Sassari, Italy – A genetic variation that hinders the growth of the malaria parasite has been identified by researchers at the Institute of Genetic and Biomedical Research of the National Research Council (Cnr-Irgb) in Cagliari and the University of Sassari. This discovery, published in the journal Nature, sheds light on the biological mechanisms behind protection from the disease and may pave the way for new therapeutic interventions.
Malaria continues to cause over 600,000 deaths annually, primarily in tropical countries. However, the severity of infection varies significantly among individuals, with some developing life-threatening complications while others experience milder symptoms. Understanding these differences is a critical challenge in modern medicine.
The research team’s findings originated from genomic analyses of approximately 7,000 volunteers participating in the SardiNIA study in Ogliastra, a large population genetics project examining how the genetic makeup of Sardinian inhabitants influences health-related traits. Researchers identified a DNA variant associated with specific characteristics of red blood cells, the cells where the malaria parasite lives.
Further investigation revealed that the variant reduces the activity of the CCND3 gene, which regulates the development of red blood cell precursors. This results in larger red blood cells with unique characteristics. “With experiments lasting several years, we explained in detail the molecular and biological mechanisms underlying these observations,” explained Maria Giuseppina Marini, first author of the study, along with Maura Mingoia and Maristella Steri of the Cnr-Irgb.
Researchers believe the genetic variation offers a glimpse into how humans have adapted to historical disease pressures. “Human genetics preserves traces of past diseases,” said Francesco Cucca, a geneticist at the University of Sassari and Cnr-Irgb, who coordinated the study. “This allows us to identify biological adaptations selected by evolution.”
Evolutionary analyses suggest the variant became common in Sardinia as it provided a survival advantage. “We therefore hypothesized that malaria, historically endemic in Sardinia, could be the evolutionary pressure that favored the spread of the variant,” Cucca added.
When red blood cells from individuals carrying the variant were infected with Plasmodium falciparum—the parasite responsible for most malaria cases—the parasite’s growth was significantly inhibited, ultimately leading to its death. “We observed a strong inhibition of parasite growth up to its death,” explained Antonella Pantaleo of the University of Sassari, who coordinated the laboratory infection experiments. “The phenomenon is linked to an increase in oxidative stress in red blood cells, a mechanism similar to that which protects people with G6PD deficiency, creating an inhospitable environment for the parasite in these cells.”
While the variant is prevalent in Sardinia, This proves absent in regions where malaria remains widespread. Researchers suggest it may have emerged in Europe after Homo sapiens migrated out of Africa. This “natural experiment” offers a promising new avenue for therapeutic development. “Nature has shown us an effective way to block malaria,” Cucca concluded. “The challenge now is to transform this biological mechanism into a therapy: to reproduce pharmacologically the protective effect of the variant to protect populations that today live with the disease.”
The study provides a solid scientific foundation for developing new, targeted drugs inspired by human evolution. The findings underscore the potential of leveraging evolutionary insights to combat infectious diseases and improve global health outcomes.
