Researchers from the La Jolla Institute for Allergy & Immunology and Cardiff University discovered that a specific human CMV protein, known as UL141, blocked the cell-surface expression of TNF-related apoptosis-inducing ligand (TRAIL) death receptors normally involved in destroying infected cells. Death receptors (DRs) of the TNFR superfamily usually promote apoptosis and regulate immune homeostasis during infection, and NK cells produce high levels of TRAIL to induce apoptosis of tumour cells and cells infected with viruses.
However, the UL141 glycoprotein was shown to bind directly to TRAIL DRs and impede their transport through the Golgi apparatus, thus preventing their expression on the surface of the cell. As such, UL141 protected virus-infected cells from TRAIL and TRAIL-dependent natural killer (NK) cell-mediated killing.
The results of this research therefore go some way to explaining how human CMV works to block the efforts of the body's immune system to clear the virus.
“By uncovering this mechanism, we’ve provided an important piece of the CMV puzzle that could enable vaccine counter strategies that flush out and eliminate virus-infected cells,” said Chris Benedict of the La Jolla Institute, in a press release. “While important in cancer, it has also become quite clear that TRAIL signalling by the immune system is very significant in viral infections, such as CMV. By discovering that this protein (UL141) inhibits TRAIL’s ability to carry out its killing function, we believe we have revealed a pivotal piece of the cellular apparatus that needs to be considered when developing an effective vaccine.”
CMV can cause numerous birth defects and severe disease in immunocompromised patients, and development of a vaccine against the virus is now listed as a high priority by the National Institute of Medicine.
The research paper, published in Cell Host & Microbe, is available here.
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