Abstract
Inserted (I) domains function as ligand-binding domains in adhesins that support cell adhesion and migration in many eukaryotic phyla. These adhesins include integrin αβ heterodimers in metazoans and single subunit transmembrane proteins in apicomplexans such as TRAP in Plasmodium and MIC2 in Toxoplasma. Here we show that the I domain of TRAP is essential for sporozoite gliding motility, mosquito salivary gland invasion and mouse infection. Its replacement with the I domain from Toxoplasma MIC2 fully restores tissue invasion and parasite transmission, while replacement with the aX I domain from human integrins still partially restores liver infection. Mutations around the ligand binding site allowed salivary gland invasion but led to inefficient transmission to the rodent host. These results suggest that apicomplexan parasites appropriated polyspecific I domains in part for their ability to engage with multiple ligands and to provide traction for emigration into diverse organs in distant phyla.
Highlights
Domains with similar overall structures, initially described in von Willebrand factor A (VWA domains), are found in cell-surface proteins including integrins, extracellular matrix, and complement components, and mediate a diversity of functions including cell adhesion, migration, and signaling (Whittaker and Hynes, 2002)
In several independent experiments in which mosquitoes fed on infected mice, only few trapDI or trap(-) sporozoites could be observed within the mosquito salivary glands, whereas for trap wild type ~10,000 sporozoites were observed per mosquito (Figure 2B, Table 1)
To determine whether mutant parasites retained the ability to migrate steadily on microscope slides, that is to glide in circles (Vanderberg, 1974), sporozoites were isolated from hemolymph and activated by addition of 3% bovine serum albumin (BSA)
Summary
Domains with similar overall structures, initially described in von Willebrand factor A (VWA domains), are found in cell-surface proteins including integrins, extracellular matrix, and complement components, and mediate a diversity of functions including cell adhesion, migration, and signaling (Whittaker and Hynes, 2002). One protein called TRAP, which is found on the surface of the sporozoites, is important for their migration and the infection of the salivary glands or liver. Mutations of amino acids within the MIDAS motif of the single I domain in TRAP decreased the capacity of sporozoites to enter salivary glands and liver cells as well as to infect mice (Wengelnik et al, 1999; Matuschewski et al., 2002). These mutant sporozoites were still able to migrate in vitro. Our results show that I domains have the capacity to be poly-specific and permit TRAP to function as an adhesin in both vertebrate and arthropod hosts
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