CD47 as a Potential Target to Therapy for Infectious Diseases

Abstract

The integrin associated protein (CD47) is a widely and moderately expressed glycoprotein in all healthy cells. Cancer cells are known to induce increased CD47 expression. Similar to cancer cells, all immune cells can upregulate their CD47 surface expression during infection. The CD47-SIRPa interaction induces an inhibitory effect on macrophages and dendritic cells (dendritic cells) while CD47-thrombospondin-signaling inhibits T cells. Therefore, the disruption of the CD47 interaction can mediate several biologic functions. Upon the blockade and knockout of CD47 reveals an immunosuppressive effect of CD47 during LCMV, influenza virus, HIV-1, mycobacterium tuberculosis, plasmodium and other bacterial pneumonia infections. In our recent study we shows that the blockade of CD47 using the anti-CD47 antibody increases the activation and effector function of macrophages, dendritic cells and T cells during viral infection. By enhancing both innate and adaptive immunity, CD47 blocking antibody promotes antiviral effect. Due to its broad mode of action, the immune-stimulatory effect derived from this antibody could be applicable in nonresolving and (re)emerging infections. The anti-CD47 antibody is currently under clinical trial for the treatment of cancer and could also have amenable therapeutic potential against infectious diseases. This review highlights the immunotherapeutic targeted role of CD47 in the infectious disease realm.

A Potential Role of the CD47/SIRPalpha Axis in COVID-19 Pathogenesis

“…CD47 is the receptor of thrombospondin-1 (THBS1) and the counter-receptor for signal regulatory protein-α (SIRPα). CD47 interaction with SIRPα inhibits the activation of macrophages and dendritic cells, and thrombospondin-1/ CD47 signaling inhibits T cell activation [22,23]. Cellular surface levels of CD47 modulate immune responses in infectious diseases caused by parasites, bacteria, and viruses [22].…”

“…CD47 interaction with SIRPα inhibits the activation of macrophages and dendritic cells, and thrombospondin-1/ CD47 signaling inhibits T cell activation [22,23]. Cellular surface levels of CD47 modulate immune responses in infectious diseases caused by parasites, bacteria, and viruses [22]. Typically, high CD47 levels prevent the immune recognition of virus-infected cells [22,24].…”

Role of Apoptotic Cell Clearance in Pneumonia and Inflammatory Lung Disease

“…The engagement of SIRPα recruits phosphatases to the efferocyte plasma membrane which antagonizes protein and lipid kinase activity induced by efferocytic receptors [ 283 , 284 ]. The inhibition of efferocytosis by SIRPα signaling is thought to underly many diseases that are characterized by defective efferocytosis [ 285 , 286 ], and as such, anti-CD47 therapy has been explored as a potential therapeutic approach for treating these diseases [ 287 , 288 ]. For example, atherosclerosis—which is characterized by the accumulation of uncleared apoptotic macrophages beneath the heart vasculature—is responsive to anti-CD47 therapy [ 285 ], with this therapy reversing the efferocytic defects that arise early in disease [ 161 ].…”

The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes

“…Similarly, during viral infections, CD47 expression increases on both immune cells and infected tissues due to an indirect effect of TNFα-NFκB1-signaling ( 64 ). It is hypothesized that this effect occurs to prevent the over-activation of immune cells during infection, but it remains unknown whether viruses or bacteria can directly influence CD47 expression to evade detection by the immune system ( 64 ). Regardless, once downregulation or blockade of SIRPα:CD47 signaling occurs, most immune cells exhibit enhanced anti-viral capabilities ( 64 ).…”

“…It is hypothesized that this effect occurs to prevent the over-activation of immune cells during infection, but it remains unknown whether viruses or bacteria can directly influence CD47 expression to evade detection by the immune system ( 64 ). Regardless, once downregulation or blockade of SIRPα:CD47 signaling occurs, most immune cells exhibit enhanced anti-viral capabilities ( 64 ). In line with these findings, adoptively transferred CD47-deficient red blood cells (RBCs) are cleared more quickly than CD47 + RBCs in non-autoimmune C57BL/6 recipient mice, supporting the notion that CD47 expression is required for successful “don’t eat me” signaling ( 65 ).…”