Luzia H. Carvalho

Fundação Oswaldo Cruz

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Cor Jésus Fernandes Fontes

Universidade Federal de Mato Grosso

Cristiana Ferreira Alves de Brito

Fundação Oswaldo Cruz

Taís Nóbrega de Sousa

Karolinska Institutet

Flora Satiko Kano

Fundação Oswaldo Cruz

John H. Adams

Center for Global Health

Irene S. Soares

Universidade de São Paulo

Francis B. Ntumngia

University of South Florida

Antoniana U. Krettli

Fundação Oswaldo Cruz

Bruno Antônio Marinho Sanchez

Universidade Federal de Mato Grosso

Luiz F. F. Guimarães

Fundação Oswaldo Cruz

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Universidade Federal de Minas Gerais

Universidade de São Paulo

Universidade Estadual Paulista (Unesp)

Universidade Federal de Mato Grosso

Faculdade de Medicina de São José do Rio Preto

Faculdades Oswaldo Cruz

Fundação de Medicina Tropical

Instituto Evandro Chagas

University of Bonn

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Asymptomatic Plasmodium vivax malaria in the Brazilian Amazon: Submicroscopic parasitemic blood infects Nyssorhynchus darlingi

PLoS neglected tropical diseases (2021)

Gregório Guilherme Almeida Pedro Augusto Carvalho Costa Maísa da Silva Araújo Gabriela Ribeiro Gomes Alex F. Carvalho

Individuals with asymptomatic infection due to Plasmodium vivax are posited to be important reservoirs of malaria transmission in endemic regions. Here we studied a cohort of P . vivax malaria patients in a suburban area in the Brazilian Amazon. Overall 1,120 individuals were screened for P . vivax infection and 108 (9.6%) had parasitemia detected by qPCR but not by microscopy. Asymptomatic individuals had higher levels of antibodies against P . vivax and similar hematological and biochemical parameters compared to uninfected controls. Blood from asymptomatic individuals with very low parasitemia transmitted P . vivax to the main local vector, Nyssorhynchus darlingi . Lower mosquito infectivity rates were observed when blood from asymptomatic individuals was used in the membrane feeding assay. While blood from symptomatic patients infected 43.4% (199/458) of the mosquitoes, blood from asymptomatic infected 2.5% (43/1,719). However, several asymptomatic individuals maintained parasitemia for several weeks indicating their potential role as an infectious reservoir. These results suggest that asymptomatic individuals are an important source of malaria parasites and Science and Technology for Vaccines granted by Conselho Nacional de may contribute to the transmission of P . vivax in low-endemicity areas of malaria.

Plasmodium (life cycle)

10.1371/journal.pntd.0009077

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Citations (22)

Increased susceptibility of blood type O individuals to develop anemia in Plasmodium vivax infection

Infection Genetics and Evolution (2017)

Sarah Stela Resende Vanessa Gonçalves Milagres Daniel Gonçalves Chaves Cor Jésus Fernandes Fontes Luzia H. Carvalho

10.1016/j.meegid.2017.03.001

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Citations (9)

Influence of HLA-DRB-1 alleles on the production of antibody against CSP, MSP-1, AMA-1, and DBP in Brazilian individuals naturally infected with Plasmodium vivax

Acta Tropica (2011)

Luciane Moreno Storti-Melo Daniela Reis da Costa Wanessa Christina Souza-Neiras Gustavo Capatti Cassiano Vanja Suely Calvosa D’Almeida Couto

We evaluated the influence of allelic frequency of the human leukocyte antigen (HLA) -DRB1 on the acquisition of antibody response against malaria sporozoite and merozoite peptides in patients with Plasmodium vivax malaria acquired in endemic areas of Brazil. IgG antibodies were detected by enzyme-linked immunosorbent assay against four peptides of circumsporozoite protein (CSP) (amino, carboxyl, and VK210 and VK247 repeats) and peptides of merozoite surface protein 1 (MSP-1), apical membrane antigen 1 (AMA-1), and Duffy-binding protein (DBP). We found an association between HLA-DR3 and HLA-DR5 alleles and lack of antibody response to CSP amino terminal, as well as an association between HLA-DR3 and the highest antibody response to MSP1 (Pv200L). In conclusion, we suggest a potential regulatory role of the HLA-DRB1 alleles in the production of antibodies to a conserved region of P. vivax CSP and MSP1 in Brazilian population exposed to malaria.

Circumsporozoite protein

Merozoite surface protein

Allotype

10.1016/j.actatropica.2011.10.009

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Citations (26)

The Interface Between Inflammatory Mediators and MicroRNAs in Plasmodium vivax Severe Thrombocytopenia

Frontiers in Cellular and Infection Microbiology (2021)

Marina L. S. Santos Roney S. Coimbra Taís Nóbrega de Sousa Luiz F. F. Guimarães Matheus de Souza Gomes

Severe thrombocytopenia can be a determinant factor in the morbidity of Plasmodium vivax , the most widespread human malaria parasite. Although immune mechanisms may drive P. vivax -induced severe thrombocytopenia (PvST), the current data on the cytokine landscape in PvST is scarce and often conflicting. Here, we hypothesized that the analysis of the bidirectional circuit of inflammatory mediators and their regulatory miRNAs would lead to a better understanding of the mechanisms underlying PvST. For that, we combined Luminex proteomics, NanoString miRNA quantification, and machine learning to evaluate an extensive array of plasma mediators in uncomplicated P. vivax patients with different degrees of thrombocytopenia. Unsupervised clustering analysis identified a set of PvST-linked inflammatory (CXCL10, CCL4, and IL-18) and regulatory (IL-10, IL-1Ra, HGF) mediators. Among the mediators associated with PvST, IL-6 and IL-8 were critical to discriminate P. vivax subgroups, while CCL2 and IFN-γ from healthy controls. Supervised machine learning spotlighted IL-10 in P. vivax -mediated thrombocytopenia and provided evidence for a potential signaling route involving IL-8 and HGF. Finally, we identified a set of miRNAs capable of modulating these signaling pathways. In conclusion, the results place IL-10 and IL-8/HGF in the center of PvST and propose investigating these signaling pathways across the spectrum of malaria infections.

10.3389/fcimb.2021.631333

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Exploring the naturally acquired response to Pvs47 gametocyte antigen

Frontiers in Immunology (2024)

Gisele Tatiane Soares da Veiga Rafael Amaral Donassolo Sófia Forcellini Julia Weber Ferraboli Mario Antonio Kujbida

Malaria represents a challenging global public health task, with Plasmodium vivax being the predominant parasite in Brazil and the most widely distributed species throughout the world. Developing a vaccine against P. vivax malaria demands innovative strategies, and targeting gametocyte antigens shows promise for blocking transmission prevention. Among these antigens, Pvs47, expressed in gametocytes, has shown remarkable efficacy in transmission blocking. However, remains underexplored in vaccine formulations. This study employed in silico methods to comprehensively characterize the physicochemical properties, structural attributes, epitope presence, and conservation profile of Pvs47. Additionally, we assessed its antigenicity in individuals exposed to malaria in endemic Brazilian regions. Recombinant protein expression occurred in a eukaryotic system, and antigenicity was evaluated using immunoenzymatic assays. The responses of naturally acquired IgM, total IgG, and IgG subclasses were analyzed in three groups of samples from Amazon region. Notably, all samples exhibited anti-Pvs47 IgM and IgG antibodies, with IgG3 predominating. Asymptomatic patients demonstrated stronger IgG responses and more diverse subclass responses. Anti-Pvs47 IgM and IgG responses in symptomatic individuals decrease over time. Furthermore, we observed a negative correlation between anti-Pvs47 IgM response and gametocytemia in samples of symptomatic patients, indicating a gametocyte-specific response. Additionally, negative correlation was observed among anti-Pvs47 antibody response and hematocrit levels. Furthermore, comparative analysis with widely characterized blood antigens, PvAMA1 and PvMSP1 19 , revealed that Pvs47 was equally or more recognized than both proteins. In addition, there is positive correlation between P. vivax blood asexual and sexual stage immune responses. In summary, our study unveils a significant prevalence of anti-Pvs47 antibodies in diverse Amazonian samples and the importance of IgM response for gametocytes depuration. These findings regarding the in silico characterization and antigenicity of Pvs47 provide crucial insights for potential integration into P. vivax vaccine formulations.

Antigenicity

10.3389/fimmu.2024.1455454

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Evaluating seroprevalence to circumsporozoite protein to estimate exposure to three species of Plasmodium in the Brazilian Amazon

Infectious Diseases of Poverty (2018)

Virgínia Araújo Pereira Juan Camilo Sánchez‐Arcila Mariana Pinheiro Alves Vasconcelos Amanda Ribeiro Ferreira Lorene de Souza Videira

Brazil has seen a great decline in malaria and the country is moving towards elimination. However, for eventual elimination, the control program needs efficient tools in order to monitor malaria exposure and transmission. In this study, we aimed to evaluate whether seroprevalence to the circumsporozoite protein (CSP) is a good tool for monitoring the exposure to and/or evaluating the burden and distribution of Plasmodium species in the Brazilian Amazon.Cross-sectional surveys were conducted in a rural area of Porto Velho, Rondônia state. Parasite infection was detected by microscopy and polymerase chain reaction. Antibodies to the sporozoite CSP repeats of Plasmodium vivax, P. falciparum, and P. malariae (PvCS, PfCS, and PmCS) were detected using the enzyme-linked immunosorbent assay technique. Human leukocyte antigen (HLA)-DRB1 and DQB1 genes were typed using Luminex® xMAP® technology.The prevalence of immunoglobulin G against P. vivax CSP peptide (62%) was higher than P. falciparum (49%) and P. malariae (46%) CSP peptide. Most of the studied individuals had antibodies to at least one of the three peptides (72%), 34% had antibodies to all three peptides and 28% were non-responders. Although the majority of the population was not infected at the time of the survey, 74.3% of parasite-negative individuals had antibodies to at least one of the CSPs. Importantly, among individuals carrying the haplotypes DRB1*04~DQB1*03, there was a significantly higher frequency of PfCS responders, and DRB1*16~DQB1*03 haplotype for PvCS and PfCS responders. In contrast, HLA-DRB1*01 and HLA-DQB1*05 allelic groups were associated with a lack of antibodies to P. vivax and P. falciparum CSP repeats, and the haplotype DRB1*01~DQB1*05 was also associated with non-responders, including non-responders to P. malariae.Our results show that in low transmission settings, naturally acquired antibody responses against the CSP repeats of P. vivax, P. falciparum, and P. malariae in a single cross-sectional study may not represent a valuable marker for monitoring recent malaria exposure, especially in an area with a high prevalence of P. vivax. Furthermore, HLA class II molecules play an important role in antibody response and require further study with a larger sample size. It will be of interest to consider HLA analysis when using serosurveillance to monitor malaria exposure among genetically diverse populations.

Circumsporozoite protein

Seroprevalence

Tropical Medicine

10.1186/s40249-018-0428-1

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Ribosomal and non-ribosomal PCR targets for the detection of low-density and mixed malaria infections

Malaria Journal (2019)

Lara Cotta Amaral Daniela Rocha Robortella Luiz F. F. Guimarães Jean Ezequiel Limongi Cor Jésus Fernandes Fontes

The unexpected high proportion of submicroscopic malaria infections in areas with low transmission intensity challenges the control and elimination of malaria in the Americas. The current PCR-based assays present limitations as most protocols still rely on amplification of few-copies target gene. Here, the hypothesis was that amplification of different plasmodial targets-ribosomal (18S rRNA) and non-ribosomal multi-copy sequences (Pvr47 for Plasmodium vivax and Pfr364 for Plasmodium falciparum)-could increase the chances of detecting submicroscopic malaria infection.A non-ribosomal real-time PCR assay targeting Pvr47/Pfr364 (NR-qPCR) was established and compared with three additional PCR protocols, two of them based on 18S rRNA gene amplification (Nested-PCR and R-qPCR) and one based on Pvr47/Pfr364 targets (NR-cPCR). The limit of detection of each PCR protocol, at single and artificial mixed P. vivax/P. falciparum infections, was determined by end-point titration curves. Field samples from clinical (n = 110) and subclinical (n = 324) malaria infections were used to evaluate the impact of using multiple molecular targets to detect malaria infections.The results demonstrated that an association of ribosomal and non-ribosomal targets did not increase sensitivity to detect submicroscopic malaria infections. Despite of that, artificial mixed-malaria infections demonstrated that the NR-qPCR was the most sensitive protocol to detect low-levels of P. vivax/P. falciparum co-infections. Field studies confirmed that submicroscopic malaria represented a large proportion (up to 77%) of infections among asymptomatic Amazonian residents, with a high proportion of infections (~ 20%) identified only by the NR-qPCR.This study presents a new species-specific non-ribosomal PCR assay with potential to identify low-density P. vivax and P. falciparum infections. As the majority of subclinical infections was caused by P. vivax, the commonest form of malaria in the Amazon area, future studies should investigate the potential of Pvr47/Pfr364 to detect mixed-malaria infections in the field.

Parasitology

Tropical Medicine

10.1186/s12936-019-2781-3

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Citations (30)

Plasmodium vivax Duffy binding protein: baseline antibody responses and parasite polymorphisms in a well‐consolidated settlement of the Amazon Region

Tropical Medicine & International Health (2012)

Flora Satiko Kano Bruno Antônio Marinho Sanchez Taís Nóbrega de Sousa Michaelis L Tang Jéssica Saliba

Abstract Objective To investigate risk factors associated with the acquisition of antibodies against Plasmodium vivax Duffy binding protein (PvDBP) – a leading malaria vaccine candidate – in a well‐consolidated agricultural settlement of the Brazilian Amazon Region and to determine the sequence diversity of the PvDBP ligand domain (DBP II ) within the local malaria parasite population. Methods Demographic, epidemiological and clinical data were collected from 541 volunteers using a structured questionnaire. Malaria parasites were detected by conventional microscopy and PCR, and blood collection was used for antibody assays and molecular characterisation of DBP II . Results The frequency of malaria infection was 7% (6% for P. vivax and 1% for P. falciparum ), with malaria cases clustered near mosquito breeding sites. Nearly 50% of settlers had anti‐PvDBP IgG antibodies, as detected by enzyme‐linked immunosorbent assay (ELISA) with subject’s age being the only strong predictor of seropositivity to PvDBP. Unexpectedly, low levels of DBP II diversity were found within the local malaria parasites, suggesting the existence of low gene flow between P. vivax populations, probably due to the relative isolation of the studied settlement. Conclusion The recognition of PvDBP by a significant proportion of the community, associated with low levels of DBP II diversity among local P. vivax , reinforces the variety of malaria transmission patterns in communities from frontier settlements. Such studies should provide baseline information for antimalarial vaccines now in development.

Parasitology

10.1111/j.1365-3156.2012.03016.x

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Citations (33)

Duffy Antigen Receptor for Chemokine (DARC) Polymorphisms and Its Involvement in Acquisition of Inhibitory Anti-Duffy Binding Protein II (DBPII) Immunity

PLoS ONE (2014)

Flávia A. Souza-Silva Leticia M. Torres-Martı́nez Jessica R. Santos-Alves Michaelis L Tang Bruno Antônio Marinho Sanchez

The Plasmodium vivax Duffy binding protein (PvDBP) and its erythrocytic receptor, the Duffy antigen receptor for chemokines (DARC), are involved in the major P. vivax erythrocyte invasion pathway. An open cohort study to analyze DARC genotypes and their relationship to PvDBP immune responses was carried out in 620 volunteers in an agricultural settlement of the Brazilian Amazon. Three cross-sectional surveys were conducted at 6-month intervals, comprising 395, 410, and 407 subjects, respectively. The incidence rates of P. vivax infection was 2.32 malaria episodes per 100 person-months under survey (95% confidence interval [CI] of 1.92-2.80/100 person-month) and, of P. falciparum, 0.04 per 100 person-months (95% CI of 0.007–0.14/100 person-month). The distribution of DARC genotypes was consistent with the heterogeneous ethnic origins of the Amazon population, with a predominance of non-silent DARC alleles: FY*A > FY*B. The 12-month follow-up study demonstrated no association between DARC genotypes and total IgG antibodies as measured by ELISA targeting PvDBP (region II, DBPII or regions II–IV, DBPII-IV). The naturally acquired DBPII specific binding inhibitory antibodies (BIAbs) tended to be more frequent in heterozygous individuals carrying a DARC-silent allele (FY*BES). These results provide evidence that DARC polymorphisms may influence the naturally acquired inhibitory anti-Duffy binding protein II immunity.

10.1371/journal.pone.0093782

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Antimalarial chemotherapy with natural products and chemically defined molecules

Memórias do Instituto Oswaldo Cruz (1991)

Luzia H. Carvalho Antoniana U. Krettli

In the present work we have described the in vivo antimalarial actrivity of six different plants. Two of them (Verninia brasiliana and Eupatorium squalidum) were tested in a randomic approach among 273 crude extracts from plants; four (Acanhospermum australe, Esenbeckia febrifuga, Lisianthus specious and Tachia guianensis) were selected after screening 22 crude extracts from different medicinal and some of them showed antimalarial activity in vitro. Some aspects of recent research with natural products aiming to produce drugs are discussed.

Eupatorium

10.1590/s0074-02761991000600041

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Citations (62)