Cristiane Guimarães Morais

Universidade Federal de Minas Gerais

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Érika Martins Braga

Universidade Federal de Minas Gerais

Cor Jésus Fernandes Fontes

Universidade Federal de Mato Grosso

Irene S. Soares

Universidade de São Paulo

Lilian Lacerda Bueno

Universidade Federal de Minas Gerais

Marcus Lacerda

Fundação de Medicina Tropical

Ricardo Toshio Fujiwara

Universidade Federal de Minas Gerais

Antoniana U. Krettli

Fundação Oswaldo Cruz

Luíza Carvalho Mourão

Universidade Federal de Minas Gerais

Luzia H. Carvalho

Fundação Oswaldo Cruz

Fernanda Fortes de Araújo

Fundação Oswaldo Cruz

Cooperative Institutions

Universidade Federal de Minas Gerais

Fundação Oswaldo Cruz

Universidade Federal de Mato Grosso

Ministério da Saúde

Institut des Sciences Biologiques

Universidade Federal de Viçosa

Universidade de São Paulo

Instituto Evandro Chagas

Fundação de Medicina Tropical

Universidade Federal do Sul da Bahia

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Immunoglobulin GM 3 23 5,13,14 phenotype is strongly associated with IgG1 antibody responses to Plasmodium vivax vaccine candidate antigens PvMSP1-19 and PvAMA-1

Malaria Journal (2010)

Janardan P. Pandey Cristiane Guimarães Morais Cor Jésus Fernandes Fontes Érika Martins Braga

Humoral immune responses play a key role in the development of immunity to malaria, but the host genetic factors that contribute to the naturally occurring immune responses to malarial antigens are not completely understood. The aim of the present investigation was to determine whether, in subjects exposed to malaria, GM and KM allotypes--genetic markers of immunoglobulin gamma and kappa-type light chains, respectively--contribute to the magnitude of natural antibody responses to target antigens that are leading vaccine candidates for protection against Plasmodium vivax.Sera from 210 adults, who had been exposed to malaria transmission in the Brazilian Amazon endemic area, were allotyped for several GM and KM determinants by a standard hemagglutination-inhibition method. IgG subclass antibodies to P. vivax apical membrane antigen 1 (PvAMA-1) and merozoite surface protein 1 (PvMSP1-19) were determined by an enzyme-linked immunosorbent assay. Multiple linear regression models and the non-parametric Mann-Whitney test were used for data analyses.IgG1 antibody levels to both PvMSP1-19 and PvAMA-1 antigens were significantly higher (P = 0.004, P = 0.002, respectively) in subjects with the GM 3 23 5,13,14 phenotype than in those who lacked this phenotype.Results presented here show that immunoglobulin GM allotypes contribute to the natural antibody responses to P. vivax malaria antigens. These findings have important implications for the effectiveness of vaccines containing PvAMA-1 or PvMSP1-19 antigens. They also shed light on the possible role of malaria as one of the evolutionary selective forces that may have contributed to the maintenance of the extensive polymorphism at the GM loci.

Parasitology

10.1186/1475-2875-9-229

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Citations (15)

Plasmodium vivax recombinant vaccine candidate AMA-1 plays an important role in adaptive immune response eliciting differentiation of dendritic cells

Vaccine (2009)

Lilian Lacerda Bueno Cristiane Guimarães Morais Irene S. Soares Leoneide Érica Maduro Bouillet Oscar Bruña‐Romero

The Apical Membrane Antigen-1 (AMA-1) is a well-characterized and functionally important merozoite protein and is currently considered a major candidate antigen for a malaria vaccine. Previously, we showed that AMA-1 has an influence on cellular immune responses of malaria-naïve subjects, resulting in an alternative activation of monocyte-derived dendritic cells and induction of a pro-inflammatory response by stimulated PBMCs. Although there is evidence, from human and animal malaria model systems that cell-mediated immunity may contribute to both protection and pathogenesis, the knowledge on cellular immune responses in vivax malaria and the factors that may regulate this immunity are poorly understood. In the current work, we describe the maturation of monocyte-derived dendritic cells of P. vivax naturally infected individuals and the effect of P. vivax vaccine candidate Pv-AMA-1 on the immune responses of the same donors. We show that malaria-infected subjects present modulation of DC maturation, demonstrated by a significant decrease in expression of antigen-presenting molecules (CD1a, HLA-ABC and HLA-DR), accessory molecules (CD40, CD80 and CD86) and FcγRI (CD64) receptor (P ≤ 0.05). Furthermore, Pv-AMA-1 elicits an upregulation of CD1a and HLA-DR molecules on the surface of monocyte-derived dendritic cells (P = 0.0356 and P = 0.0196, respectively), and it is presented by AMA-1-stimulated DCs. A significant pro-inflammatory response elicited by Pv-AMA-1-pulsed PBMCs is also demonstrated, as determined by significant production of TNF-α, IL-12p40 and IFN-γ (P ≤ 0.05). Our results suggest that Pv-AMA-1 may partially revert DC down-modulation observed in infected subjects, and exert an important role in the initiation of pro-inflammatory immunity that might contribute substantially to protection.

CD80

CD86

Monocyte

10.1016/j.vaccine.2009.07.031

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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

Microbes and Infection (2012)

Luíza Carvalho Mourão Cristiane Guimarães Morais Lilian Lacerda Bueno M. Carolina Jimenez Irene S. Soares

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. PvMSP-1₁₉ was the most immunogenic antigen and the frequency of responders to this protein tended to increase in P. vivax patients with higher parasitemia. For both antigens, IgG antibody responses tended to be lower in patients who had experienced their first bout of malaria. Furthermore, anemic patients presented higher IgG antibody responses to PvMSP-3α₃₅₉₋₇₉₈. Since the humoral response involves a number of antibodies acting simultaneously on different targets, we performed a Principal Component Analysis (PCA). Anemic patients had, on average, higher first principal component scores (IgG1/IgG2/IgG3/IgG4 anti-MSP3α), which were negatively correlated with hemoglobin levels. Since antibodies against PfMSP-3 have been strongly associated with clinical protection, we cannot exclude the possibility of a dual role of PvMSP-3 specific antibodies in both immunity and pathogenesis of vivax malaria. Our results confirm the high immunogenicity of the conserved C terminus of PvMSP-1 and points to the considerable immunogenicity of polymorphic PvMSP-3α₃₅₉₋₇₉₈ during natural infection.

10.1016/j.micinf.2012.02.011

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Citations (31)

Plasmodium vivax: Induction of CD4+CD25+FoxP3+ Regulatory T Cells during Infection Are Directly Associated with Level of Circulating Parasites

PLoS ONE (2010)

Lilian Lacerda Bueno Cristiane Guimarães Morais Fernanda Fortes de Araújo Juliana de Assis Silva Gomes Rodrigo Corrêa‐Oliveira

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. vivax infection is still poorly characterized. In the current study, we demonstrated that patients with acute P. vivax infection presented a significant augmentation of circulating Tregs producing anti-inflammatory (IL-10 and TGF-beta) as well as pro-inflammatory (IFN-gamma, IL-17) cytokines, which was further positively correlated with parasite burden. Surface expression of GITR molecule and intracellular expression of CTLA-4 were significantly upregulated in Tregs from infected donors, presenting also a positive association between either absolute numbers of CD4(+)CD25(+)FoxP3(+)GITR(+) or CD4(+)CD25(+)FoxP3(+)CTLA-4(+) and parasite load. Finally, we demonstrate a suppressive effect of Treg cells in specific T cell proliferative responses of P. vivax infected subjects after antigen stimulation with Pv-AMA-1. Our findings indicate that malaria vivax infection lead to an increased number of activated Treg cells that are highly associated with parasite load, which probably exert an important contribution to the modulation of immune responses during P. vivax infection.

Regulatory T cell

10.1371/journal.pone.0009623

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Citations (91)

Association of the IgG response to Plasmodium falciparum merozoite protein (C-terminal 19 kD) with clinical immunity to malaria in the Brazilian Amazon region.

American Journal of Tropical Medicine and Hygiene (2002)

Érika Martins Braga Rosa Barros Tânia Afonso Reis Cor Jésus Fernandes Fontes Cristiane Guimarães Morais

The antibody response to the C-terminal 19-kD fragment of Plasmodium falciparum merozoite surface protein-1 (PfMSP1-19) was investigated in groups of subjects living in areas of Brazil with different levels of malaria transmission. The prevalence and the levels of IgG to PfMSP1-19 increased with the time of exposure and were positively correlated with the absence of clinical symptoms in parasitemic patients. The frequency of positive response and the mean level of IgG were higher in areas where malaria prevalence was more intense, especially among asymptomatic patients. The serum absorbance values of the IgG1 isotype were significantly higher among subjects with long-term exposure and in asymptomatic infections. These data suggest a protective role of IgG1 in naturally acquired immunity in spite of the unstable transmission levels in the Brazilian Amazon.

Isotype

Humoral immunity

Merozoite surface protein

Cellular immunity

10.4269/ajtmh.2002.66.461

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Citations (75)

ANTIBODIES TO PLASMODIUM VIVAX APICAL MEMBRANE ANTIGEN 1: PERSISTENCE AND CORRELATION WITH MALARIA TRANSMISSION INTENSITY

American Journal of Tropical Medicine and Hygiene (2006)

Cristiane Guimarães Morais Irene S. Soares Luzia H. Carvalho Cor Jésus Fernandes Fontes Antoniana U. Krettli

The antibody responses to the apical membrane antigen 1 of the Plasmodium vivax (PvAMA-1) were investigated in subjects living in areas of Brazil with different levels of malaria transmission. The prevalence and the levels of IgG to PvAMA-1 increased with the time of exposure. The frequency of a positive response and the mean IgG level were higher in areas where malaria prevalence was more intense, especially among non-infected subjects exposed to moderate transmission over a period of 20 years. The proportions and levels of IgG1and IgG3 isotypes were significantly higher among those subjects with long-term exposure. Antibodies, mainly IgG1, to PvAMA-1 persisted for seven years among subjects briefly exposed to malaria in an outbreak outside the Brazilian malaria-endemic area. These data show the highly immunogenic properties of PvAMA-1 and emphasize its possible use as a malaria vaccine candidate.

Persistence (discontinuity)

10.4269/ajtmh.2006.75.582

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Citations (56)

Interleukin-17 producing T helper cells are increased during natural Plasmodium vivax infection

Acta Tropica (2012)

Lilian Lacerda Bueno Cristiane Guimarães Morais Marcus Lacerda Ricardo Toshio Fujiwara Érika Martins Braga

Recent evidences have demonstrated the importance of Th17 cells in host defense against infectious diseases. However, little is known about their role in parasitic infections. Here, we showed that uncomplicated acute vivax malaria induce a significant expansion of IL-17-producing CD4+ T cells associated to a pro-inflammatory cytokine profile. Furthermore, we demonstrated a correlation between numbers of IL-17+CD4+ T cells and circulating CD4+ T-cells producing IFN-γ, IL-10 and TGF-β. Finally, correlations between number of these cells and morbidity or parasitemia were not detected. Further studies are underway to investigate whether IL-17-producing CD4+ T cells are critically involved in the immunity against Plasmodium vivax infection.

10.1016/j.actatropica.2012.02.071

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Citations (39)

IgG isotype to C-terminal 19�kDa of Plasmodium vivax merozoite surface protein 1 among subjects with different levels of exposure to malaria in Brazil

Parasitology Research (2005)

Cristiane Guimarães Morais Irene S. Soares Luzia H. Carvalho Cor Jésus Fernandes Fontes Antoniana U. Krettli

Merozoite surface protein

Isotype

Asymptomatic carrier

Subclass

10.1007/s00436-005-1314-x

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Citations (53)

Allele-specific antibodies to Plasmodium vivax merozoite surface protein-1: prevalence and inverse relationship to haemoglobin levels during infection

Malaria Journal (2016)

Nuno Sepúlveda Cristiane Guimarães Morais Luíza Carvalho Mourão Matheus França Freire Cor Jésus Fernandes Fontes

Antigenic polymorphisms are considered as one of the main strategies employed by malaria parasites to escape from the host immune responses after infections. Merozoite surface protein-1 (MSP-1) of Plasmodium vivax, a promising vaccine candidate, is a highly polymorphic protein whose immune recognition is not well understood. The IgG responses to conserved (MSP-119) and polymorphic (block 2 and block 10) epitopes of PvMSP-1 were evaluated in 141 P. vivax infected patients. Ten recombinant proteins corresponding to block 2 (variants BR07, BP29, BP39, BP30, BEL) and block 10 (BR07, BP29, BP39, BP01, BP13) often observed in Brazilian P. vivax isolates were assessed by ELISA in order to determine levels of specific antibodies and their respective seroprevalence. The magnitude and the frequency of variant-specific responses were very low, except for BR07 variant (>40%), which was the predominant haplotype as revealed by block 10 PvMSP-1 gene sequencing. By contrast, 89% of patients had IgG against the C-terminal conserved domain (PvMSP-119), confirming the high antigenicity of this protein. Using multiple linear and logistic regression models, there was evidence for a negative association between levels of haemoglobin and several IgG antibodies against block 2 variant antigens, with the strongest association being observed for BP39 allelic version. This variant was also found to increase the odds of anaemia in these patients. These findings may have implications for vaccine development and represent an important step towards a better understanding of the polymorphic PvMSP-1 domain as potential targets of vaccine development. These data highlight the importance of extending the study of these polymorphic epitopes of PvMSP-1 to different epidemiological settings.

Merozoite surface protein

Antigenic variation

Antigenicity

Parasitology

10.1186/s12936-016-1612-z

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Citations (4)

Identification of a Highly Antigenic Linear B Cell Epitope within Plasmodium vivax Apical Membrane Antigen 1 (AMA-1)

PLoS ONE (2011)

Lilian Lacerda Bueno Francisco Pereira Lobo Cristiane Guimarães Morais Luíza Carvalho Mourão Ricardo Andrez Machado‐de‐Ávila

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. Also, we demonstrated a strong association between AMA-1 and DII IgG and IgG subclass responses. We analyzed the primary sequence of PvAMA-1 for B cell linear epitopes co-occurring with intrinsically unstructured/disordered regions (IURs). The B cell epitope comprising the amino acid sequence 290–307 of PvAMA-1 (SASDQPTQYEEEMTDYQK), with the highest prediction scores, was identified in domain II and further selected for chemical synthesis and immunological testing. The antigenicity of the synthetic peptide was identified by serological analysis using sera from P. vivax-infected individuals who were knowingly reactive to the PvAMA-1 ectodomain only, domain II only, or reactive to both antigens. Although the synthetic peptide was recognized by all serum samples specific to domain II, serum with reactivity only to the full-length protein presented 58.3% positivity. Moreover, IgG reactivity against PvAMA-1 and domain II after depletion of specific synthetic peptide antibodies was reduced by 18% and 33% (P = 0.0001 for both), respectively. These results suggest that the linear epitope SASDQPTQYEEEMTDYQK is highly antigenic during natural human infections and is an important antigenic region of the domain II of PvAMA-1, suggesting its possible future use in pre-clinical studies.

Antigenicity

Epitope mapping

10.1371/journal.pone.0021289

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Citations (48)