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

However, the complement of the latter ROP and GRA proteins is greatly reduced compared to that of other tissue cyst-forming coccidia such as Toxoplasma or Neospora. While mouse models have shown ROP5 and ROP18, which are absent from S. neurona, to impact virulence in Toxoplasma, the lack of a suitable such model, i.e., immunocompetent mice, for S. neurona means that little is known about its strain virulence determinants. Additionally, all strains induce fatal encephalitis in immunodeficient mice, irrespective of the dose. Only two ROPKs were conserved with E. tenella, implying specialization in the ROPK machinery required for the different life cycles. Hence, the reduced complement of ROPKs within the S. neurona genome likely underscores the important role the expanded repertoire of ROPKs plays in promoting Toxoplasma and Neospora host and niche adaptation among the susceptible hosts in which these parasites establish transmissible infections. Likewise, the distinctive set of ROPKs previously reported for E. tenella and thought to map to the sporozoite rhoptry (47) might suggest a specialized role for these proteins during the initial establishment of infection. Consistent with a transition from a strictly enteric coccidian pathogen to a tissue-invasive one capable of establishing longterm, chronic infection by encystment within host cells, S. neurona expresses a distinct surface antigen coat of SRS proteins that promote parasite recognition, attachment, and long-term encystment within host cells to promote transmissibility of infection. In comparison to T. gondii and N. caninum, however, the S. neurona SRS protein repertoire is surprisingly small and less divergent (25) ; there is a dramatic reduction in the number of SRS proteins composed of fam7 and fam8 domains, with the vast majority of the 23 SnSRS-encoding genes composed of fam2 domains. Previous studies of T. gondii suggest that proteins composed of the former domains modulate host immune responses and mediate critical roles in parasite virulence. Our data suggest that with only a single copy of a fam7-and fam8-containing SRS protein, S. neurona has evolved other mechanisms for control of immune activation and/or that such control is not required for the successful transmission of this highly prevalent protozoan pathogen. The latter point is consistent with observed differences between the S. neurona and Toxoplasma/Neospora life cycles. Sarcocystis spp., once encysted, undergo a terminal commitment to their gamont stage, requiring access to their definitive host to complete their life cycle. In contrast, both Toxoplasma and Neospora are capable of recrudescing their infection after encystation, and expansion of fam7 and fam8 domain SRS proteins capable of altering host protective immunity may function to increase the cyst burden or alter intermediate-host behavior, promoting transmission of the parasite to the definitive host to complete its life cycle. Alternatively, Sarcocystis spp. are exclusively restricted to sexual development within the intestine of the definitive host, whereas Toxoplasma infection of its felid definitive host results in both sexual development and asexual expansion of infection, so the expanded repertoire of fam7 and fam8 domain SRS proteins may promote dissemination of infection to a wide range of tissue and cell types and vaccinate the definitive host against reinfection.