Diverse gut pathogens exploit the host engulfment pathway via a conserved mechanism

ABSTRACT Macrophages clear infections by engulfing and digesting pathogens within phagolysosomes. Pathogens escape this fate by engaging in a molecular arms race; they use WxxxE motif-containing “effector” proteins to subvert the host cells they invade and seek refuge within protective vacuoles. Here we define the host component of the molecular arms race as an evolutionarily conserved polar ‘hotspot’ on the PH-domain of ELMO1 ( E ngu l fment and Cell Mo tility1), which is targeted by diverse WxxxE -effectors. Using homology modeling and site-directed mutagenesis, we show that a lysine triad within the ‘patch’ directly binds all WxxxE -effectors tested: SifA ( Salmonella) , IpgB1 and IpgB2 ( Shigella ), and Map (enteropathogenic E. coli ). Using an integrated SifA•host protein-protein interaction (PPI) network, in-silico network perturbation, and functional studies we show that the major consequences of preventing SifA•ELMO1 interaction are reduced Rac1 activity and microbial invasion. That multiple effectors of diverse structure, function, and sequence bind the same hotpot on ELMO1 suggests that the WxxxE -effector(s)•ELMO1 interface is a convergence point of intrusion detection and/or host vulnerability. We conclude that the interface may represent the fault line in co-evolved molecular adaptations between pathogens and the host and its disruption may serve as a therapeutic strategy. GRAPHICAL ABSTRACT In brief This work defines the nature of a conserved molecular interface, assembled between diverse W xxxE motif-containing effector proteins encoded by gut pathogens and the host innate immune sensor, ELMO1, via which pathogens exploit the host’s engulfment machinery.