Work

Toxoplasma gondii Fatty Acid Elongases are Important for Virulence and Persistence

Year: 2026

Type: preprint

Abstract: Toxoplasma gondii is an apicomplexan parasite which can infect a diverse range of warm-blooded host species. This promiscuous lifestyle requires metabolic flexibility yet our understanding of the metabolic pathways in this parasite remains incomplete. This gap includes the endoplasmic reticulum localised fatty acid elongation (FAE) pathway, which is responsible for synthesis of long (LCFA) and very long chain fatty acids (VLCFA), thus contributing to critical functions such as lipid storage and membrane biogenesis. Analyses of FAE in the commonly studied type I T. gondii strain revealed its contribution to the production of LCFA and VLCFA in vitro . However, the cystogenic type II T. gondii, which is responsible for most toxoplasmosis cases worldwide, was not studied. These type II parasites can readily differentiate between virulent and immune-evasive stages whereas type I cannot. This ability to readily transition between life stages, which are metabolically fundamentally different, prompts the question of whether the FAE pathway may play different roles in their distinct phenotype. Here we address this question, first confirming the role of the FAE enzymes, TgELO-A & B, in the production of LCFA and VLCFA in a type II T. gondii strain. Next, we demonstrated that their deletion leads to defects in replication and invasion when grown under lipid-restricted conditions. The mutants were further shown to be attenuated in mice as demonstrated by extended survival. Importantly, FAE enzyme deletion caused reduced brain cyst burdens. These findings highlight the importance of FAE for parasite survival under metabolic stress and in vivo . Importance Toxoplasma gondii infects a wide range of hosts and persists for life in multiple tissues, making metabolic flexibility essential for its success. Fatty acid elongation (FAE), mediated by elongase (ELO) enzymes, enables the parasite to modify both de novo synthesised and host-scavenged fatty acids to support membrane biogenesis, lipid storage, and adaptation to changing nutrient environments. Previous studies in the type I strain established the importance of FAE for parasite metabolism, but its role in the clinically relevant, cystogenic type II lineage—which causes most cases of human toxoplasmosis and forms long-lived, immune-evasive bradyzoite cysts— remained unknown. Here, we address this gap by characterising type II ELO mutants and show that disruption of FAE remodels the parasite lipidome, impairs fitness under fatty acid-limiting conditions, and reduces virulence and chronic persistence in mice. These findings identify FAE as a key metabolic pathway underpinning adaptation and persistence during chronic infection.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.07.29.741455