Induction of an Epithelial Integrin αvβ6 in Human Cytomegalovirus-Infected Endothelial Cells Leads to Activation of Transforming Growth Factor-β1 and Increased Collagen Production

Abstract

Human cytomegalovirus (CMV) infection is a major cause of morbidity in immunosuppressed individuals, and congenital CMV infection is a leading cause of birth defects in newborns. Infection with pathogenic viral strains alters cell-cell and cell-matrix interactions, affecting extracellular matrix remodeling and endothelial cell migration. The multifunctional cytokine transforming growth factor (TGF)-␤1 regulates cell proliferation, differentiation, and extracellular matrix remodeling. Secreted as a latent protein complex, TGF-␤1 requires activation before binding to receptors that phosphorylate intracellular effectors. TGF-␤1 is activated by integrin ␣v␤6, which is strongly induced in the epithelium by injury and inflammation but has not previously been found in endothelial cells. Here , we report that CMV infection induces integrin ␣v␤6 expression in endothelial cells , leading to activation of TGF-␤1 , signaling through its receptor ALK5 , and phosphorylation of its intracellular effector Smad3. Infection of endothelial cells was also found to stimulate collagen synthesis through a mechanism dependent on both TGF-␤1 and integrin ␣v␤6. Immunohistochemical analysis showed integrin ␣v␤6 up-regulation in capillaries proximal to foci of CMV infection in lungs , salivary glands , uterine decidua , and injured chorionic villi of the placenta , demonstrating both its induction in endothelium and upregulation in epithelium in vivo. Our results suggest that activation of TGF-␤1 by integrin ␣v␤6 contributes to pathological changes and may impair endothelial cell functions in tissues that are chronically infected with CMV.

Inhibition of NF-κB Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

“…56,57 Infection with human Cytomegalovirus has been associated with induction of integrin ␣v␤6 expression in endothelial cells, leading to activation of TGF-␤ and collagen synthesis. 58 Analyses of integrin-␤6 expression in MHV68-IB␣M-infected lungs show reduced levels compared with MHV68-MR from day 9 to 90 pi ( Figure 6E). Because we observed normal levels of latent TGF-␤ at day 9 during the acute phase of replication in the MHV68-IB␣M-infected lung, the establishment of latency during the early phase of chronic infection in alveolar epithelial cells is likely to contribute to maintain the high levels of active TGF-␤ in the infected lung at late times after infection.…”

Thrombocytopenia and hemostatic disorders in chronic graft versus host disease

“…Recent work has provided evidence for the activation of TGF-b in a variety of cells and tissues infected by CMV, inducing further downstream signaling that could alter vascular function and lead to development of fibrosis. 82 Such results might suggest another possibly important pathophysiological mechanism that link together cGVHD, CMV infection, TGF-b, and thrombocytopenia. Thrombocytopenia because of low thrombopoietin (TPO) level is generally thought to be relatively rare; however, it has not been thoroughly investigated in the cGVHD setting.…”

Cytomegalovirus and human immunosenescence

“…One possibility may reside in the cell types acting as CMV reservoirs and their intimate interactions with immune cells (i.e. antigen presenting cells such as DCs, as well as endothelial cells [64][65][66]). …”