This study was further supported by the DFG grants LA1419/7-1, LA1419/10-1, the collaborative research center CCR974 and the Research Training Groups RTG2098
This study was further supported by the DFG grants LA1419/7-1, LA1419/10-1, the collaborative research center CCR974 and the Research Training Groups RTG2098. Conflicts of Interest The authors declare no conflicts of interest.. 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. Keywords: anti-CD47, macrophages, dendritic cells, T cells, therapy, viral contamination 1. Introduction The CD47 is expressed on both hematopoietic and non-hematopoietic cells and plays crucial role in immune regulation and maintenance of homeostasis [1,2,3]. Its expression level varies depending on cell types and pathophysiological conditions. In normal physiological conditions, all healthy cells express moderate level of CD47. However, migrating stem cells and young red blood cells exhibit increased levels of CD47 to evade macrophage attack [4,5,6,7,8]. In pathologic conditions, varieties of cancer cells are known to induce increased CD47 surface expression as a mechanism to evade macrophage mediated phagocytosis [9,10,11]. In addition to cancer, all immune cells upregulate CD47 upon BMS-265246 pathogen invasion [12]. Typically, poxvirus has been shown to encode expression of CD47-like protein and this strongly inhibits the activation of macrophages and T cells. Thus, the CD47 expression in poxvirus is an immune evasion mechanism to promote its virulence and pathogenesis [13,14]. The two most known interactions of CD47 is with signal regulatory protein alpha (SIRPa) and thrombospodin-1 (TSP-1). SIRPa is usually widely expressed on macrophages and dendritic cells while thrombonspondin-1 is usually a secreted matricellular glycoprotein [12]. The CD47-SIRPa conversation induces an antiphagocytic signal in macrophages and dendritic cells. This conversation leads to the recruitment and activation of Src homology phosphate (SHP-1 and SHP-2) thereby inhibiting the myosin-IIA and this results in prevention of phagocytosis [12,15]. The mechanism of CD47-mediated suppression on innate immune cells is usually via the recruitment and activation of Src homology two domain-containing phosphatases, SHP-1 and SHP-2. Activated SHP-1 and SHP-2 dephosphorylate immune-receptor tyrosine-based inhibitory motifs (ITIMs), thereby preventing downstream activation-signaling in macrophages, dendritic cells and NK cells [16,17,18,19,20,21,22,23]. The disruption of CD47/SIRPa-signaling increases macrophage mediated phagocytosis of diseased vascular tissue and cancer cells. This leading to regression of much different type of tumors both in vivo and in vitro [24,25,26,27,28,29]. BTF2 Similar to cancers, there is growing evidence that this inhibition of CD47/SIRPa conversation induces an antimicrobial effect during infections [30,31,32,33]. Thrombospondin-1 is usually a multifunctional protein that plays several crucial functions in regulating cell proliferation and differentiation. Although it is usually shown to bind to multiple proteins, the most studied interaction is with CD47 [34,35]. The CD47-TSP-1 conversation on antigen presenting cells (APCs) inhibits inflammasomes and interleukin 1b (IL-1b) and also inhibits T cells proliferation, activation and cytotoxicity [36]. In addition to overexpression of CD47 by cancer cells as a survival mechanism, TSP-1 ligation of CD47 is shown to increase proliferation and survival of cutaneous T-cell lymphomas (CTCL) and hence blockade of CD47/TSP-1 interaction results in CTCL regression [37,38]. As an inhibitory innate immune checkpoint molecule, the CD47-signaling pathways have been found to be an important in regulating both innate and adaptive immunity. The blockade of CD47 using anti-CD47 antibody shows a promising therapeutic effect on different tumors. Indeed, several studies around the genetic inactivation or blockade of CD47 demonstrate therapeutic potential during contamination. Recently, Cham et al. Shown that CD47 blockade mediates comparable BMS-265246 immunotherapeutic effect during viral contamination due to increased activation of both innate and adaptive BMS-265246 immune response after CD47 blockade. However, the use of anti-CD47 antibody in other infections remains to be investigated. In this review, we recapitulate anti-CD47 antibody as a potential therapeutic target for infectious diseases. 2. CD47 Expression and Infection The level of CD47 expression determines the susceptibility of target cells to be licensed for destruction by macrophages. For instance, young red blood cells (RBCs) are guarded from phagocytosis due to increased level of CD47 expression while BMS-265246 the loss of such antiphagocytic protein on older RBCs leads to their rapid clearance.