Biology subjects

Formaglio, P.

Publications and source records attributed to Formaglio, P..

3 recordsLinked to original sources

bioRxiv2022

Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

The uptake and digestion of host hemoglobin by malaria parasites during blood stage growth leads to significant oxidative damage of membrane lipids. Repair of lipid peroxidation damage is crucial for parasite survival. Here, we demonstrate that Plasmodium falciparum imports a host antioxidant enzyme, peroxiredoxin 6 (PRDX6), during hemoglobin uptake from the red blood cell cytosol. PRDX6 is a lipid peroxidation repair enzyme with phospholipase A2 (PLA2) activity. Inhibition of PRDX6 with a PLA2 inhibitor, Darapladib, increases lipid peroxidation damage in the parasite and disrupts transport of hemoglobin-containing vesicles to the food vacuole, causing parasite death. Furthermore, inhibition of PRDX6 synergistically reduces the survival of artemisinin-resistant parasites following co-treatment of parasite cultures with artemisinin and Darapladib. Thus, PRDX6 is a unique host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance. GRAPHICAL ABSTRACT O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

cell biology↗

bioRxiv2022

Downregulation of the secreted protein with an altered thrombospondin repeat (SPATR) impacts the infectivity of malaria sporozoites

The identification of surface proteins of the sporozoite stage of malaria parasites important for sporozoite infectivity could aid in the improvement of the efficacy of vaccines targeting pre-erythrocytic stages. Thus, we set out to disclose the role of the secreted protein with an altered thrombospondin repeat (SPATR), which is highly expressed in sporozoites. Previous studies showed an essential function in blood stages, while no role was detected in sporozoites despite high expression. To achieve downregulation of expression in sporozoites while maintaining blood stage expression, a promoter swap approach was used to generate a mutant where the Plasmodium berghei spatr gene was placed under transcriptional control of the hado gene promoter. Downregulation of expression in oocysts and sporozoites resulted in formation of sporozoites with impaired motility, strongly reduced capacity to invade salivary glands, and decreased infectivity to mice. In conclusion, we revealed a new role for SPATR in sporozoite infectivity, highlighting the importance to use complementary methods in studies on sporozoite biology.

microbiology↗

bioRxiv2021

Malaria transmission relies on concavin-mediated maintenance of Plasmodium sporozoite cell shape

During transmission of malaria-causing parasites from mosquitoes to mammals, Plasmodium sporozoites migrate rapidly in the skin to search for a blood vessel. The high migratory speed and narrow passages taken by the parasites suggest considerable strain on the sporozoites to maintain their shape. Here we report on a newly identified protein, concavin, that is important for maintenance of the sporozoite shape inside salivary glands of mosquitoes and during migration in the skin. Concavin-GFP localized at the cytoplasmic periphery of sporozoites and concavin(-) sporozoites progressively rounded up upon entry of salivary glands. These rounded concavin(-) sporozoites failed to pass through the narrow salivary ducts and were hence rarely ejected by mosquitoes. However, normally shaped concavin(-) sporozoites could be transmitted and migrated in the skin or skin like environments. Strikingly, motile concavin(-) sporozoites could disintegrate while migrating through narrow strictures in the skin leading to parasite arrest or death and decreased transmission efficiency. We suggest that concavin contributes to cell shape maintenance by riveting the plasma membrane to the subtending inner membrane complex. SIGNIFICANCEMalaria parasites are transmitted by Anopheles mosquitoes and rely on rapid migration for establishing an infection. We identified and characterized a protein, named concavin, essential for maintaining the shape of the sporozoite. Concavin is a membrane associated protein facing the cytoplasm suggesting that it contributes to riveting the plasma membrane to the subtending inner membrane complex. Sporozoites lacking concavin can round up in the salivary glands, are less well transmitted to mice and disintegrate while migrating in the skin. Hence, concavin is essential for parasite transmission and infectivity. Highlights- A membrane associated protein is essential for Plasmodium shape maintenance -Migrating parasites disintegrate in the absence of concavin -First protein essential for cellular integrity of Plasmodium sporozoites -Thickened and deformed Plasmodium sporozoites fail to be transmitted by mosquitoes

microbiology↗