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

• Published in: bioRxiv
• Main Authors: Pszenny, Viviana, Sikorski, Patricia M, Raghavendran Ramaswamy, Parker, Michelle L, Adedoyin, Gloria, Boulanger, Martin J, Grigg, Michael E
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 17.10.2022
• Subjects: Cell adhesion; Coat protein; Complement activation; Complement component C3; Complement factor H; Crystal structure; Disease tolerance; Heparin; Inflammation; Parasites; Proteoglycans
• DOI: 10.1101/2022.10.17.512461

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. Δsrs57 parasites showed a reduction in both C3 deposition and FH recruitment indicating that TgSRS57 is a C3 acceptor and regulates complement activation. However, Δsrs57 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 Δsrs57parasites 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. Competing Interest Statement The authors have declared no competing interest.