Biology subjects

Formaglio, P.

Publications and source records attributed to Formaglio, P..

5 recordsLinked to original sources

bioRxiv2025

Spatiotemporal analysis of sporozoite maturation and infectivity

Plasmodium sporozoites must undergo tightly regulated developmental transitions to become infectious and be successfully transmitted from the mosquito vector to a mammalian host. While transcriptomic studies have revealed stage-specific changes across sporozoite populations, the functional consequences of these transitions remain unclear. Here, using P. berghei, we characterised over time the infectivity of sporozoite forms collected from the midgut, haemolymph, salivary glands and saliva. We show that salivary gland invasion is required but not sufficient for sporozoite optimal infectivity, with the acquisition of hepatocyte cell traversal and invasion progressively increasing until a plateau from 18 days post-infection onwards. Using a stage-specific fluorescent reporter as maturation marker, we correlated its high expression with time and infectivity for each compartment but only salivary gland sporozoites acquired maximal infectivity. Notably, our data suggest that salivated sporozoites--the natural transmission form--exhibit enhanced infectivity relative to gland-resident forms both in vitro and in vivo early after salivary gland invasion. This difference decreases following optimal maturation inside the glands over time. These observations show a crescent gradient of sporozoite maturation and infectiveness from the midgut to the saliva when isolated at the same time of infection, which is mainly regulated by the sporozoite invasion of salivary glands.

microbiology↗

bioRxiv2024

Late killing of Plasmodium berghei in the liver by an anti-circumsporozoite protein monoclonal antibody

Plasmodium sporozoites are inoculated into the skin during the bite of an infected mosquito. This motile stage invades cutaneous blood vessels to reach the liver and infect hepatocytes. The circumsporozoite protein (CSP) on the sporozoite surface is an important antigen targeted by protective antibodies in immunoprophylaxis or elicited by vaccination. Antibody-mediated protection mainly unfolds during parasite skin migration, but rare and potent protective antibodies additionally neutralize sporozoite in the liver. Here, using a rodent malaria model, microscopy and bioluminescence imaging, we show a late neutralizing effect of 3D11 anti-CSP monoclonal antibody (mAb) in the liver. The need for several hours to eliminate parasites in the liver was associated with an accumulation of 3D11 effects, starting with the inhibition of sporozoite motility, sinusoidal extravasation, cell invasion, and terminating with the parasite killing inside the invaded cell. This late neutralizing activity could be helpful to identify more potent therapeutic mAbs with stronger activity in the liver.

microbiology↗

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↗