CD47-SIRPα Interactions Regulate Macrophage Uptake of Plasmodium falciparum-Infected Erythrocytes and Clearance of Malaria In Vivo.
CD47 engagement by the macrophage signal regulatory protein alpha (SIRPα) inhibits phagocytic activity and protects red blood cells (RBCs) from erythrophagocytosis. The role of CD47-SIRPα in the innate immune response to Plasmodium falciparum infection is unknown. We hypothesized that disruption of SIRPα signaling may enhance macrophage uptake of malaria parasite-infected RBCs. To test this hypothesis, we examined in vivo clearance in CD47-deficient mice infected with Plasmodium berghei ANKA and in vitro phagocytosis of P. falciparum-infected RBCs by macrophages from SHP-1-deficient (Shp-1(-/-)) mice and NOD.NOR-Idd13.Prkdc(scid) (NS-Idd13) mice, as well as human macrophages, following disruption of CD47-SIRPα interactions with anti-SIRPα antibodies or recombinant SIRPα-Fc fusion protein. Compared to their wild-type counterparts, Cd47(-/-) mice displayed significantly lower parasitemia, decreased endothelial activation, and enhanced survival. Using macrophages from SHP-1-deficient mice or from NS-Idd13 mice, which express a SIRPα variant that does not bind human CD47, we showed that altered SIRPα signaling resulted in enhanced phagocytosis of P. falciparum-infected RBCs. Moreover, disrupting CD47-SIRPα engagement using anti-SIRPα antibodies or SIRPα-Fc fusion protein also increased phagocytosis of P. falciparum-infected RBCs. These results indicate an important role for CD47-SIRPα interactions in innate control of malaria and suggest novel targets for intervention.
SAR Laboratories, Sandra Rotman Centre for Global Health, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada.
Kodjo
K
Ayi
SAR Laboratories, Sandra Rotman Centre for Global Health, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada.
Ziyue
Z
Lu
SAR Laboratories, Sandra Rotman Centre for Global Health, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada.
Lena
L
Serghides
Princess Margaret Cancer Centre and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Jenny M
JM
Ho
SAR Laboratories, Sandra Rotman Centre for Global Health, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada.
Constance
C
Finney
Princess Margaret Cancer Centre and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Jean C Y
JCY
Wang
SAR Laboratories, Sandra Rotman Centre for Global Health, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.|Department of Medicine, University of Washington, Seattle, Washington, USA.|Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada.
W Conrad
WC
Liles
SAR Laboratories, Sandra Rotman Centre for Global Health, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada kevin.kain@uhn.ca.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.|Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, Toronto General Hospital-University Health Network, University of Toronto, Toronto, Ontario, Canada.
Kevin C
KC
Kain
D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology; D006790:Host-Parasite Interactions; D007113:Immunity, Innate; D008264:Macrophages / Q000469:parasitology* / Q000502:physiology*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology*; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000276:immunology; D010963:Plasmodium falciparum / Q000254:growth & development / Q000276:immunology*; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction
D051928:CD47 Antigen; D016207:Cytokines; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic