RESUMO
Mary Lopez-Perez works on immunology and pathogenesis of malaria. In this mSphere of Influence article, she reflects on how the paper "Functional antibodies against VAR2CSA in nonpregnant populations from Colombia exposed to Plasmodium falciparum and Plasmodium vivax" by S. Gnidehou, J. Doritchamou, E. M. Arango, A. Cabrera, et al. (Infect Immun 82:2565-2573, 2014, https://doi.org/10.1128/IAI.01594-14) made her cautious of relying exclusively on recombinant proteins when evaluating antibody responses.
Assuntos
Formação de Anticorpos , Malária Falciparum/imunologia , Malária Vivax/imunologia , Anticorpos Antiprotozoários/imunologia , Colômbia , Feminino , Humanos , Imunoglobulina G/imunologia , Plasmodium falciparum , Plasmodium vivax , Gravidez , Proteínas RecombinantesRESUMO
Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure. We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA. The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5ε domain of VAR2CSA that are recognized by SD1 antibodies. Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes.IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.
Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Epitopos/imunologia , Imunidade Heteróloga , Plasmodium falciparum/imunologia , Plasmodium vivax/imunologia , Proteínas de Protozoários/imunologia , Receptores de Superfície Celular/imunologia , Animais , Brasil , Adesão Celular , Sulfatos de Condroitina/metabolismo , Colômbia , Reações Cruzadas , Mapeamento de Epitopos , Humanos , Malária Falciparum/imunologia , Malária Vivax/imunologia , Camundongos , Uganda , Fatores de Virulência/imunologiaRESUMO
Clinical immunity to malaria is associated with the acquisition of IgG specific for members of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family of clonally variant antigens on the surface of infected erythrocytes (IEs). The VAR2CSA subtype of PfEMP1 mediates IE binding in the placenta. VAR2CSA-specific IgG is normally acquired only after exposure to placental parasites. However, it was recently reported that men and children from Colombia often have high levels of functional VAR2CSA-specific IgG. This potentially undermines the current understanding of malaria immunity in pregnant women, and we thus conducted a study to assess further the levels of VAR2CSA-specific IgG in pregnant and nonpregnant Colombians. Plasma IgG against two full-length recombinant PfEMP1 proteins (one of the VAR2CSA type and one not) produced in baculovirus-transfected insect cells was detected frequently among Colombian men, children, and pregnant women with acute or previous malaria exposure. In contrast, IgG reactivity to a homologous full-length VAR2CSA-type protein expressed in Chinese hamster ovary (CHO) cells was low and infrequent among the Colombian plasma samples, as was reactivity to both corresponding native PfEMP1 proteins. Moreover, human and rabbit antibodies specific for Plasmodium vivax Duffy-binding protein (PvDBP), a protein with some homology to PfEMP1, did not react with VAR2CSA-type recombinant or native proteins, although the mouse monoclonal and PvDBP-specific antibody 3D10 was weakly reactive with recombinant proteins expressed in baculovirus-transfected insect cells. Our data indicate that the previously reported Colombian IgG reactivity to recombinant VAR2CSA is not malaria specific and that the acquisition of VAR2CSA-specific IgG is restricted to pregnancy, in Colombia and elsewhere.
Assuntos
Antígenos de Protozoários/imunologia , Reações Falso-Positivas , Imunoensaio/métodos , Imunoglobulina G/sangue , Malária Falciparum/imunologia , Malária Vivax/imunologia , Complicações Infecciosas na Gravidez/imunologia , Adolescente , Adulto , Idoso , Animais , Anticorpos Antiprotozoários/sangue , Criança , Pré-Escolar , Colômbia , Feminino , Glicosilação , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Gravidez , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Adulto JovemRESUMO
Malaria in pregnancy can cause serious adverse outcomes for the mother and the fetus. However, little is known about the effects of submicroscopic infections (SMIs) in pregnancy, particularly in areas where Plasmodium falciparum and Plasmodium vivax cocirculate. A cohort of 187 pregnant women living in Puerto Libertador in northwest Colombia was followed longitudinally from recruitment to delivery. Malaria was diagnosed by microscopy, reverse transcription-quantitative PCR (RT-qPCR), and placental histopathology. Gestational age, hemoglobin concentration, VAR2CSA-specific IgG levels, and adhesion-blocking antibodies were measured during pregnancy. Statistical analyses were performed to evaluate the impact of SMIs on birth weight and other delivery outcomes. Twenty-five percent of women (45/180) were positive for SMIs during pregnancy. Forty-seven percent of infections (21/45) were caused by P. falciparum, 33% were caused by P. vivax, and 20% were caused by mixed Plasmodium spp. Mixed infections of P. falciparum and P. vivax were associated with lower gestational age at delivery (P = 0.0033), while other outcomes were normal. Over 60% of women had antibodies to VAR2CSA, and there was no difference in antibody levels between those with and without SMIs. The anti-adhesion function of these antibodies was associated with protection from SMI-related anemia at delivery (P = 0.0086). SMIs occur frequently during pregnancy, and while mixed infections of both P. falciparum and P. vivax were not associated with a decrease in birth weight, they were associated with significant risk of preterm birth. We propose that the lack of adverse delivery outcomes is due to functional VAR2CSA antibodies that can protect pregnant women from SMI-related anemia.
RESUMO
Pregnancy-associated malaria (PAM) poses a threat to both the mother and fetus, increasing the risk of severe maternal anemia, fetal growth restriction and low birth weight infants. Two vaccines are currently in development to protect women from Plasmodium falciparum in pregnancy. Both vaccine constructs target the ID1-DBL2X domain of VAR2CSA, a protein expressed on the surface of infected erythrocytes (IEs) that mediates parasite sequestration in the placenta. Although development of an effective vaccine may be hampered by ID1-DBL2X polymorphisms expressed by field isolates, a recent study showed that genetic variation of this domain in South American parasite populations is much lower than in other geographical locations. This suggests that a recombinant vaccine designed to be efficacious in Africa and Asia is likely to be efficacious in South America. However, these studies did not include Colombian parasite populations in their analyses, which are known to be genetically distinct from other South American parasite populations due to their independent introduction from Africa. Therefore, we sought to determine the genetic variation of the ID1-DBL2X domain in Colombian parasites to assess the potential efficacy of the vaccine against PAM in this region. Through sequence analysis and population genetics, we show that there is a low degree of genetic variation amongst Colombian parasite populations and that a vaccine containing conserved antigen variants for worldwide populations is likely to be protective against PAM in Colombia. Our analysis also points towards an African origin for Colombian parasite populations, and suggests that their introduction into Colombia was a recurrent process encompassing multiple introduction events.