Human cytomegalovirus IE2 protein regulates macrophage-mediated immune escape by upregulating GRB2 expression in...

Although cytomegalovirus (HCMV) infection is asymptomatic in healthy individuals, the virus can remain latent for many years due to its ability to evade host immune surveillance. However, reactivation of HCMV can lead to life-threatening disease. Recent studies have shown that HCMV infection mediates immune escape by regulating macrophage activity, although the role of the HCMV-encoded IE2 protein is unclear. A ul122 transgenic mouse model was created to stably expresses the IE2 protein, and the proportion of M1 and M2 macrophage populations in their spleen and bone marrow was compared to that in wild-type controls. In addition, the phagocytic function of the macrophages was evaluated in terms of neutral red dye uptake. Spleen and bone marrow macrophages in IE2-expressing mice were mainly of the M2 phenotype and displayed enhanced phagocytic function compared to that in control mice. The relative levels of expression of macrophage-related GRB2 and of IL-4, IFN-γ, IL-13, and TNF-α were also analyzed in the spleen and bone marrow of the two groups. The IE2-expressing mice had increased expression of GRB2 and increased expression of the M2-related cytokines IL-4 and IL-13. Taken together, the current results suggest that HCMV IE2 polarizes the host macrophages to the M2 type via a GRB2/IL-4-related pathway, which enables long-term survival of the virus in the host.