Distribution of Plasmodium falciparum apical membrane antigen-1 cluster one loop haplotypes and their association with malaria symptoms in Bandiagara, Mali

Although overall malaria incidence has decreased sharply over the past two decades, progress has stalled since 2015. The human host maintains a complex set of interactions with Plasmodium falciparum, the parasite species causing most malaria deaths. Understanding the genetic factors of parasites that play a role in malaria pathogenesis and host immune responses could help identify proteins that are essential for parasite survival and aid in the design of more effective tools against malaria, including more effective malaria vaccines. Clinical malaria phenotypes are a function of parasite density, genetic makeup of both parasites and hosts, malnutrition, coinfection, environmental factors, and potentially parasite and host epigenetic factors. We aimed to investigate the relationship between parasite genetics, focused on apical membrane antigen 1 (AMA1), a blood-stage vaccine candidate antigen involved in erythrocyte invasion, and clinical phenotypes. AMA1 haplotype dynamics have shown that the encoding gene cluster one loop (c1L) is the target of invasion-inhibiting antibodies. Herein, we hypothesized that variants of c1L may be associated with malaria symptoms. Using ama1 gene sequences generated from samples from 100 children during a three-year malaria incidence study conducted in Bandiagara, Mali, we assessed whether specific haplotypes were associated with disease phenotypes of children presenting with clinical malaria. After adjusting for study participant location, specific c1L haplotypes were not associated with malaria symptoms or disease phenotypes. None of the most frequent haplotypes were linked to clinical malaria, defined as any temperature greater than 37.5 °C and parasitemia greater than or equal to 2,500 parasites per microliter. Our findings suggest that malaria symptoms may be driven by infections with new allele(s) rather than specific allele(s) already seen by an individual.