Immune responses toPlasmodium vivax pre-erythrocytic stage antigens in naturally exposed Duffy-negative humans: a potential model for identification of liver-stage antigens

Abstract

Duffy antigen is the receptor used by Plasmodium vivax to invade erythrocytes. Consequently, individuals lacking Duffy antigen [Fy(-)] do not develop blood-stage infections. We hypothesized that naturally exposed Fy(-) humans may develop immune responses mainly to pre-erythrocytic stages and could be used to study acquired immunity to P. vivax and to identify liver-stage antigens. We report here that antibody and IFN-c responses to known sporozoite antigens were significantly induced by natural exposure in Fy(-) humans, whereas responses to blood-stage antigens were significantly induced in Fy(+) humans. IFN-c responses to sporozoite antigens were lower in Fy(+) than in Fy(-) humans, indicating that in Fy(+) humans blood-stage infections may have suppressed T cell responses to pre-erythrocytic stages. We evaluated the immune responses to 18 novel P. vivax homologs of P. falciparum sporozoite proteins identified from the P. vivax genome sequence. Eight proteins recalled IFN-c responses in P. vivax-exposed but not in unexposed individuals. Of these, 3 antigens elicited IFN-c responses in Fy(-) but not in Fy(+) individuals. These results suggest that differential immune responses observed in naturally exposed Fy(-) and Fy(+) individuals can be exploited to identify P. vivax stage-specific antigens.

Role of TGF‐β and PGE2 in T cell responses during Plasmodium yoelii infection

“…Using mouse malaria model infections, it was observed that CD8 + T cells and protection against liver infection are induced by natural infections only when blood-stage development is inhibited by drug treatments, but not when blood-stage infections were fully developed [20][21][22]. Recently, it was found that in P. vivax endemic areas, individuals that do not develop blood stages because they do not have the Duffy antigen had significantly higher IFN-c responses to sporozoite antigens, suggesting again that blood-stage infections inhibit T cell responses to pre-erythrocytic stages [23].…”

A T-cell response to a liver-stagePlasmodiumantigen is not boosted by repeated sporozoite immunizations

“…Traditionally, pooled synthetic peptides are used in IFN-γ (IFNγ) enzyme-linked immunosorbent spot (ELISPOT) assays to identify T-cell targets (29), but even with pooling strategies (30), these approaches require complex, expensive peptide libraries. In lieu of peptides, plasmidencoded parasite genes can be transfected into antigen-presenting cells (APCs) (31), but this approach is low throughput and difficult because of the A/T-richness of Plasmodial genes. Instead here, we used a minigene-based high-throughput screen (HTS) for CTLs (32) to study a library of Plasmodium yoelii-derived antigens in sporozoite-vaccinated mice.…”

Plasmodium vivax Pre-Erythrocytic–Stage Antigen Discovery: Exploiting Naturally Acquired Humoral Responses

“…5,8 These donors have been shown to develop significantly fewer antibodies to blood-stages antigens compared with Fy+ donors. 46,47 To investigate the antibody responses induced by natural exposure to P. vivax infection, the protein arrays containing 91 P. vivax proteins were interrogated with 60 sera from P. vivax-exposed individuals and 7 control sera from unexposed individuals (Figure 1). The exposed donors were further subdivided into two groups according to their Fy genotype (Fy+ or Fy−).…”

“…Previously, we showed that Fy− individuals exposed to P. vivax in Colombia responded predominantly to pre-erythrocytic antigens rather than erythrocytic antigens. 14 The lack of DARC on Fy− erythrocytes and the resulting prevention or reduction of blood-stage parasitemia may consequently reduce the frequency of exposure to erythrocytic parasites in the Fy− population compared with the Fy+ population. [14][15][16] Furthermore, it has been shown that, in both murine (P. yoelii) and human (P. falciparum) malaria, bloodstage infections suppress T-cell responses against liver-stage antigens.…”

“…14 The lack of DARC on Fy− erythrocytes and the resulting prevention or reduction of blood-stage parasitemia may consequently reduce the frequency of exposure to erythrocytic parasites in the Fy− population compared with the Fy+ population. [14][15][16] Furthermore, it has been shown that, in both murine (P. yoelii) and human (P. falciparum) malaria, bloodstage infections suppress T-cell responses against liver-stage antigens. [17][18][19] Immune responses to P. vivax pre-erythrocyticstage antigens may, therefore, be stronger in Fy− than Fy+ individuals, because exposure of Fy− individuals to erythrocytic parasites in the bloodstream would be limited.…”