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. 2018 Jul 23;86(8):e00136-18.
doi: 10.1128/IAI.00136-18. Print 2018 Aug.

IgG Responses to the Plasmodium falciparum Antigen VAR2CSA in Colombia Are Restricted to Pregnancy and Are Not Induced by Exposure to Plasmodium vivax

Mary Lopez-Perez  1 , Mads Delbo Larsen  1   2 , Rafael Bayarri-Olmos  2 , Paulina Ampomah  3 , Liz Stevenson  1 , Myriam Arévalo-Herrera  4   5 , Sócrates Herrera  4 , Lars Hviid  6   7
Affiliations

IgG Responses to the Plasmodium falciparum Antigen VAR2CSA in Colombia Are Restricted to Pregnancy and Are Not Induced by Exposure to Plasmodium vivax

Mary Lopez-Perez et al. Infect Immun. .

Expression of concern in

Abstract

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.

Keywords: CHO cells; Colombia; IgG; PfEMP1; Plasmodium falciparum; Plasmodium vivax; PvDBP; VAR2CSA; adaptive immunity; antibodies; baculovirus; humoral immunity; insect cells; malaria; placental malaria; pregnancy; recombinant antigens.

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Figures

FIG 1
FIG 1
Antibody response to full-length recombinant PfEMP1 proteins produced in baculovirus-transfected insect cells. (A to D) IgG levels against a recombinant, full-length VAR2CSA-type PfEMP1 protein (FV2BIC) (A and B) and a full-length non-VAR2CSA-type PfEMP1 protein (FV6BIC) (C and D) produced in baculovirus-transfected insect cells were determined by an ELISA. Individual data for all samples sets are described in Table 1 (A and C). Individual data for samples in set 2c (Colombian pregnant women) and set 5 (Ghanaian women) were sorted by parity (primigravid [Primi] and multigravid [Multi]) (B and D). Medians and interquartile ranges are also shown. (E and F) Correlation (rs) between IgG levels specific for FV2BIC and FV6BIC in Colombian (set 1 and set 2) (E) and Ghanaian (set 5) (F) samples. The statistical significance levels of the correlations are also shown. In all panels, the values are expressed in arbitrary units (AU) (see Materials and Methods for details), and dashed lines indicate the negative cutoff values (mean levels plus 2 SD for Danish controls).
FIG 2
FIG 2
Antibody responses to native PfEMP1 and recombinant PfEMP1 proteins produced in baculovirus-transfected insect cells. (A and B) Levels of IgG specific for native VAR2CSA-type (IT4VAR04) PfEMP1 (A) and native non-VAR2CSA-type (HB3VAR06) PfEMP1 (B) expressed on the surface of IEs and measured by flow cytometry. (C and D) Correlation (rs) between IgG levels specific for recombinant (FV2BIC) and native (IT4VAR04) VAR2CSA-type PfEMP1 in samples from Colombian exposed, healthy, and naturally infected individuals (set 1 and set 2) (C) or from Colombian pregnant women only (D). (E and F) Correlation (rs) between IgG levels specific for recombinant (FV6BIC) and native (HB3VAR06) non-VAR2CSA-type PfEMP1 in Colombian samples (set 1 and set 2) (E) or in samples from Colombian pregnant women only (set 2c) (F). (G and H) Correlation (rs) between IgG levels specific for recombinant (FV2BIC) and native (IT4VAR04) VAR2CSA-type PfEMP1 (G) and between IgG levels specific for recombinant (FV6BIC) and native (HB3VAR06) non-VAR2CSA-type PfEMP1 (H) in samples from Ghanaian women. The statistical significance levels of the correlations are also shown. The panel layout is the same as in Fig. 1.
FIG 3
FIG 3
Antibody responses to native PfEMP1 and recombinant PfEMP1 proteins produced in insect or CHO cells. IgG levels against recombinant (FV2BIC and FV2CHO) and the corresponding native (IT4VAR04) VAR2CSA-type PfEMP1 proteins were determined by an ELISA (recombinant proteins) or flow cytometry (native protein). (A) Individual FV2CHO-specific IgG levels in all samples (sample sets 1 to 6). (B and C) Correlation (rs) between IgG levels specific for FV2BIC and FV2CHO in Colombian (set 1 and set 2) (B) and Ghanaian (set 5) (C) samples. (D) Correlation (rs) between IgG levels specific for FV2CHO and the corresponding native VAR2CSA-type protein in Colombian samples (set 1 and set 2). The panel layout is the same as in Fig. 1.
FIG 4
FIG 4
Antibody levels to recombinant PfEMP1 full-length proteins in plasma pools tested in serial ELISAs. Shown are IgG levels in pooled plasma from Danish control donors (set 6) (A to C), unexposed Colombians (sets 3a, 4a, and 4b) (D to F), Colombian pregnant women (set 2c) (G to I), and Ghanaian women (set 5) (J to L). In each of the three ELISA series (series 1 [A, D, G, and J], series 2 [B, E, H, and K], and series 3 [C, F, I, and L]), the plasma pools were transferred directly from the first to the second ELISA plates and then from the second to the third ELISA plates. In series 1, an FV2BIC-specific ELISA was used for all three consecutive measurements. In series 2, the first two measurements were FV2CHO specific, while the third ELISA was FV2BIC specific. In series 3, the first two measurements were FV6BIC specific, while the third ELISA was FV2BIC specific. To allow comparison of data among panels, levels are expressed as how many folds higher they were than the levels in the corresponding control ELISAs without antigen (first and second ELISAs) and shown as means and SD. *, P < 0.05; ***, P < 0.001 (using Kruskal-Wallis test followed by Dunn's multiple-comparison analysis).
FIG 5
FIG 5
Induction of IgG responses to recombinant PfEMP1 proteins following experimental exposure to P. vivax-infected mosquitoes. Shown are plasma levels of IgG in samples from set 3 (open symbols) at the time of microscopically detectable parasitemia (patency) and 45 days after infection (follow-up) and in samples from set 4 (closed symbols) following seven rounds of immunization by infected mosquito bites (Post_imm) and 6 months after PvCHMI infection (Post_CHMI). Levels of IgG specific for FV2BIC (A), FV2CHO (B), FV6BIC (C), and PvDBP (D) are shown. Data from individual donors are linked by lines. The panel layout is otherwise the same as in Fig. 1.
FIG 6
FIG 6
Reactivity of PvDBP-specific IgG with recombinant PfEMP1 proteins. Shown are ELISA reactivities of PvDBP-specific human (DBL10) and mouse (3D10) monoclonal antibodies (mAb) (A, C, and E) and PvDBP-specific rabbit antiserum (B, D, and F) with the recombinant full-length PfEMP1 proteins FV2BIC (A and B), FV2CHO (C and D), and FV6BIC (E and F). (A, C, and E) Reactivities of irrelevant (Ebola virus-specific) human monoclonal IgG (EBL040), mouse polyclonal IgG, as well as the VAR2CSA-type PfEMP1-specific human monoclonal antibody PAM1.4. (B, D, and F) IgG reactivities in human plasma pools from unexposed Colombians, infected pregnant Colombians, exposed Ghanaian women, unexposed Danish adults, and preimmune rabbit serum are shown for comparison. Serial 2-fold dilution series are shown for all antibody reagents.
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References

    1. . 2017. World malaria report 2017. World Health Organization, Geneva, Switzerland.
    1. Chaparro-Narvaez PE, Lopez-Perez M, Rengifo LM, Padilla J, Herrera S, Arevalo-Herrera M. 2016. Clinical and epidemiological aspects of complicated malaria in Colombia, 2007-2013. Malar J 15:269. doi:10.1186/s12936-016-1323-5. - DOI - PMC - PubMed
    1. Hviid L. 2005. Naturally acquired immunity to Plasmodium falciparum malaria in Africa. Acta Trop 95:270–275. doi:10.1016/j.actatropica.2005.06.012. - DOI - PubMed
    1. Hviid L, Jensen AT. 2015. PfEMP1—a parasite protein family of key importance in Plasmodium falciparum malaria immunity and pathogenesis. Adv Parasitol 88:51–84. doi:10.1016/bs.apar.2015.02.004. - DOI - PubMed
    1. Desai M, Ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, Newman RD. 2007. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 7:93–104. doi:10.1016/S1473-3099(07)70021-X. - DOI - PubMed

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