Systems-Based Analysis of the Sarcocystis neurona Genome Identifies Pathways That Contribute to a Heteroxenous Life Cycle

Blazejewski, Tomasz; Nursimulu, Nirvana; Pszenny, Viviana; Dangoudoubiyam, Sriveny; Namasivayam, Sivaranjani; Chiasson, Melissa A.; Chessman, Kyle; Tonkin, Michelle; Swapna, Lakshmipuram S.; Hung, Stacy S.; Bridgers, Joshua; Ricklefs, Stacy M.; Boulanger, Martin J.; Dubey, Jitender P.; Porcella, Stephen F.; Kissinger, Jessica C.; Howe, Daniel K.; Grigg, Michael E.; Parkinson, John

Together, our data support a model in which, following the split with the Eimeria lineage, the ancestor of Sarcocystis and Toxoplasma gained the ability to invade intermediate hosts and form tissue cysts. This transition required the evolution of SRS family proteins as structural constituents of the cyst wall, as well as immune evasion molecules protecting the parasite from sterilizing immunity. Subsequently, while the Sarcocystis lineage abandoned the use of the PV during its schizont stage in the intermediate host, committing the parasite to its sexual cycle after encystation, the Toxoplasma lineage Figure Legend Continued diphosphate-fructose-6-phosphate 1-phosphotransferase; FBA, fructose-bisphosphate aldolase; PK, pyruvate kinase; Cyt, cytosol; Mito, mitochondrion; PC, pyruvate carboxylase; CS, citrate synthase; AH, aconitate hydratase; ID, isocitrate dehydrogenase (NADPÏ©); OD, oxoglutarate dehydrogenase (succinyltransferring); DS, dihydrolipoyllysine-residue succinyltransferase; SL, succinate-CoA ligase (ADP-forming); SD, succinate dehydrogenase (ubiquinone); FH, fumarate hydratase; MD, malate dehydrogenase; frc, fructose. (D) Relationship between fructose, glucose, and sucrose import and growth. maintained the use of a PV during intermediate-host infection. The use of the PV could conceivably shield the parasite from the host developing an effector memory CD8 T cell response that is naturally induced by the presence of parasite antigens in the cytosol of infected host cells. This, in turn, allows Toxoplasma to recrudesce postencystation and, aided by an expanded repertoire of ROPK, GRA, and SRS proteins, provides further opportunities to increase the cyst burden and extend its host range. In addition to addressing questions of host range and specificity, we expect that the availability of this resource will help drive the development of novel therapeutics that are urgently required for these devastating pathogens. Further, reference genome mapping will facilitate genus-wide and population studies that focus on questions of host specialization and virulence mechanisms. The latter, for example, might be expected to inform on the spate of fatal infections in marine mammals to resolve at the genome level the genetic basis of the emergence of these disease-producing strains. Key to these studies will be the generation of robust expression data sets that allow the identification of critical proteins associated with distinct stages of the parasite's life cycle.