A Conserved Molecular Motor Drives Cell Invasion and Gliding Motility across Malaria Life Cycle Stages and Other Apicomplexan Parasites

Abstract

Apicomplexan parasites constitute one of the most significant groups of pathogens infecting humans and animals. The liver stage sporozoites of Plasmodium spp. and tachyzoites of Toxoplasma gondii, the causative agents of malaria and toxoplasmosis, respectively, use a unique mode of locomotion termed gliding motility to invade host cells and cross cell substrates. This amoeboid-like movement uses a parasite adhesin from the thrombospondin-related anonymous protein (TRAP) family and a set of proteins linking the extracellular adhesin, via an actin-myosin motor, to the inner membrane complex. The Plasmodium blood stage merozoite, however, does not exhibit gliding motility. Here we show that homologues of the key proteins that make up the motor complex, including the recently identified glideosome-associated proteins 45 and 50 (GAP40 and GAP50), are present in P. falciparum merozoites and appear to function in erythrocyte invasion. Furthermore, we identify a merozoite TRAP homologue, termed MTRAP, a micronemal protein that shares key features with TRAP, including a thrombospondin repeat domain, a putative rhomboid-protease cleavage site, and a cytoplasmic tail that, in vitro, binds the actinbinding protein aldolase. Analysis of other parasite genomes shows that the components of this motor complex are conserved across diverse Apicomplexan genera. Conservation of the motor complex suggests that a common molecular mechanism underlies all Apicomplexan motility, which, given its unique properties, highlights a number of novel targets for drug intervention to treat major diseases of humans and livestock.Parasites from the phylum Apicomplexa represent some of the most significant human and agricultural pathogens. Their ranks include Theileria parva and Theileria annulata, parasites that give rise to lymphoproliferative diseases of cattle, the opportunistic pathogens Toxoplasma gondii and Cryptosporidium parvum that can cause life-threatening, prolonged infection in immunocompromised patients, and the most lethal of the group, the genus Plasmodium, in particular Plasmodium falciparum, the cause of millions of human deaths and as many as 500 million infections annually (1).Apicomplexa are a monophyletic group of obligate intracellular parasites that invade a wide range of host cells but lack the classical means of motility such as a flagellum or cilia. Instead, they move by a unique form of actin-based locomotion called gliding motility (for recent reviews, see Refs. 2-4). Efficient motility and invasion requires the release of proteins from secretory organelles located at the apical prominence, the defining structure of the phylum. These organelles, the micronemes, rhoptries, and dense granules contain many of the key proteins needed for directional attachment, cell invasion, and establishment of the parasitophorous vacuole (PV) 5 within the host cell (5). Much of our understanding of gliding motility comes from studies with the liver stage parasite from Plasmodium spp., the sporozoite, or the morphologically similar tac...

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

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Immobilization of the Type XIV Myosin Complex inToxoplasma gondii

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