Innate immune sensing of Plasmodium sporozoite cell traversal drives protective T cell responses

Attenuated Plasmodium sporozoites (SPZs) are being tested as a potential malaria vaccine as they elicit robust adaptive immune responses that protect against parasite challenge. Yet how they engage the innate immune system remains poorly understood. Here we isolated pure GFP+ Plasmodium berghei and Plasmodium falciparum SPZs, and sorted them onto mouse bone marrow-derived macrophages or human peripheral blood mononuclear cells to assess innate immune activation using bulk and single-cell RNA sequencing. SPZs induced a distinctive activation pattern in vitro resembling cell wounding responses, consistent with their ability to traverse host cells en route to the liver. Cell traversal-deficient SPZs failed to activate bone marrow-derived macrophages and showed impaired priming of protective CD8+ T cell immunity in vivo. The cell wounding response was independent of inflammasome or Toll-like receptor signalling but required γδ T cells, which are known to support CD8+ T cell responses against Plasmodium. This reveals an innate sensing mechanism triggered by parasite cell traversal that underpins the potent immunogenicity of Plasmodium SPZs.