Abstract
Invasive, motile life cycle stages (zoites) of apicomplexan parasites possess a cortical membrane skeleton composed of intermediate filaments with roles in zoite morphogenesis, tensile strength and motility. Its building blocks include a family of proteins called alveolins that are characterized by conserved “alveolin” domains composed of tandem repeat sequences. A subset of alveolins possess additional conserved domains that are structurally unrelated and the roles of which remain unclear. In this structure-function analysis we investigated the functional contributions of the “alveolin” vs. “non-alveolin” domains of IMC1h, a protein expressed in the ookinete and sporozoite life cycle stages of malaria parasites and essential for parasite transmission. Using allelic replacement in Plasmodium berghei, we show that the alveolin domain is responsible for targeting IMC1h to the membrane skeleton and, consequently, its deletion from the protein results in loss of function manifested by abnormally-shaped ookinetes and sporozoites with reduced tensile strength, motility and infectivity. Conversely, IMC1h lacking its non-alveolin conserved domain is correctly targeted and can facilitate tensile strength but not motility. Our findings support the concept that the alveolin module contains the properties for filament formation, and show for the first time that tensile strength makes an important contribution to zoite infectivity. The data furthermore provide new insight into the underlying molecular mechanisms of motility, indicating that tensile strength is mechanistically uncoupled from locomotion, and pointing to a role of the non-alveolin domain in the motility-enhancing properties of IMC1h possibly by engaging with the locomotion apparatus.
Highlights
Plasmodium species, the causative agents of malaria, have a complex life cycle in vertebrate host and mosquito vector
Multiple alignment of amino acid sequences of IMC1h orthologs from different Plasmodium species clearly reveals the presence of its single conserved “alveolin” module, as well as a conserved carboxy-terminal module that is structurally unrelated (Tremp and Dessens, 2011)
Plasmodium alveolins have important roles in morphogenesis, tensile strength and motility of the zoite stages, and in many cases their disruption leads to loss of parasite fitness, infectivity and transmission (Khater et al, 2004; Tremp et al, 2008, 2014; Tremp and Dessens, 2011)
Summary
Plasmodium species, the causative agents of malaria, have a complex life cycle in vertebrate host and mosquito vector. The merozoite, ookinete, and sporozoite constitute the three motile and invasive stages in the Plasmodium life cycle These so-called “zoite” stages possess a characteristic cortical structure termed the pellicle. Two PhIL1 interacting proteins: PIP2 and PIP3, show structural homology with alveolins (Kono et al, 2013; Parkyn Schneider et al, 2017) It has been shown in the rodent malaria species P. berghei that disruption of the alveolins IMC1a, IMC1b, or IMC1h gives rise to morphological aberrations that are accompanied by reduced tensile strength of the zoite stages in which they are expressed. IMC1h is expressed in both the ookinete and sporozoite life cycle stages of the parasite, where it carries out equivalent roles (Tremp and Dessens, 2011; Volkmann et al, 2012), allowing our investigations to be conducted across two distinct zoite stages. The implications of these results are discussed in the context of parasite infectivity
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