Influenza A deliberately enhances levels of the human p53 protein to reduce anti-viral gene and protein expression

November 30, 2018, Agency for Science, Technology and Research (A*STAR), Singapore
Influenza A deliberately enhances levels of the human p53 protein to reduce anti-viral gene and protein expression
The Influenza A virus deliberately enhances the activity of the human p53 protein, and this downregulates the expression of anti-viral interferon-induced transmembrane proteins and genes (IFITMs), allowing the virus to take hold (left). In cells without p53, IFITM expression is high, thus blocking viral progression (right). Credit: A*STAR Singapore Immunology Network

Genome editing technology is helping A*STAR scientists unravel how the Influenza A virus (IAV) exploits human anti-viral responses.

IAV remains a key challenge for global health resources, not least because of wide variations in symptom severity experienced by different people, even when they are infected by the same strain. This implies that there are at play during the initial host-viral interaction.

Ee Chee Ren, Bei Wang and their team at A*STAR's Singapore Immunology Network have worked for several years on the , which plays various roles in cancer, cellular stress responses, and host anti-viral responses. Many viruses target p53 to reduce it, but IAV is unusual because it works instead to activate p53. The reason is unclear; ordinarily, enhanced p53 benefits the host because it helps to kill infected cells and enhances immune responses.

"We were curious about the role of p53 in IAV infection," says Ren. "We used CRISPR/Cas9 genome editing technology to generate human lung cells without p53 for the first time. This gave us the key to identify p53's role during IAV infection."

The coordinated expression of the interferon-induced transmembrane (IFITM) is crucial for restricting IAV infection. Previous studies have shown that variations in IFITM genes in humans can render a person more susceptible to severe IAV symptoms. Ren's team infected the p53 null cells, and human 'wild-type' or normal lung cells with the same strain of IAV. Using genome-wide microarray analysis, they found that the viral-induced overexpression of p53 in wild-type cells significantly reduced the expression of three IFITM genes.

"This was a surprise, but it makes sense," says Wang. "IFITM genes and their proteins are strongly associated with a host's individual to viral infection. It seems IAV may have evolved to exploit p53."

The researchers demonstrated that enhanced IFITM expression in the without p53 meant IAV struggled to take hold. The level of p53 positively correlated with the severity of viral infectivity in cell cultures. Restricting IFITM expression via p53 extends the period that a host is susceptible to infection, allowing the virus access to its target cell population.

"There are many drugs in development that can interfere with p53 pathways, and our discovery means that such drugs could be tested for anti-influenza effect as well," says Ren. "Influenza is short-term, so treatment would only be needed during its acute phase."

Explore further: Certain IFITM proteins block and inhibit cell-to-cell transmission of HIV

More information: Bei Wang et al. Influenza A Virus Facilitates Its Infectivity by Activating p53 to Inhibit the Expression of Interferon-Induced Transmembrane Proteins, Frontiers in Immunology (2018). DOI: 10.3389/fimmu.2018.01193

Related Stories

Certain IFITM proteins block and inhibit cell-to-cell transmission of HIV

September 28, 2015
There is little doubt that the Human Immunodeficiency Virus, or HIV, is devastating. More than 1.2 million people in the United States are living with HIV and more than 47,000 people are diagnosed annually. Now, University ...

Study reveals new therapeutic target for slowing the spread of flu virus

June 22, 2018
Influenza A (flu A) hijacks host proteins for viral RNA splicing and blocking these interactions caused replication of the virus to slow, according to new research published in Nature Communications by Kristin W. Lynch, Ph.D., ...

Natural immunity may lead fight against liver disease

October 27, 2015
University of Adelaide researchers have uncovered the role played by a family of genes, which can suppress hepatitis C virus (HCV) infection within the liver.

Key molecule for flu infection identified

May 30, 2018
After decades of research, a research team has discovered the key receptor molecule that enhances the infection of the influenza A virus, providing a novel target for anti-flu drug development.

Recommended for you

New genetic study could lead to better treatment of severe asthma

December 12, 2018
The largest-ever genetic study of people with moderate-to-severe asthma has revealed new insights into the underlying causes of the disease which could help improve its diagnosis and treatment.

Taking the virus out of a mosquito's bite

December 12, 2018
They approach with the telltale sign—a high-pitched whine. It's a warning that you are a mosquito's next meal. But that mosquito might carry a virus, and now the virus is in you. Now, with the help of state-of-the-art technology, ...

Researchers discover unique immune cell likely drives chronic inflammation

December 11, 2018
For the first time, researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population ...

Macrophage cells key to helping heart repair—and potentially regenerate, new study finds

December 11, 2018
Scientists at the Peter Munk Cardiac Centre have identified the type of cell key to helping the heart repair and potentially regenerate following a heart attack.

Study identifies a key cellular mechanism that triggers pneumonia in humans

December 11, 2018
The relationship between influenza and pneumonia has long been observed by health workers. Its genetic and cellular mechanisms have now been investigated in depth by scientists in a study involving volunteers and conducted ...

Immune cells sacrifice themselves to protect us from invading bacteria

December 11, 2018
Immune systems are working overtime as winter approaches. Stomach flu can turn the strongest individual into a bedridden convalescent. Viruses are spreading in kindergartens. This year's flu is approaching in full swing. ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.