Disruption of the CD47-SIRPα Axis Causes Profound Reduction of Parasitaemia in Mice Infected With Babesia microti.

Abstract

Human babesiosis is an emerging disease in North America caused by the red blood cell (RBC)-infecting parasite Babesia microti. Despite a rise in clinical cases in recent years, the pathogenesis and host immune response to B. microti infection remain unclear. CD47 is a 'marker of self' transmembrane glycoprotein expressed on cell membranes that inhibits phagocytosis through interactions with macrophage signal-regulatory protein alpha (SIRPα). We posit that disruption of CD47-SIRPα signalling will induce macrophage uptake of Babesia-infected RBCs and reduce parasitaemia in susceptible hosts. To evaluate this, we compared the in vivo clearance of B. microti in CD47 knockout (CD47^-/-) mice and wild-type C57BL/6J mice. Our results showed pronounced differences in infection kinetics between the two mouse strains. C57BL/6J mice showed steadily increasing parasitaemia that peaked at an average of 12%, whereas CD47^-/- mice exhibited parasitaemia that never exceeded 1.5% throughout infection. Parasitaemia became undetectable by Day 21 in C57BL/6J and by Day 16 in CD47^-/- mice, indicating resolution of infection. These results imply that, in the absence of CD47, growth of B. microti is diminished due to more efficient phagocytosis of infected RBCs by macrophages. We propose that CD47-SIRPα signalling plays a key role in the innate response to Babesia and suggest CD47 modulation as a new therapeutic target for the treatment of babesiosis.