<i>Toxoplasma</i> surface coat protein TgSRS57 (TgSAG3) regulates complement deposition, Factor H recruitment, and promotes parasite persistence

ABSTRACT The surface coat of Toxoplasma gondii possesses a lectin-like activity that activates host complement. Serum resistance relies on specific recruitment of host regulators Factor H (FH) and C4BP to the parasite surface to inactivate bound C3 and evade the complement system. TgSRS57 (TgSAG3) was previously reported to possess a lectin-like activity specific for sulfated proteoglycans (SPGs) that facilitated host cell attachment and parasite invasion. To investigate whether TgSRS57 actively recruits Factor H to the parasite surface to regulate the complement cascade, we generated Type I RH and Type II CZ1 knockout strains. Δ srs57 parasites showed a reduction in both C3 deposition and FH recruitment indicating that TgSRS57 is a C3 acceptor and regulates complement activation. However, Δ srs57 parasites showed no attachment defect, possessed normal extracellular survival and intracellular replication kinetics, and were more virulent than WT strains in low dose murine infections, contrary to previous findings. To better understand the genetic and cellular data, we determined the 1.59Å resolution TgSRS57 crystal structure. Notably, TgSRS57 did not possess a dimer dependent basic surface groove as originally modeled, nor did it bind heparin. However, approximately 10 distinct parasite proteins were identified that interact specifically with SPGs. Infection studies showed that Type II Δ srs57 parasites achieved higher parasite burdens and elevated inflammatory responses compared to WT parasites. Infection of C3 deficient mice established that TgSRS57-dependent protection was C3-dependent and that T. gondii actively parasitizes the complement system. Our results suggest that the interaction between TgSRS57 and C3 plays a critical role in disease tolerance by controlling both parasite proliferation and persistence in vivo . AUTHOR SUMMARY The Toxoplasma gondii surface coat is dominated by a superfamily of developmentally expressed, antigenically distinct adhesins collectively called the SRS proteins, which are structurally analogous to the Plasmodium 6-CYS surface proteins. These proteins are thought to possess lectin-like activities, facilitate parasite attachment and entry into host cells, and regulate innate effectors of the host immune response. Disease tolerance in hosts is critically dependent on the induction of sufficient immunity to limit parasite replication and promote host survival without inducing bystander immune damage. In this study we employed a combination of genetic, cellular and structural biology approaches to establish that the surface antigen TgSRS57 regulates complement C3 deposition on parasite surfaces by specifically recruiting host Factor H to actively resist serum killing and limit the formation of the C5b-9 membrane attack complex. Further, that the presence of C3 was host protective, as C3-deficient mice failed to control parasite replication. The ability of the parasites to inactivate C3 was also necessary to resist serum killing and promote chronic infection. Because complement exists as a potent inflammatory mediator, the active regulation of complement by Toxoplasma ensures that the parasite is not lysed by C3 but also limits the induction of lethal immunopathology, thereby promoting an immune balance, disease tolerance, and the long-term persistence of transmissible parasites.

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