Innate immune sensing of cell traversal by <i>Plasmodium</i> sporozoites drives protective T cell responses

Abstract Attenuated Plasmodium sporozoites elicit robust adaptive immune responses that protect against parasite challenge, yet how they engage the innate immune system remains poorly understood. To obtain sterile preparation of sporozoites we used flow cytometry to isolate pure GFP + P. berghei and P. falciparum sporozoites, which were sorted onto murine bone marrow–derived macrophages (BMDMs) or human PBMCs to assess innate immune activation. Sporozoites induced a distinctive activation pattern resembling cell wounding responses, consistent with their ability to traverse host cells en route to the liver. Traversal-deficient sporozoites failed to activate BMDMs and showed impaired priming of protective CD8 + T cell immunity. This wounding response was independent of inflammasome or Toll-like receptor signaling but required γδ T cells, which are known to support CD8 + T cell responses against Plasmodium . These findings reveal a previously unappreciated innate sensing mechanism triggered by cell traversal that underpins the potent immunogenicity of Plasmodium sporozoites.