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NIH Scientists Identify Possible Mechanism of Virus-Induced Brain Damage

La Crosse virus uses immune system proteins to induce death of nerve cells

Photo of SARM1 in brains of mice infected with La Crosse virus
The immune system protein SARM1 (red) extends to the string-like fibers (axons) of nerve cells in the brains of mice infected with La Crosse virus. Scientists are examining how SARM1 interacts with mitochondria in the axons to induce death of the nerve cells. Credit: NIAID

Scientists know that early immune responses to viral infection can inhibit virus replication. But a new study from National Institutes of Health (NIH) scientists suggests that, in the brain, the same process can lead to the destruction of neurons, the information-processing cells of the central nervous system. The results are described online in the March 14, 2013, issue of Immunity.

Background

La Crosse virus (LACV) is known to infect neurons and cause brain damage. Discovered in 1963 in Wisconsin, LACV is a common cause of encephalitis, or brain swelling, in children under age 16.  There are about 80 cases of severe LACV disease in the United States each year. In addition, less severe cases of LACV are significantly under-reported or under-diagnosed, according to the Centers for Disease Control and Prevention. There is no specific treatment for La Crosse virus. Mosquitoes spread the virus from small rodents, such as chipmunks and squirrels, to humans. LACV is fatal in less than 2 percent of cases, but it also can result in seizures, coma, paralysis, and other neurological disorders.

 

Results of Study

By studying LACV infection in cell cultures of neurons and in mice, scientists from  NIAID determined that LACV uses a protein called MAVS to activate early immune responses. They then showed how MAVS induces another immune system protein, SARM1, to kill neurons (SARM1 binds to and damages mitochondria—the cells’ energy source). In study models where scientists removed SARM1, significantly fewer neurons died despite similar LACV infection.

Normally, MAVS stimulates the immune system to produce type 1 interferon, which limits infecting virus from replicating and spreading. In neurons, however, MAVS activation results in the death of the neuron by inducing the production of SARM1.

Significance

Activation of early immune responses is common in a number of neurological diseases, ranging from Alzheimer’s disease to viral encephalitis. By showing that these early immune responses can induce neuronal death in the brain, this study suggests that activating SARM1 could do the same in other neurological diseases.

Next Steps

The NIAID scientists plan to determine if SARM1 causes neuronal death in other neurological disease. The group also is exploring why neurons in the brain are sensitive to this pathway of cell death whereas other types of cells in the brain are not.

Reference

Mukherjee et al. Activation of the innate signaling molecule MAVS by Bunyavirus infection upregulates the adaptor protein SARM leading to neuronal death. Immunity DOI: 10.1016/j.immuni.2013.02.013 (2013).

 

 

Last Updated March 13, 2013

Last Reviewed March 13, 2013