Subversion of natural killer cell responses by a cytomegalovirus-encoded soluble CD48 decoy receptor

Abstract

Throughout evolution, cytomegaloviruses (CMVs) have been capturing genes from their hosts, employing the derived proteins to evade host immune defenses. We have recently reported the presence of a number of CD48 homologs (vCD48s) encoded by different pathogenic viruses, including several CMVs. However, their properties and biological relevance remain as yet unexplored. CD48, a cosignaling molecule expressed on the surface of most hematopoietic cells, modulates the function of natural killer (NK) and other cytotoxic cells by binding to its natural ligand 2B4 (CD244). Here, we have characterized A43, the vCD48 exhibiting the highest amino acid sequence identity with host CD48. A43, which is encoded by owl monkey CMV, is a soluble molecule released from the cell after being proteolytically processed through its membrane proximal region. A43 is expressed with immediate-early kinetics, yielding a protein that is rapidly detected in the supernatant of infected cells. Remarkably, surface plasmon resonance assays revealed that this viral protein binds to host 2B4 with high affinity and slow dissociation rates. We demonstrate that soluble A43 is capable to abrogate host CD48:2B4 interactions. Moreover, A43 strongly binds to human 2B4 and prevents 2B4-mediated NK-cell adhesion to target cells, therefore reducing the formation of conjugates and the establishment of immunological synapses between human NK cells and CD48-expressing target cells. Furthermore, in the presence of this viral protein, 2B4-mediated cytotoxicity and IFN-γ production by NK cells are severely impaired. In summary, we propose that A43 may serve as a functional soluble CD48 decoy receptor by binding and masking 2B4, thereby impeding effective NK cell immune control during viral infections. Thus, our findings provide a novel example of the immune evasion strategies developed by viruses.

SLAM Family Receptor Signaling in Viral Infections: HIV and Beyond

“…Can be blocked via interactions with CMV SLAMF2 decoy receptor [43] Influenza viral HA protein [44] T cell exhaustion [45][46][47][48][49][50] NK cells, CD8 + T cells, NKT cells, γδ T cells, monocytes, basophils, eosinophils, DCs, mast cells SLAMF5 (CD84) DC pro-inflammatory signaling [19] Germinal center formation [33] B cells, T cells, monocytes, macrophages, DCs, platelets, thymocytes, NK cells, NKT cells, basophils, eosinophils.…”

“…Due to SLAMF2's importance in regulating CMI, it was theorized that some viruses may attempt to modulate SLAMF2 to circumvent its role in combating viral infections. Indeed, it was found that cytomegalovirus (CMV), HIV, and potentially, human T cell leukemia virus type 1 (HTLV-1), have evolved to do just this [41,43,57,58]. CMV is able to evade SLAMF2-mediated immune responses via two independent mechanisms: down-regulation of SLAMF2 on infected cells via the viral protein m154 [41] and by producing a soluble SLAMF2 decoy receptor [43].…”

“…Indeed, it was found that cytomegalovirus (CMV), HIV, and potentially, human T cell leukemia virus type 1 (HTLV-1), have evolved to do just this [41,43,57,58]. CMV is able to evade SLAMF2-mediated immune responses via two independent mechanisms: down-regulation of SLAMF2 on infected cells via the viral protein m154 [41] and by producing a soluble SLAMF2 decoy receptor [43]. The CMV viral protein m154 was shown to directly down-regulate SLAMF2 in infected macrophages via proteolytic degradation (Figure 2A) [41].…”

“…This led to impaired NK cell cytotoxicity against CMV infected cells and, critically, infection with a m154 deficient CMV virus displayed an attenuated phenotype in vivo [41]. Certain strains of CMV, notably Owl Monkey CMV, encode a decoy SLAMF2 protein in their genome [43]. Infection of cells with these viruses was observed to secret high levels of a soluble SLAMF2 decoy protein [43].…”

Viral ecosystem: An epidemiological hypothesis

“…Some plant viruses increase the plant survival by preventing the induction of stress caused by cold and drought . Throughout evolution, some viruses such as Herpesviridae family have been capturing genes from their hosts that leads to evade recognition by host immune system and remain latent in host cells . Therefore, the ability to launch latent infection is a particular feature of Herpesviridae family such as cytomegalovirus (CMV)…”