Biology subjects

Henshall, I. G.

Publications and source records attributed to Henshall, I. G..

2 recordsLinked to original sources

bioRxiv2026

Kelch13 stochastics determine drug survival in resistant malaria parasites

As resistance to the frontline antimalarial artemisinin (ART) in the deadliest malaria species Plasmodium falciparum spreads, it threatens the gains made in reducing global malaria burden over the last decades. Mutations in the gene encoding Kelch13 (K13) hold a central role in ART resistance. Yet even in clonal populations harbouring a resistance conferring k13 mutation, only a portion of parasites survive drug exposure. Here we show that stochastic cell- to-cell variation of cellular K13 levels determines survival of individual parasites. Using isogenic parasite lines, we establish that decreased cellular K13 levels correlate with resistance and in addition a fitness cost through an increased cell cycle length. As resistance increases, parasites show a shift of the stochastic range towards lower K13 levels, increasing the proportion of drug survivors. While this range was inherited, individual parasites with differing K13 levels gave rise to progeny across the full spectrum. Hence, while the resistance fitness profile of each parasite line is defined by the range of K13 levels, the fate of individual parasites within that range is determined by stochastics. These findings provide an explanation why only a portion of genetically identical parasites survive drug exposure and reveal a system where the stochastics of a single protein determine individual parasite drug survival and fitness.

microbiology↗

bioRxiv2025

An abundant merozoite surface protein of Plasmodium falciparum modulates susceptibility to inhibitory antibodies

Malaria merozoite surface proteins (MSPs), are thought to have important roles in red blood cell (RBC) invasion and their exposure on the parasite surface makes them attractive vaccine candidates. However, their role in invasion has not been directly demonstrated and their biological functions are unknown. One of the most abundant proteins is PfMSP2, which is likely an ancestral protein that has been maintained in the Plasmodium falciparum lineage and is a focus of vaccine development, whose function remains unknown. Using CRISPR-Cas9 gene-editing, we removed PfMSP2 from two different P. falciparum lines with no impact on parasite replication or phenotype in vitro, demonstrating that it is not essential for RBC invasion. However, loss of PfMSP2 led to increased inhibitory potency of antibodies targeting other merozoite proteins involved in invasion, particularly PfAMA1. In a solid-phase model, increasing concentrations of PfMSP2 protein reduced binding of different antibodies against PfAMA1 in a dose dependent manner. These data suggest that PfMSP2 can modulate the susceptibility of merozoites to protective inhibitory antibodies. The results of this study change our understanding of the potential functions of PfMSP2 and establishes a new concept in malaria where a surface protein can reduce the protective efficacy of antibodies targeting a different antigen. These findings have important implications for understanding malaria immunity and informing vaccine development.

microbiology↗