The αTSR Domain of Plasmodium Circumsporozoite Protein Bound Heparan Sulfates and Elicited High Titers of Sporozoite Binding Antibody After Displayed by Nanoparticles

• Published in: International journal of nanomedicine Vol. 18; pp. 3087 - 3107
• Main Authors: Xia, Ming, Vago, Frank, Han, Ling, Huang, Pengwei, Nguyen, Linh, Boons, Geert-Jan, Klassen, John S, Jiang, Wen, Tan, Ming
• Format: Journal Article
• Language: English
• Published: New Zealand Dove 2023; Dove Medical Press
• Subjects: malaria; malaria vaccine; norovirus; Original Research; plasmodium; receptor binding domain; s60 nanoparticle; αtsr domain; S60 nanoparticle; receptor binding domain; Plasmodium; norovirus; malaria vaccine; malaria; αTSR domain
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S406314

Malaria is a devastating infectious illness caused by protozoan parasites. The circumsporozoite protein (CSP) on sporozoites binds heparan sulfate proteoglycan (HSPG) receptors for liver invasion, a critical step for prophylactic and therapeutic interventions. In this study, we characterized the αTSR domain that covers region III and the thrombospondin type-I repeat (TSR) of the CSP using various biochemical, glycobiological, bioengineering, and immunological approaches. We found for the first time that the αTSR bound heparan sulfate (HS) glycans through support by a fused protein, indicating that the αTSR is a key functional domain and thus a vaccine target. When the αTSR was fused to the S domain of norovirus VP1, the fusion protein self-assembled into uniform S -αTSR nanoparticles. Three-dimensional structure reconstruction revealed that each nanoparticle consists of an S nanoparticle core and 60 surface displayed αTSR antigens. The nanoparticle displayed αTSRs retained the binding function to HS glycans, indicating that they maintained authentic conformations. Both tagged and tag-free S -αTSR nanoparticles were produced via the system at high yield by scalable approaches. They are highly immunogenic in mice, eliciting high titers of αTSR-specific antibody that bound specifically to the CSPs of sporozoites at high titer. Our data demonstrated that the αTSR is an important functional domain of the CSP. The S -αTSR nanoparticle displaying multiple αTSR antigens is a promising vaccine candidate potentially against attachment and infection of parasites.