How the Flu Virus Invades the Brain

Summary: Researchers uncovered how the influenza virus may infiltrate the brain, leading to a serious condition known as influenza-associated encephalopathy (IAE). The study identifies endothelial cells, which form the blood-brain barrier, as the primary entry points for the virus.

The team found that traditional antivirals that block viral replication were ineffective against this mode of invasion, but those that inhibit viral protein synthesis showed promise in reducing symptoms and mortality in a mouse model. This breakthrough offers potential new treatment avenues for IAE and similar viral encephalopathies.

Key Fact:

1. Influenza-associated encephalopathy (IAE) is a serious brain disorder caused when the flu virus breaches the blood-brain barrier.
2. The research highlights endothelial cells as the virus’s entry point into the brain, with traditional antivirals proving ineffective in treating this invasion.
3. Antivirals targeting viral protein synthesis showed effectiveness in a mouse model, suggesting a new treatment strategy for IAE.

Source: Osaka University

It might start simply, with a cough or sneeze…but in some cases, the flu virus can make its way to your brain, causing serious symptoms or even death through a disease known as influenza-associated encephalopathy (IAE).

Now, in a study published in Acta Neuropathologica, researchers have revealed that IAE may be caused by the virus entering the brain through a specific cell type, and have identified possible treatment strategies.

Although IAE is increasingly common, surprisingly little is known about how the influenza virus actually gets into the brain and causes symptoms of encephalopathy (a general term for brain disorders).

Notably, a definitive treatment for IAE remains lacking, something that researchers from Osaka University wanted to address.

To study how influenza viruses might cause IAE, the research team used a range of methods. As well as looking for virus particles in the brains of people who died from IAE, they created a mouse model of the disease by injecting influenza A virus into the blood. They also used cell culture methods to look at how well the virus infects different cell types.

“In the human brains, the virus-injected mice, and the cultured cells, the influenza virus tended to accumulate in endothelial cells,” explains lead author of the study Shihoko Kimura-Ohba.

“These cells create a barrier between the blood and the brain, and are important for protecting the brain from harmful substances.”

Accordingly, in both the human brains and the mouse model, the barrier between the blood and the brain was compromised. Furthermore, the researchers noticed that the virus wasn’t actually reproducing within these endothelial cells—but there were a lot of proteins made by the virus.

“When we saw this viral protein accumulation in the brain, we realized that antiviral medications aimed at stopping viral proliferation were unlikely to help,” says Tomonori Kimura, senior author of the study. “However, antivirals aimed at stopping viral transcription and translation—vital processes for making proteins—are also available.”

When the team tried these classes of antivirals in endothelial cells treated with influenza virus, they observed less viral proteins and cell death. In the mouse model of IAE, these antivirals were also very effective when used early enough, suggesting that they may be useful in human patients.

Given that many different kinds of viruses, including COVID-19, can cause encephalopathy, these findings have wide-ranging impacts. Moreover, although IAE care is improving, more than half of all patients die or have long-lasting symptoms.

A better understanding of how viruses can cause encephalopathy will be important for developing new, effective treatments.

About this neurology and virology research news

Author: Saori Obayashi
Source: Osaka University
Contact: Saori Obayashi – Osaka University
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy” by Shihoko Kimura-Ohba et al. Acta Neuropathologica

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Abstract

Viral entry and translation in brain endothelia provoke influenza-associated encephalopathy

Influenza-associated encephalopathy (IAE) is extremely acute in onset, with high lethality and morbidity within a few days, while the direct pathogenesis by influenza virus in this acute phase in the brain is largely unknown.

Here we show that influenza virus enters into the cerebral endothelium and thereby induces IAE.

Three-weeks-old young mice were inoculated with influenza A virus (IAV). Physical and neurological scores were recorded and temporal-spatial analyses of histopathology and viral studies were performed up to 72 h post inoculation.

Histopathological examinations were also performed using IAE human autopsy brains. Viral infection, proliferation and pathogenesis were analyzed in cell lines of endothelium and astrocyte. The effects of anti-influenza viral drugs were tested in the cell lines and animal models.

Upon intravenous inoculation of IAV in mice, the mice developed encephalopathy with brain edema and pathological lesions represented by micro bleeding and injured astrocytic process (clasmatodendrosis) within 72 h.

Histologically, massive deposits of viral nucleoprotein were observed as early as 24 h post infection in the brain endothelial cells of mouse models and the IAE patients.

IAV inoculated endothelial cell lines showed deposition of viral proteins and provoked cell death, while IAV scarcely amplified. Inhibition of viral transcription and translation suppressed the endothelial cell death and the lethality of mouse models.

These data suggest that the onset of encephalopathy should be induced by cerebral endothelial infection with IAV.

Thus, IAV entry into the endothelium, and transcription and/or translation of viral RNA, but not viral proliferation, should be the key pathogenesis of IAE.