Deletion of Plasmodium yoelii Merozoite Surface Protein 8 Protects Mice From Lethal Blood‐Stage Malaria and Is Associated With Enhanced Splenic CCL19‐CCR7 Signaling

Merozoite surface protein 8 (MSP8) is a conserved blood-stage antigen implicated in erythrocyte invasion and vaccine-induced protection, but its role in coordinating host immunity during malaria remains unclear. Here, we combined MSP8 immunization, CRISPR/Cas9-mediated deletion of Plasmodium yoelii (P. yoelii) msp8, and perturbation of chemokine-receptor signaling to define how MSP8 shapes disease outcome in the lethal murine model of malaria. Mouse antisera against Plasmodium falciparum MSP8 partially inhibited merozoite invasion of human erythrocytes in vitro, and PyMSP8 immunization conferred partial protection against lethal P. yoelii 17XL challenge, supporting the notion that MSP8 functions both as an invasion-related antigen and as a target of the protective immune responses. A full-length pymsp8 knockout line (P. yoelii 17XL ΔMSP8) was generated successfully and ΔMSP8 strain infected mice exhibited reduced peak parasitemia, attenuated splenomegaly, and a self-resolving course. Transcriptomic, immunoblot, and immunohistochemical analyses revealed MSP8 deficiency upregulated chemokine CCL19 and preserved its receptor CCR7 in the spleen of infected mice, accompanied by increased IFN-γ level in spleen and serum. Functional knockdown of CCR7 using adeno-associated virus (AAV)-delivered shRNA partially abrogated the survival advantage of ΔMSP8 infection, lowered splenic CCR7 and IFN-γ levels and increased the mortality. Together, these data support a model in which parasite-expressed MSP8 is associated with reduced activity of a splenic CCL19-CCR7 axis that inducing IFN-γ-driven protective responses, whereas loss of MSP8 preserves and enhances this chemokine pathway and converts otherwise lethal infection into a self-resolving outcome. Targeting MSP8 or therapeutically augmenting CCL19-CCR7 signaling therefore represent complementary strategies for malaria vaccines and host-directed interventions.