Propulsive cell entry diverts pathogens from immune degradation by remodeling the phagocytic synapse

Abstract

AbstractPhagocytosis is a critical immune function for infection control and tissue homeostasis. This process is typically described as non-moving pathogens being internalized and degraded in phagolysosomes. For pathogens that evade immune degradation, the prevailing view is that virulence factors that biochemically disrupt the biogenesis of phagoslysosomes are required. In contrast, here we report that physical forces exerted by pathogens during cell entry divert them away from the canonical phagolysosomal degradation pathway, and this altered intracellular fate is determined at the time of phagocytic synapse formation. We used the eukaryotic parasiteToxoplasma gondiias a model because liveToxoplasmauses gliding motility to actively invade into host cells. To differentiate the effect of physical forces from that of virulence factors in phagocytosis, we developed a strategy that used magnetic forces to induce propulsive entry of inactivatedToxoplasmainto macrophage cells. Experiments and computer simulations collectively reveal that large propulsive forces suppress productive activation of receptors by hindering their spatial segregation from phosphatases at the phagocytic synapse. Consequently, the inactivated parasites, instead of being degraded in phagolysosomes, are engulfed into vacuoles that fail to mature into degradative units, following an intracellular pathway strikingly similar to that of the live motile parasite. Using opsonized beads, we further confirmed that this mechanism is general, not specific to the parasite used. These results reveal previously unknown aspects of immune evasion by demonstrating how physical forces exerted during active cell entry, independent of virulence factors, can help pathogens circumvent phagolysosomal degradation.