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Genetic Screening May Predict Risk of CMV Infection

By LabMedica International staff writers
Posted on 10 Jan 2017
Researchers have found that the protein nucleotide-binding oligomerization domain 1 (NOD1) is involved in regulating cytomegalovirus (CMV) infection and that loss-of-function NOD1 variants may result in higher susceptibility to CMV infection, which can lead to devastating developmental defects in fetuses and severe disease in people with weakened immune systems.

The new study, led by researchers Johns Hopkins University School of Medicine (Baltimore, MD, USA), provides what appears to be the first reported evidence that NOD1, a protein with a well-known role in inducing the innate immune response, has an integral role in control of CMV and that certain NOD1 variants may increase risk of susceptibility.

Image: A ribbon model illustration of the nucleotide-binding oligomerization domain 1 (NOD1) protein. Researchers have found that a genetic mutation that alters NOD1 structure may increase susceptibility to human cytomegalovirus (Image courtesy of Wikimedia).
Image: A ribbon model illustration of the nucleotide-binding oligomerization domain 1 (NOD1) protein. Researchers have found that a genetic mutation that alters NOD1 structure may increase susceptibility to human cytomegalovirus (Image courtesy of Wikimedia).

CMV is transmitted from person to person through body fluids. Most people show no signs or symptoms of infection, while others develop symptoms such as a fever, sore throat, and fatigue. In addition, CMV causes colitis in individuals with Crohn’s disease and patients with suppressed immune systems, making it a significant risk to transplant recipients.

Furthermore, CMV has not drawn the same attention in the medical and scientific community as the much less common Zika virus, despite causing similar neurological complications, said Prof. Boger. According to the US Centers for Disease Control and Prevention (CDC), 1 in 150 babies in the US is born with a congenital CMV infection, and of those, 1 in 5 suffers from complications, which can include hearing loss, vision loss, cerebral palsy, cognitive impairments, and microcephaly.

“Our results suggest that this protein explains why not every person is at the same risk for CMV, and that we might someday be able to develop tests to identify and manage those who are at an increased risk for CMV-related disease,” said Ravit Boger, MD, associate professor at Johns Hopkins medical schoo. Building upon previous research in which Prof. Boger’s team identified NOD2 as a protein that controls CMV infection, its sister molecule NOD1 was found in the new study to also be important. “We do not yet know how NOD1 accomplishes this function, or if NOD1 and NOD2 coordinate or work independently in the control of CMV,” said Prof. Boger.

Using human fibroblasts that make up connective tissue, the team tested whether NOD1 activity could affect CMV replication in the cultured cells. They upregulated NOD1 by treating the cells with a bacterial fragment. They also tested genetically engineered cells that contain nonfunctional NOD1. The results showed that cells in which NOD1 was activated had decreased levels of CMV replication compared to controls.

In mouse experiments, the researchers treated the animals with two doses of iE-DAP, another bacterial NOD1 activator, and subsequently infected them with mouse CMV. Two weeks later, organs and intracardiac blood were collected from the mice and cells were cultured. The cultured cells were monitored for areas of cell death as an indicator of viral activity. Compared to untreated control mice, virus replication in iE-DAP-treated mice was significantly reduced.

How mutations in NOD1 protein determine its function against CMV remains to be determined. Prof. Boger cautions that NOD1 is not the only factor in determining risk of CMV infection, rather it is one piece of a larger puzzle in determining risk. The team will now investigate the cell signaling pathways involving the NOD proteins to help pin down how NOD1 and NOD2 interact with CMV.

The study, by Fan YH et al, was published November 14, 2016, in the journal Proceedings of the National Academy of Science (PNAS).

Related Links:
Johns Hopkins University School of Medicine


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