PITTSBURGH, Nov. 28, 2012 – A new study published online in PLOS ONE reveals that primitive human stem cells are resistant to human cytomegalovirus (HCMV), one of the leading prenatal causes of congenital intellectual disability, deafness and deformities worldwide. Researchers from the University of Pittsburgh School of Medicine found that as stem cells and other primitive cells mature into neurons, they become more susceptible to HCMV, which could allow them to find effective treatments for the virus and to prevent its potentially devastating consequences.
"Previous studies have focused on other species and other cell types, but those studies did not evaluate what the cytomegalovirus does to human brain cells," said Vishwajit Nimgaonkar, M.D., Ph.D., professor of psychiatry at the University of Pittsburgh School of Medicine, and senior author of the report. "This study is the first of its kind, and the first to discover that primitive stem cells are actually resistant to HCMV."
Access to cultured human neurons, necessary to understand the pathogenic effects of HCMV, has been limited by difficulties in growing the brain cells in the laboratory. Yet through human-induced pluripotent stem (iPS) cells, researchers were able to overcome this hurdle.
The study authors derived live iPS cells by reprogramming cells called fibroblasts obtained from human skin biopsies. The iPS cells were then induced to mature through several stages into neurons, the primary cells in the brain. The researchers were able to evaluate the patterns of damage caused by HCMV on all these cells.
The research findings suggest:
- Human iPS cells do not permit a full viral replication cycle, suggesting for the first time that these cells can resist CMV infection
- CMV infection distorts iPS cell differentiation into neurons, and that may be a mechanism by which infected babies develop impairments of brain maturation and intellectual ability
- iPS-derived mature neurons are more susceptible to CMV infection and once infected show effects including defective function that have been shown in other animal studies and in other human tissues, and the neurons die a few days after infection lab studies, possibly reflecting the impact of CMV on the human brain
"The findings were quite surprising, but this is only the first in a series of studies on HCMV," added Nimgaonkar. "There is a lot of interest in what we can do to treat the infection, and current work is already underway to screen for new drugs that could be used to fight these viruses."
Between 50 and 80 percent of people in the U.S. have been infected by HCMV by the time they reach 40. Infections are rarely serious, but the virus does not leave the body. CMV is also the most common congenital infection in the U.S., and occurs when a mother contracts CMV during pregnancy and passes the virus to her unborn child. According to the U.S. Centers for Disease Control and Prevention, one of every 150 children is born with CMV infection and one in five of them develops permanent problems, such as intellectual disability, vision and hearing loss, and seizures.
Pitt researchers are collaborating with the Drug Discovery Institute to further understand the cellular system and determine which agents are most effective against HCMV and similar viruses, and which treatments would be safe for human use.
The lead author of the report is Leonardo D'Aiuto, Ph.D., of the University of Pittsburgh. Collaborators on this study include Roberto Di Maio, Ph.D., Brianna Heath, Giorgio Raimondi, Ph.D., Jadranka Milosevic, Ph.D., Annie M Watson, Mikhil Bamne, Ph.D., W Tony Parks, M.D., Lei Yang, Ph.D., Bo Lin, Ph.D, Toshio Miki, M.D., Ph.D., Jocelyn Danielle Mich-Basso, Etienne Sibille, Ph.D., all of the University of Pittsburgh, and Ravit Arav-Boger, M.D., Sarven Sabunciyan, Ph.D., Robert Yolken, M.D., all of Johns Hopkins School of Medicine.
This work was supported by grants from the Stanley Medical Research Institute, the National Institute of Mental Health (RC2 MH089859, MH62480, U01 MH85269), the National Center for Research Resources (1 UL1 RR024153), the NIH Roadmap for Medical Research and the Department of Psychiatry, University of Pittsburgh.
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As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1997. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
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Journal
PLoS ONE