Blocking TLR4 pathway may help control Ebola infection

Ebola virus
Boston University scientists curbed the host response to Ebola infection by inhibiting TLR4 in macrophages. (CDC Global CC BY 2.0)

The Ebola virus causes a disease that is often fatal, in part by infecting white blood cells called macrophages and disrupting their immune response. Boston University scientists found that using drugs that block the protein TLR4 can suppress this response and potentially control infection.

Macrophages are responsible for detecting and destroying pathogens, but the Ebola virus activates them through the Toll-like receptor 4 (TLR4) pathway, causing an inappropriate immune response. The Ebola-infected macrophages end up producing excess cytokines and chemokines—proteins that promote inflammation and worsen the disease.

The researchers studied how macrophages react to Ebola virus and Reston virus, which is related to Ebola but does not cause disease in humans. Unlike the Ebola-infected macrophages, Reston-infected macrophages were not activated. They also found that TLR4-blocking drugs could stop the activation of Ebola-infected macrophages.

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"We used transcriptomics analysis performed by our collaborators at the University of Washington, Seattle, and other assays to look specifically at the inflammatory response in infected macrophages," explained corresponding author Elke Mühlberger, associate professor of microbiology at Boston University School of Medicine.

"This lack of activation in human macrophages might be one of the reasons why Reston virus does not cause disease in humans," Mühlberger said. "More importantly, it showed that it is possible to keep macrophages that are exposed to Ebola virus silent by using drugs that inhibit TLR4 activation. This could be a promising treatment option for Ebola virus disease."

There are no licensed drugs or vaccines for Ebola, though several new candidates are in clinical trials. Merck, Johnson & Johnson and GlaxoSmithKline all have vaccine candidates in Phase 3, with Merck planning to file for approval by the end of the year.

Meanwhile, Stanford-led researchers have targeted Ebola and dengue viruses with the cancer drugs Tarceva (erlotinib) and Sutent (sunitinib). The combo therapy inhibits two enzymes that normally promote the spread of the viruses.

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