NEW YORK – A malaria-causing parasite shifts its gene expression during the dry season, when mosquitoes that typically spread it are scarce, a new study has found.
Plasmodium falciparumcauses more than 200 million cases of malaria each year and led to the deaths of almost 400,000 individuals in 2018. In many regions of Africa, where malaria is endemic, the mosquitoes that transmit the parasite are only present during the wet season, which lasts about six months. How P. falciparum persists during the dry season as a subclinical infection has been unclear.
A team led by researchers at Heidelberg University Hospital in Germany compared P. falciparum in blood samples of asymptomatic individuals from Mali collected during the dry season and during the wet season. As they reported in Nature Medicine on Monday, the researchers found that parasites isolated during the dry season had a different gene expression profile than those isolated during the wet season. Samples further differed in how long infected red blood cells circulated and how they adhered to the vascular endothelium.
"We propose that P. falciparum virulence in areas of seasonal malaria transmission is regulated so that the parasite decreases its endothelial binding capacity, allowing increased splenic clearance, and enabling several months of subclinical parasite persistence," Heidelberg's Silvia Portugal and her colleagues wrote in their paper.
For their cohort study, the researchers followed about 600 individuals in Kalifabougou, Mali. In this cohort, clinical presentation of malaria largely occurred during the wet season between June and December, but PCR-based testing uncovered that between 10 percent and 20 percent of individuals had subclinical malarial infections during the dry season between January and May.
Subclinical infections rarely caused symptoms and were associated with a minimal immune response among participants.
A genetic analysis of parasites isolated from infected individuals indicated that the P. falciparum that persist during the dry season are the same as those that cause clinical malaria during the wet season. But through an RNA sequencing analysis of samples from two dozen children, the researchers found more than 1,600 genes that were differentially expressed among the parasites during those two time frames. These genes included ones involved in a number of metabolic pathways, as well as in phagosomes, DNA replication, and homologous replication.
However, the researchers noted that a culturing analysis showed P. falciparum replication is not impeded during the dry season. But they did find thatoward the end of the season, however, circulatingP. falciparum tends to be further along in its 48-hour asexual replication cycle than is typically observed during the wet season.
The researchers additionally found that infected red blood cells from individuals with malaria at the end of the dry season are more likely to be cleared in an in vitro model of the spleen. Using a mathematical model, they noted that differences in growth and removal of infected red blood cells could be governed by differences in their ability to adhere to the vascular epithelium — low-adhesion parasites are typically removed from the circulation by the spleen.
Var genes — which encode parasite membrane proteins — appeared to have increased expression in the wet season, but the finding was not statistically significant, the researchers noted.
Still, the results suggested that during the dry season, red blood cells infected by P. falciparum circulate for longer into their replicative cycle, which enables the spleen to clear them. This then limits parasite levels in the blood and avoids immune activation or the development of symptoms.