile also pointed to PfRh2a, PfRh5 and EBA-181 as being possibly the major players in this invasion pathway. Notably, our studies demonstrate the uniqueness of the Peruvian P. falciparum field isolates in terms of their invasion profiles and ligand polymorphisms, and present a unique opportunity for studying the ability of P. falciparum parasites to expand their invasion repertoire after being reintroduced to human populations. The present study is directly relevant to asexual blood stage vaccine design focused on invasion pathway proteins, suggesting that regional invasion variants and global geographical variation are likely to preclude a simple one size fits all type of vaccine.
•Infected individuals with rs6910730A allele had higher IL-6, IL-10, and IFN-γ levels.•IL-5, IL-6, IL-10, TNF-α, and IFN-γ were increased in rs2234237T and infected.•The rs2234246CT genotype group ...and infected had higher levels of TNF-α, and IFN-γ.•IFN-γ was higher in the infected group with rs4711668C allele.•The trem-1 polymorphisms had no impact of the sTREM-1 levels.
The immunopathology during malaria depends on the level of inflammatory response generated. In this scenario, the TREM-1 has been associated with the severity of infectious diseases and could play an important role in the inflammatory course of malaria. We aimed to describe the allelic and genotypic frequency of four polymorphisms in the trem-1 gene in Plasmodium vivax-infected patients and to verify the association of these polymorphisms with clinical and immunological factors in a frontier area of the Brazilian Amazon.
We included 76 individuals infected with P. vivax and 144 healthy controls living in the municipality of Oiapoque, Amapá, Brazil. The levels of TNF-α, IL-10, IL-2, IL-4, IL-5, and IFN-γ were measured by flow cytometry, while IL-6, sTREM-1, and antibodies against PvMSP-119 were evaluated by ELISA. The SNPs were genotyped by qPCR technique. Polymorphisms analysis, allelic and genotype, frequencies, and HWE calculation were determined by x2 test in R Software. The association between the parasitemia, gametocytes, antibodies, cytokines, and sTREM-1 with the genotypes of malaria and control groups was performed using the Kruskal-Wallis test, these analyzes were conducted in SPSS Software, at 5% significance level.
All SNPs were successfully genotyped. Allelic and genotypic distribution was in Hardy-Weinberg Equilibrium. Furthermore, several associations were identified between malaria and control groups, with increased levels of IL-5, IL-6, IL-10, TNF-α, and IFN-γ in the infected individuals with rs6910730A, rs2234237T, rs2234246T, rs4711668C alleles compared to the homozygous wild-type and heterozygous genotypes of the controls (p-value < 0.05). No association was found for these SNPs and the levels of IL-2, and sTREM-1.
The SNPs on the trem-1 gene are associated with the effector molecules of the innate immunity and may contribute to the identification and effective participation of trem-1 in the modulation of the immune response. This association may be essential for the establishment of immunization strategies against malaria.
The coinfection between malaria (ML) and arboviral diseases represents a major global public health problem, particularly in tropical and subtropical countries. Despite its relevance, this topic is ...still insufficiently discussed in the current literature. Here, we aimed to investigate the worldwide distribution, symptoms, and diagnosis during coinfection between ML and arboviral diseases. We conducted a systematic review following the Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and assessed the selection and eligibility criteria, created and diagrammed maps, and analysed major symptoms with 95% confidence intervals (CI) using prevalence ratio and effect size, also performing latent class analysis. A total of 85,485 studies were retrieved, of which 56 were included: 57.14% in Asia, 25% in Africa, 14.30% in South America, and 3.56% in Europe. A total of 746 individuals were reported to be coinfected with Plasmodium and arbovirus. Concurrent ML, Dengue (DEN), Chikungunya (CHIK), and Zika (ZIK) patients are more likely to present headache and skin rash. Regarding diagnosis, 58,253 were made, of which 38,176 were positive (ML and at least one arboviral disease). The magnitude of these pathogens' coexistence points out the pressing need for improvements in public health policies towards diagnosis and prevention of both diseases, especially in endemic areas.The coinfection between malaria (ML) and arboviral diseases represents a major global public health problem, particularly in tropical and subtropical countries. Despite its relevance, this topic is still insufficiently discussed in the current literature. Here, we aimed to investigate the worldwide distribution, symptoms, and diagnosis during coinfection between ML and arboviral diseases. We conducted a systematic review following the Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and assessed the selection and eligibility criteria, created and diagrammed maps, and analysed major symptoms with 95% confidence intervals (CI) using prevalence ratio and effect size, also performing latent class analysis. A total of 85,485 studies were retrieved, of which 56 were included: 57.14% in Asia, 25% in Africa, 14.30% in South America, and 3.56% in Europe. A total of 746 individuals were reported to be coinfected with Plasmodium and arbovirus. Concurrent ML, Dengue (DEN), Chikungunya (CHIK), and Zika (ZIK) patients are more likely to present headache and skin rash. Regarding diagnosis, 58,253 were made, of which 38,176 were positive (ML and at least one arboviral disease). The magnitude of these pathogens' coexistence points out the pressing need for improvements in public health policies towards diagnosis and prevention of both diseases, especially in endemic areas.
In Brazil, Plasmodium vivax infection accounts for around 80% of malaria cases. This infection has a substantial impact on the productivity of the local population as the course of the disease is ...usually prolonged and the development of acquired immunity in endemic areas takes several years. The recent emergence of drug-resistant strains has intensified research on alternative control methods such as vaccines. There is currently no effective available vaccine against malaria; however, numerous candidates have been studied in the past several years. One of the leading candidates is apical membrane antigen 1 (AMA1). This protein is involved in the invasion of Apicomplexa parasites into host cells, participating in the formation of a moving junction. Understanding how the genetic diversity of an antigen influences the immune response is highly important for vaccine development. In this study, we analyzed the diversity of AMA1 from Brazilian P. vivax isolates and 19 haplotypes of P. vivax were found. Among those sequences, 33 nonsynonymous PvAMA1 amino acid sites were identified, whereas 20 of these sites were determined to be located in predicted B-cell epitopes. Nonsynonymous mutations were evaluated for their influence on the immune recognition of these antigens. Two distinct haplotypes, 5 and 16, were expressed and evaluated for reactivity in individuals from northern Brazil. Both PvAMA1 variants were reactive. Moreover, the IgG antibody response to these two PvAMA1 variants was analyzed in an exposed but noninfected population from a P. vivax endemic area. Interestingly, over 40% of this population had antibodies recognizing both variants. These results have implications for the design of a vaccine based on a polymorphic antigen.
•Cytokines: Cytokine levels contribute to clinical manifestations such as parasitemia, severity, and susceptibility in malaria infections.•MSP-119: No associations between SNPs studied of TLRs and ...antibody levels of MSP-1 were observed.•P. vivax: This is the predominant and spread worldwide malaria specie, despite an alarming number of people becoming infected each year, is still considered a neglected disease.•TLRs: Play a critical role in the innate immune response to malaria. They recognize specific parasite-derived molecules and initiate immune signaling pathways.•SNPs: In TLR genes play an important role in malaria pathogenesis and have been associated with susceptibility and parasitemia.
The innate immune response plays an important role during malaria. Toll-like receptors (TLR) are capable of recognizing pathogen molecules. We aimed to evaluate five polymorphisms in TLR-4, TLR-6, and TLR-9 genes and their association with cytokine levels and clinical parameters in malaria from the Brazil-French Guiana border.
A case-control study was conducted in Amapá, Brazil. P. vivax patients and individuals not infected were evaluated. Genotyping of five SNPs was carried out by qPCR. Circulating cytokines were measured by CBA. The MSP-119 IgG antibodies were performed by ELISA.
An association between TLR4 A299G with parasitemia was observed. There was an increase for IFN-ɤ, TNF-ɑ, IL-6, and IL-10 in the TLR-4 A299G and T3911, TLR-6 S249P, and TLR-9 1486C/T, SNPs for the studied malarial groups. There were significant findings for the TLR-4 variants A299G and T3911, TLR-9 1237C/T, and 1486C/T. For the reactivity of MSP-119 antibodies levels, no significant results were found in malaria, and control groups.
The profile of the immune response observed by polymorphisms in TLRs genes does not seem to be standard for all types of malaria infection around the world. This can depend on the human population and the species of Plasmodium.
Duffy blood group polymorphisms are important in areas where Plasmodium vivax predominates, because this molecule acts as a receptor for this protozoan. In the present study, Duffy blood group ...genotyping in P. vivax malaria patients from four different Brazilian endemic areas is reported, exploring significant associations between blood group variants and susceptibility or resistance to malaria.
The P. vivax identification was determined by non-genotypic and genotypic screening tests. The Duffy blood group was genotyped by PCR/RFLP in 330 blood donors and 312 malaria patients from four Brazilian Amazon areas. In order to assess the variables significance and to obtain independence among the proportions, the Fisher's exact test was used.
The data show a high frequency of the FYA/FYB genotype, followed by FYB/FYB, FYA/FYA, FYA/FYB-33 and FYB/FYB-33. Low frequencies were detected for the FYA/FYX, FYB/FYX, FYX/FYX and FYB-33/FYB-33 genotypes. Negative Duffy genotype (FYB-33/FYB-33) was found in both groups: individuals infected and non-infected (blood donors). No individual carried the FYX/FYB-33 genotype. Some of the Duffy genotypes frequencies showed significant differences between donors and malaria patients.
The obtained data suggest that individuals with the FYA/FYB genotype have higher susceptibility to malaria. The presence of the FYB-33 allele may be a selective advantage in the population, reducing the rate of infection by P. vivax in this region. Additional efforts may contribute to better elucidate the physiopathologic differences in this parasite/host relationship in regions endemic for P. vivax malaria, in particular the Brazilian Amazon region.
Humoral immune responses against proteins of asexual blood-stage malaria parasites have been associated with clinical immunity. However, variations in the antibody-driven responses may be associated ...with a genetic component of the human host. The objective of the present study was to evaluate the influence of co-stimulatory molecule gene polymorphisms of the immune system on the magnitude of the humoral immune response against a Plasmodium vivax vaccine candidate antigen.
Polymorphisms in the CD28, CTLA4, ICOS, CD40, CD86 and BLYS genes of 178 subjects infected with P. vivax in an endemic area of the Brazilian Amazon were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The levels of IgM, total IgG and IgG subclasses specific for ICB2-5, i.e., the N-terminal portion of P. vivax merozoite surface protein 1 (PvMSP-1), were determined by enzyme-linked immuno assay. The associations between the polymorphisms and the antibody response were assessed by means of logistic regression models.
After correcting for multiple testing, the IgG1 levels were significantly higher in individuals recessive for the single nucleotide polymorphism rs3116496 in CD28 (p = 0.00004). Furthermore, the interaction between CD28 rs35593994 and BLYS rs9514828 had an influence on the IgM levels (p = 0.0009).
The results of the present study support the hypothesis that polymorphisms in the genes of co-stimulatory components of the immune system can contribute to a natural antibody-driven response against P. vivax antigens.
After a major increase in incidence between the 1970s and the 1990s, the Brazilian Amazon region now accounts for the most cases of Plasmodium falciparum malaria in the Americas. Polymorphism of 10 ...microsatellite loci in the P. falciparum genome was studied in 196 isolates obtained from 5 populations in the region. There was significant multilocus linkage disequilibrium, particularly within populations with lower proportions of mixed-genotype infections. However, most multilocus genotypes in different isolates were distinct, and there was no evidence of any recent epidemic expansion of particular clones. Genetic divergence between populations was very substantial but did not fit a simple model of isolation by distance. Thus, different foci of P. falciparum in Brazil are quite independent, with distinct population structures and minimal gene flow, a finding that has implications for strategies to control infection and to contain the spread of drug resistance at a regional level.
PDF
