The Mannose Receptor on Sinusoidal Lining Cells Mediates Two-Step Bacterial Clearance in the Human Spleen

The human spleen is the main organ in preventing invasive bacterial infection, yet the cellular mechanisms driving pathogen clearance remain poorly defined. This work shows that there is division of labour in the human spleen for eliminating bacteria from the circulation. Using a dual translational approach including ex vivo perfusion of human spleen and splenic primary cell cultures, we demonstrate that sinusoidal cells capture and retain bacteria via the CD206 receptor in the splenic red pulp to enable bactericidal activity by tissue resident macrophages. This activity was dependent on bacterial capsule, with unencapsulated bacteria being cleared irrespective of inhibition of the mannose receptor. This implies a specific two-step process to ensure efficient removal of encapsulated pathogens. These data change completely our understanding of pathogen clearance in the human spleen, with profound implications for the development of host-directed anti-infective strategies and for the evaluation of conjugate vaccine efficacy.