The mannose receptor on sinusoidal lining cells mediates two-step bacterial clearance in the human spleen

: The human spleen plays a critical role in clearing bacteria from the bloodstream, particularly during septicaemia; yet the cellular mechanisms underlying this function remain poorly defined. Using a dual translational approach including ex vivo perfusion of human spleens and splenic primary cell cultures, we identify a previously unrecognised division of tasks in splenic antibacterial defence. In the human splenic red pulp, sinusoidal lining cells capture and retain bacteria via the CD206 mannose receptor. Subsequently, the bactericidal activity by red pulp macrophages involves the scavenger receptor MARCO. This two-step process ensures efficient removal of encapsulated pathogens as inhibition of CD206 receptor impacted not only Streptococcus pneumoniae killing, independent of the capsular serotype, but also on Klebsiella pneumoniae and Escherichia coli revising the mechanism of pathogen clearance in the human spleen. Trial registration: REC 18/EM/0057 (NCT04620824) and CE: 668/2023/Sper/AOU.