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Scientists identify protein in the brain that allows West Nile virus to invade

Gert van der Hoek

In Memoriam - Editor, Senior Moderator
October 18, 2018

GALVESTON, Texas –A recent study by The University of Texas Medical Branch at Galveston identified a protein that allows the West Nile virus to invade our bodies and replicate itself, causing infection and disease. The study is available in The Journal of Clinical Investigation.
The UTMB scientists learned that the protein, Peli1, that normally helps fight infections, actually is a key link in the West Nile virus’ ability to attack the immune system.

“We identified a protein that increases the risk of West Nile virus infection and brain inflammation, gaining a better understanding of how this occurs,” said UTMB’s Tian Wang, a professor in the department of microbiology and immunology. “Our findings will ultimately help to develop treatments for West Nile infection and subsequent inflammation.”

The mosquito-borne West Nile virus has caused disease outbreaks in Asia, Europe and Australia and has been a leading cause of viral encephalitis – an inflammation of the brain – in the U.S. for more than a decade. Up to 50 percent of people who had the disease are reported to have long-term neurological damage. Currently, there is no specific treatment or available vaccine for West Nile viral infections.

Peli1 plays a key role in regulating the body’s immune response to viruses, especially within the brain cells. Peli1 produces inflammation in certain types of brain cells and promotes the release of immune cells into the central nervous system.

The research team found that the protein is essential for the West Nile virus to infect and ultimately multiply within host cells. Mice that were engineered to lack the Peli1 protein were more resistant to West Nile virus infection. Similarly, an analysis of the brain tissue of people who died from West Nile virus disease showed high levels of Peli1 compared with brain tissue of people who did not have the infection.

“Next, we plan to determine the role of Peli1 in other viral infections that preferentially attack the nervous system,” said Wang.
 
Peli1 facilitates virus replication and promotes neuroinflammation during West Nile virus infection.


J Clin Invest. 2018 Sep 24. pii: 99902. doi: 10.1172/JCI99902.

Abstract


The E3 ubiquitin ligase Pellino 1 (Peli1) is a microglia-specific mediator of autoimmune encephalomyelitis. Its role in neurotropic flavivirus infection is largely unknown. Here, we report that mice deficient in Peli1 (Peli1-/-) were more resistant to lethal West Nile virus (WNV) infection and exhibited reduced viral loads in tissues and attenuated brain inflammation.

Peli1 mediates chemokine and proinflammatory cytokine production in microglia and promotes T cell and macrophage infiltration into the CNS. Unexpectedly, Peli1 was required for WNV entry and replication in mouse macrophages and mouse and human neurons and microglia. It was also highly expressed on WNV-infected neurons and adjacent inflammatory cells from postmortem patients who died of acute WNV encephalitis.

WNV passaged in Peli1-/- macrophages or neurons induced a lower viral load and impaired activation in WT microglia and thereby reduced lethality in mice. Smaducin-6, which blocks interactions between Peli1 and IRAK1, RIP1, and IKKε, did not inhibit WNV-triggered microglia activation.

Collectively, our findings suggest a nonimmune regulatory role for Peli1 in promoting microglia activation during WNV infection and identify a potentially novel host factor for flavivirus cell entry and replication.
 
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