CD47 regulates the phagocytic clearance and replication of thePlasmodium yoeliimalaria parasite

Abstract

Several Plasmodium species exhibit a strong age-based preference for the red blood cells (RBC) they infect, which in turn is a major determinant of disease severity and pathogenesis. The molecular basis underlying this age constraint on the use of RBC and its influence on parasite burden is poorly understood. CD47 is a marker of self on most cells, including RBC, which, in conjunction with signal regulatory protein alpha (expressed on macrophages), prevents the clearance of cells by the immune system. In this report, we have investigated the role of CD47 on the growth and survival of nonlethal Plasmodium yoelii 17XNL (PyNL) malaria in C57BL/6 mice. By using a quantitative biotin-labeling procedure and a GFP-expressing parasite, we demonstrate that PyNL parasites preferentially infect high levels of CD47 (CD47hi)-expressing young RBC. Importantly, C57BL/6 CD47−/− mice were highly resistant to PyNL infection and developed a 9.3-fold lower peak parasitemia than their wild-type (WT) counterparts. The enhanced resistance to malaria observed in CD47−/− mice was associated with a higher percentage of splenic F4/80+ cells, and these cells had a higher percentage of phagocytized parasitized RBC than infected WT mice during the acute phase of infection, when parasitemia was rapidly rising. Furthermore, injection of CD47-neutralizing antibody caused a significant reduction in parasite burden in WT C57BL/6 mice. Together, these results strongly suggest that CD47hi young RBC may provide a shield to the malaria parasite from clearance by the phagocytic cells, which may be an immune escape mechanism used by Plasmodium parasites that preferentially infect young RBC.

Splenic Dendritic Cells Survey Red Blood Cells for Missing Self-CD47 to Trigger Adaptive Immune Responses

“…Finally, our demonstration that CD47-deficient RBCs can serve as adjuvants for CD4 + T cell and antibody responses adds to recent literature highlighting CD47 antagonism as an approach to augment macrophage responses against cancer cells and parasite infected RBCs (Banerjee et al, 2015; Chao et al, 2012; Tseng et al, 2013). Induction of CD4 + T cell and antibody responses during CD47-blockade treatments might contribute to the anti-tumor and anti-pathogen effects.…”

Anti-Self Phosphatidylserine Antibodies Recognize Uninfected Erythrocytes Promoting Malarial Anemia

“…CD47, a marker of young RBCs (Oldenborg, 2004) and a major ‘do-not-eat me’ signal (Sosale et al, 2015), protects P. yoelii -infected RBCs from clearance (Banerjee et al, 2015). We therefore analyzed the expression levels of this marker in uninfected RBCs, which could explain the low uptake of RBCs in the absence of anti-PS antibodies.…”

CD47-SIRPα Interactions Regulate Macrophage Uptake of Plasmodium falciparum-Infected Erythrocytes and Clearance of Malaria In Vivo

“…Alterations in CD47 or SIRP␣ abundance, structure, or function may disrupt signaling through SIRP␣, resulting in enhanced macrophage clearance of RBCs (2,36). Previous studies have linked modification of CD47 on senescent RBCs to increased phagocytic uptake (13,(37)(38)(39). P. falciparum infection exerts substantial oxidative stress on host RBCs, resulting in membrane alterations similar to those observed on senescent RBCs (40,41).…”

“…SIRP␣ is polymorphic and highly expressed on hepatic Kupffer cells and splenic red pulp macrophages, cell populations important in the innate control of malaria (11,12). A recent study of Plasmodium yoelii malaria in a nonlethal murine model reported that CD47 was an important determinant of age-specific RBC invasion and parasite burden (13). Although Plasmodium falciparum is responsible for the majority of cases of severe and cerebral malaria (CM), the role of CD47-SIRP␣ in falciparum malaria has not been reported.…”