Th208 - P66 Is a Bacterial “don’t Eat Me” Checkpoint That Mimics Mammalian CD47 and Facilitates Macrophage Evasion by Borrelia Burgdorferi

Michal Tal – BioEngineering – Massachusetts Institute of Technology; Regan Volk; Effie Bastounis; Sarah Galloway; Grace Blacker; Nitya Ramadoss; Anne Sapiro; Beth Hayes; Tal Raveh; Seemay Chou; William Robinson; Jenifer Coburn; Irving Weissman; Balyn Zaro

Abstract Text: Innate immunity, the first line of defense against pathogens, relies on efficient elimination of the invading agents by phagocytes. Thus in the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through molecular mimicry of a mammalian anti-phagocytic “don’t eat me” signal. Using a high affinity structural probe for human CD47, a dominant “don’t eat me” signal, we discovered a bacterial protein that mimics CD47’s structure on the surface of Borrelia burgdorferi (Bb), a bacterial spirochete that can cause Lyme Disease (LD) in mammals. Blockade of the mimic delays the infection in vivo. We identified P66, a known virulence factor, as the bacterial mimic of CD47, although P66 lacks sequence homology with CD47. We find that both the initial rate of phagocytosis and total number of phagocytic events are higher for p66 knockout Bb compared to wildtype upon incubation with human-serum derived macrophages. Finally, we determined that patients who return to health following treatment of LD are more likely to generate antibodies to P66 compared to patients who do not. This study demonstrates molecular mimicry as a means used by Bb to inhibit macrophages and evade phagocytic clearance. This is the first report of a bacterial protein signaling through a mammalian ‘don’t eat me’ receptor and this mechanism may have broad implications for understanding host-pathogen interactions and developing therapeutic strategies to combat bacterial infection.