Using human tissue cultures in the laboratory, investigators will explore whether a newly identified immune protein, called “interleukin-29” (IL-29), can protect human brain cells from viral infections, and can also slow the growth of deadly brain tumors called “glioblastomas.”
Human immune cells ordinarily protect the body against viruses by killing infected cells, thus preventing virus replication and the infection of nearby cells. When viruses infect the brain, however, the immune system confers protection while sparing brain cells. In the brain, infected cells can secrete protective immune proteins. One of the best-known proteins is “interferon-alpha” (IFN-a), which binds to a specific receptor found on cells, and induces changes in those cells that inhibit viral infection and replication. In fact, the IFN-a protein is used to treat chronic hepatitis B and C infections in the liver. In addition to its effects on viruses, IFN-a can also prevent cells from growing uncontrollably, and it is currently used to treat several cancers (renal, melanoma, and leukemia). However, IFN-a’s utility can be seriously compromised, since in some patients its use is associated with neurological side effects such as depression, anxiety, suicidal thoughts, and personality change. If scientists could determine how to improve the anti-viral and anti-tumor properties of IFN-a in a manner that leads to fewer side effects, this protein might then be useful for the treatment of infections and cancer in the brain.
In addition, an alternative related approach might also be feasible. Scientists have recently discovered a related family of immune proteins that also might be clinically protective, with potentially fewer side effects. The family’s most active member, IL-29, is related to IFN-a, but inhibits viral infection and tumor growth through a different cell receptor than is used by IFN-a. However, almost nothing is known about how IL-29 functions in the brain. Yale researchers, therefore, will determine the role of IL-29 in responding to brain tumors and to two viruses that are models of viral brain infection: human cytomegalovirus, a significant cause of developmental brain defects, and vesicular stomatitis virus (VSV), which is related to the virus that causes rabies. Using human cells cultured in the laboratory, they will determine: 1) whether brain cells produce IL-29 when they become infected with either of these two viruses; 2) whether IL-29’s antiviral activity protects brain cells against the viruses; and 3) whether IL-29 slows the growth of cells derived from human glioblastoma tumors. If IL-29 shows evidence of potential therapeutic benefit, future studies could then determine whether patients would benefit from this treatment, with fewer side effects compared to IFN-a.
Significance: This study is a first step in determining whether IL-29 might become a potential new immunotherapy for protecting against viral brain infections and brain tumors.