How a Novel Molecular Maneuver Helps Malaria Parasites Evade Human Immunity

Graduate student Joseph Visone and Dr. Florini investigated the mystery of var gene regulation in malaria parasites through single-cell sequencing techniques. The majority of parasites follow established patterns by activating only one var gene at any given moment. Some parasites astonish researchers by activating two or three var genes at once and a small number of parasites display complete silence in their gene activity. Parasites displaying two active var genes represent a transitional phase. Dr. Deitsch explains that malaria parasites experience a short period in which they toggle their gene expression. We captured them during the moment they changed gene expression. The most intriguing parasites were those existing in a “null state” because they exhibited almost no var gene activity. Traditional population assays would not have revealed these specific parasites according to Dr. Florini. The finding shows a secret strategy used by malaria to evade immune system detection.

Yet turning off var genes comes at a cost: The parasites face elimination by the spleen because they cannot attach to blood vessel walls in the absence of var genes. So where do they hide? The scientists led by Deitsch believe the parasites hide inside bone marrow or within the spleen vicinity's non-circulating red blood cell reservoir. The parasite finishes its lifecycle when a cell stays hidden for 24 hours according to his findings.

Dr. Deitsch plans to travel to West Africa to locate these parasite hiding spots in actual infection cases. Discovering these biological hiding places and the methods parasites use to utilize them can lead to novel approaches for fighting chronic malaria.

The National Institutes of Health provided grants AI-52390 and AI-99327 along with an F31 Predoctoral Fellowship (F31AI164897) and the Swiss NSF Early Postdoc supported this research. The Swiss NSF Early Postdoc Mobility grant (P2BEP3_191777) and the William Randolph Hearst Foundation supported this research.

References:

1. Francesca Florini, Joseph E. Visone, Evi Hadjimichael, Shivali Malpotra, Christopher Nötzel, Björn F. C. Kafsack, Kirk W. Deitsch. scRNA-seq reveals transcriptional plasticity of var gene expression in Plasmodium falciparum for host immune avoidance. Nature Microbiology, 2025; DOI: 10.1038/s41564-025-02008-5