Antiviral and Antitumor Activity of IL-29 in the Brain

Michael D. Robek, Ph.D.

Yale University School of Medicine

Funded in September, 2008: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

back to top

Protecting Against Brain Tumors and Viral Infections

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.

 

ABSTRACT

back to top

Antiviral and Antitumor Activity of IL-29 in the Brain

Interferon (IFN)-a and IFN-g have important functions in antiviral immunity because they induce expression of proteins that inhibit virus replication without damaging the infected cell.  This is particularly important in the central nervous system (CNS), where virus- or immune-mediated destruction of infected neurons is detrimental to the host. A new family of IFN-related cytokines known as IL-29, IL-28A, and IL-28B (or alternatively IFN-l1, 2, and 3) was recently identified.  These cytokines have little sequence homology to the other IFNs, and they do not bind to the IFN-a or IFN-g receptor but instead induce their antiviral activity through a unique receptor.  Although all three family members bind the same receptor, IL-29 has the most potent activity, and is therefore the focus of this proposal.  Similar to IFN-a, IL-29 expression is induced by virus infection, and it inhibits virus replication.  Also like IFN-a, in addition to its antiviral activity, IL-29 has antiproliferative activity that inhibits the growth of tumor cells.  However, the contribution of IL-29 to immunity in the human brain has not been studied.  We will therefore test the hypothesis that IL-29 plays an important role in the immune response to viruses and cancer in the brain.  To evaluate our hypothesis, we will carry out three aims.  We will (1) Identify the cell types in the brain that produce IL-29; (2) Define the cell types in the brain that are protected by the antiviral activity of IL-29; (3) Determine the sensitivity of glioblastoma to the antiproliferative activity of IL-29.  The studies proposed here will not only begin to elucidate the role of a new cytokine family in the immune response in the brain, but may also identify IL-29 as a new therapy for viral infections and cancer in the CNS.

INVESTIGATOR BIOGRAPHIES

back to top
Michael D. Robek, Ph.D.

Dr. Michael Robek is an Assistant Professor in the Department of Pathology at the Yale University School of Medicine.  He received a Ph.D. degree in 2000 from Washington University in St. Louis, where he studied T cell transformation by the human T-lymphotropic virus type 1.  He then completed his postdoctoral training at The Scripps Research Institute, where he studied the mechanism of how IFN-a inhibits hepatitis B virus replication.  Since moving to Yale in 2004, his laboratory has focused on identifying virus-host interactions that may possibly be exploited for therapeutic purposes.  These studies are currently concentrated in three areas.  First, his lab is working to generate a new therapeutic vaccine that may be useful to treat chronic viral infections.  Second, they are identifying new cellular regulatory pathways that may serve as unique targets for small-molecule antiviral therapies.  Finally, they are studying the mechanisms that underlie the control of virus replication by interferon and interferon-related cytokines in the brain and other organs. These studies have the potential to expand the repertoire of antiviral therapies beyond those currently being employed, and therefore significantly impact public health.