New Insights Into How Brain Responds To Viral Infection

While scientists have been aware of the capacity of astrocytes to trigger an innate immune response when encountering a foreign agent, this work provides a new understanding of the complex mechanisms responsible for induction and regulation of inflammation in the brain and has significant implications for both the diagnosis and treatment of brain infections.

The study is published as the cover article in the April 2009 issue of The FASEB Journal.

In the course of trying to contain and neutralize a virus that has breached the protective barrier of the central nervous system, immune mediators secreted by astrocytes may injure other cells and tissues in the vicinity and cause additional life-threatening inflammation.

By defining the nature of inflammatory responses by brain astrocytes, this study has implications for both the diagnosis of chronic infections of the central nervous system, as well as the treatment of acute and chronic brain infections. Viral infections of the brain are associated with extremely high morbidity and mortality; in most cases, the specific microbial cause is unknown. Even when a viral cause is clear, the specific antiviral tools at our disposal remain limited. This work provides a means for implementation of a more general therapeutic approach to viral brain infections that may be effective across a wide range of viruses, or even where a virus is suspected but the offending agent cannot be identified.

"Studies such as this take us one step closer to understanding both the risk and benefit associated with antiviral immune response and may lead to new treatment strategies," said W. Ian Lipkin, MD, senior author of the paper, director of the Mailman School of Public Health's Center for Infection and Immunity, John Snow Professor of Epidemiology, and professor of Neurology and Pathology.

The researchers compared two methods of exposing a cell to this virus-like challenge—one from outside the cell and the other by direct delivery into the cell's cytoplasm. By culturing the supportive cells known as astrocytes obtained from the brains of newborn mice and exposing them to a virus-like molecule (called Poly I:C) from the outside and the inside, the scientists were able to show for the first time the differences between extracellular and intracellular immune response in these supportive brain cells.

Depending on whether the virus-like challenge was introduced extracellularly or intracellularly, the astrocytes produced different levels of inflammatory mediators (cytokines). The researchers were also able to show that a sensor protein known as MDA-5 is critical for astrocytes to be able to recognize viral molecules appearing in a cell's cytoplasm, and when astrocytes were engineered to express dysfunctional MDA-5, this immune response was selectively blocked.

"These findings create an opportunity for targeted design of drugs that may help to curb infection-induced brain inflammation and restrict the extent of damage," said Joari De Miranda, MD, PhD, lead author of the paper and postdoctoral research scientist at the Mailman School of Public Health's Center for Infection and Immunity.

There are a number of diseases that this work can impact in terms of diagnosis and treatment: viral encephalitis; brain disorders associated with congenital viral infections; and neurological or neurodevelopmental disorders suspected of having an immune or inflammatory trigger, such as schizophrenia and autism. There also may be broader implications for the treatment of a wide range of immune-mediated neurologic diseases, such as multiple sclerosis and Parkinson's disease.

Other members of the research team at the Mailman School of Public Health include Mady Hornig, MD, associate professor of Epidemiology and director of translational research at the Center for Infection and Immunity, and Kavitha Yaddanapudi, PhD, postdoctoral research scientist.

This work was supported by the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases, National Heart, Lung and Blood Institute, and National Institute of Neurological Disorders and Stroke, and Google.org.