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• W3201574927 abstract "Toxoplasmosis is classified as a neglected parasitic infection necessitating public health control. It is due to Toxoplasma gondii, an obligatory intracellular parasite. One route of infection occurs following the oral ingestion of bradyzoite tissue cysts. Thereupon, bradyzoites invade enterocytes and convert rapidly to tachyzoites, leading to the acute infection. Under the tight control of host immune response, tachyzoites transform back into bradyzoites which sustain a lifelong chronic disease. If left untreated, chronic toxoplasmosis may reactivate and become fatal in immunocompromised patients. Invasion of Toxoplasma involves the formation of a tight connection between the parasite and the host cell membranes, referred to a structure called Moving Junction (MJ). In tachyzoites, the MJ is shaped by the assembly of a microneme protein, AMA1, and a rhoptry neck protein, RON2, as part of a complex involving additional RONs. Whilst the MJ process is well characterized in tachyzoites, invasion in bradyzoites remains underexplored. Here, we demonstrated that tachyzoite MJ proteins are also expressed at the MJ of invading bradyzoites, showing for the first time that bradyzoites do form a MJ during their invasion. We also characterized more paralogs of MJ proteins, which are barely expressed in tachyzoites, and demonstrated that AMA2, AMA4 and RON2L1, are highly expressed in bradyzoites. Remarkably, we found AMA4 and AMA2 at the MJ of invading bradyzoites, highlighting that bradyzoite MJ exhibits a different protein composition than that of invading tachyzoites. Moreover, we generated AMA4 knockout parasites and unraveled the importance of AMA4 for invasion in tachyzoites in some extend, but its predominant role for bradyzoite invasion and for establishing the chronic phase of infection.In light of the absence of an approved vaccine against human toxoplasmosis and the promises of a vaccine strategy based on immunization with AMA1-RON2 complex against Plasmodium, we built on the importance of MJ in invasion of both tachyzoite and bradyzoite stages, and interrogated the potential protection against toxoplasmosis by targeting MJ complexes. Immunization with recombinant AMA1 protein in complex with a RON2 peptide, revealed a high protective efficacy both after oral challenge of mice with bradyzoites (≈80% reduction of cysts burden) or intraperitoneal challenge with a lethal dose of tachyzoites (80% increased mice survival). Yet, AMA4 in complex with its binding RON2L1 peptide did not protect against acute infection, a consistent result with its low expression and function in tachyzoites. In contrast, supporting its role in the invasion of bradyzoites, AMA4-RON2L1 complex mainly protected against chronic infection. In both cases, immunization with AMA-RON2 complexes is more efficient than immunization with AMA alone. Finally, IgG against either complexes inhibited MJ formation and invasion in vitro, suggesting that the inhibition of invasion may be one plausible mechanism for in vivo protection. Importantly, antibodies against AMA1-RON2 are more efficient to inhibit the invasion of tachyzoites while antibodies against AMA4-RON2L1 target preferentially the invasion of bradyzoites; both supporting a predominant role of AMA1-RON2 in tachyzoites and AMA4-RON2L1 in bradyzoites. Altogether, these results validate different MJ complexes as potential vaccine candidates to protect against toxoplasmosis." @default.
• W3201574927 created "2021-09-27" @default.
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• W3201574927 date "2021-03-05" @default.
• W3201574927 modified "2023-09-26" @default.
• W3201574927 title "Molecular characterization of bradyzoite invasion and evaluation of vaccine candidates targeting the moving junction of toxoplasma gondii" @default.
• W3201574927 hasPublicationYear "2021" @default.
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