Plasmodium vivax VIR Proteins Are Targets of Naturally-Acquired Antibody and T Cell Immune Responses to Malaria in Pregnant Women

Citation: Requena P, Rui E, Padilla N, Martínez-Espinosa FE, Castellanos ME, Bôtto-Menezes C, et al. (2016) Plasmodium vivax VIR Proteins Are Targets of Naturally-Acquired Antibody and T Cell Immune Responses to Malaria in Pregnant Women. PLoS Negl Trop Dis 10(10): e0005009. doi:10.1371/journal.pntd.0005009
Published: October 6, 2016

Abstract
Plasmodium_vivaxP. vivax infection during pregnancy has been associated with poor outcomes such as anemia, low birth weight and congenital malaria, thus representing an important global health problem. However, no vaccine is currently available for its prevention. Vir genes were the first putative virulent factors associated with P. vivax infections, yet very few studies have examined their potential role as targets of immunity. We investigated the immunogenic properties of five VIR proteins and two long synthetic peptides containing conserved VIR sequences (PvLP1 and PvLP2) in the context of the PregVax cohort study including women from five malaria endemic countries: Brazil, Colombia, Guatemala, India and Papua New Guinea (PNG) at different timepoints during and after pregnancy. Antibody responses against all antigens were detected in all populations, with PNG women presenting the highest levels overall. P. vivax infection at sample collection time was positively associated with antibody levels against PvLP1 (fold-increase: 1.60 at recruitment -first antenatal visit-) and PvLP2 (fold-increase: 1.63 at delivery), and P. falciparum co-infection was found to increase those responses (for PvLP1 at recruitment, fold-increase: 2.25). Levels of IgG against two VIR proteins at delivery were associated with higher birth weight (27 g increase per duplicating antibody levels, p<0.05). Peripheral blood mononuclear cells from PNG uninfected pregnant women had significantly higher antigen-specific IFN-γ TH1 responses (p=0.006) and secreted less pro-inflammatory cytokines TNF and IL-6 after PvLP2 stimulation than P. vivax-infected women (p<0.05). These data demonstrate that VIR antigens induce the natural acquisition of antibody and T cell memory responses that might be important in immunity to P. vivax during pregnancy in very diverse geographical settings.

Author Summary: Naturally-acquired antibody responses to novel recombinant proteins and synthetic peptides based on sequences from P. vivax VIR antigens were evaluated in women from five distinct geographical regions endemic for malaria, during and after pregnancy. Levels of IgG to VIR antigens were indicative of cumulative malaria exposure and increased with current P. vivax infection and P. falciparum co-infection. Antibody data were consistent with levels of malaria endemicity and current prevalence in the diverse geographical areas studied. In addition, the magnitude of IgG response to two VIR antigens at delivery was associated with higher birth weight. Furthermore, T cell responses to VIR antigens were naturally induced and their magnitude varied according to P. vivax infectious status. Peripheral blood mononuclear cells from uninfected pregnant women from a highly endemic area produced higher TH1 (IFN-γ) and lower pro-inflammatory cytokines (TNF and IL-6) upon stimulation with a long synthetic peptide representing conserved globular domains of VIR antigens than P. vivax-infected women. Data suggest that further investigation on these antigens as potential targets of immunity in naturally-exposed individuals is warranted.

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