Antibody Responses to the Conserved Plasmodium falciparum Vacuolar Sorting Protein 29 in the Brazilian Amazon

Vacuolar Protein Sorting 29 (VPS29) is a highly conserved subunit of the retromer complex, which mediates retrograde transport from endosomes to the Golgi apparatus and plays a critical role in membrane trafficking, protein recycling, and organelle biogenesis. In Plasmodium falciparum, the retromer has been implicated in the formation of apical organelles essential for parasite invasion and replication. In this study, we investigated naturally acquired antibody responses to P. falciparum VPS29 (PfVPS29) and the genetic diversity of the vps29 gene in isolates from three malaria-endemic areas of the Brazilian Amazon. Naturally acquired responses to PfVPS29 were evaluated by ELISA in 533 individuals, and genetic diversity was assessed in 62 P. falciparum isolates. Only 17% of participants displayed IgG reactivity, whereas 73.5% showed IgM responses, indicating limited IgG acquisition but a predominant IgM profile associated with recent or ongoing exposure. IgG subclass analysis revealed a predominance of cytophilic IgG1 and IgG3 among responders. IgM responses were significantly boosted during P. falciparum infection. Sequence analysis revealed no polymorphisms among Brazilian isolates, and comparison with global datasets confirmed the high conservation of the PfVPS29 coding sequence. Together, these findings show that PfVPS29 is a highly conserved intracellular protein that elicits an atypical humoral response dominated by IgM, with limited class switching to IgG, like other conserved or repetitive malaria antigens. These results highlight PfVPS29 as an example of a conserved intracellular antigen that induces non-classical humoral responses in naturally exposed populations.