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An unexpected gene may help determine whether you survive flu or COVID-19
Study of blood from severely ill patients implicates a gene involved in the production of fatty acids
- 13 Aug 2024
- 11:20 PM ET
- ByJon Cohen
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After a 2013 outbreak of avian influenza in China killed about 35% of the people it infected, immunologist Katherine Kedzierska of the Peter Doherty Institute for Infection and Immunity set out to answer a baffling question: Why did some patients die while others survived?
This week in Cell, Kedzierska and colleagues at 16 other institutes around the world provide a possible answer. The sickest people, it turns out, produced significantly higher levels of an enzyme called oleoyl-acyl-carrier-protein hydrolase (OLAH), which is involved in the production of oleic acid, a fatty substance critical to human health that is found in our cell membranes. Before this study, “nothing was known that linked it to infectious diseases,” Kedzierska says.
OLAH appears to determine the odds of succumbing to several other viral respiratory diseases as well, including COVID-19 and respiratory syncytial virus (RSV). The researchers hope the finding can help identify patients at high risk of severe complications early in the disease course, and they are hunting for treatments that can bring down OLAH levels.
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“This is a very nice study,” says Yoshihiro Kawaoka, a virologist at the of the University of Wisconsin-Madison who specializes in influenza. It reflects a tremendous amount of work, adds virologist Richard Webby, an influenza researcher at St. Jude Children’s Research Hospital. But he stresses that several factors likely contribute to a person developing severe influenza. “The one thing I can never wrap my head around with such studies is how big of an impact these molecules have on their own,” he says.
The researchers started by analyzing blood samples taken from four people who died from H7N9 influenza, which ravaged Chinese poultry and first jumped to humans in 2013, leading to the largest bird flu outbreak in people to date. They compared these samples with blood from four people who survived the infection. “We embarked on this study to really understand what immune responses drove recovery,” Kedzierska explains.
As expected, the fatal cases had higher levels of inflammation driven by a “cytokine storm,” a surge of messenger molecules that direct immune cells to respond to infections. But when they analyzed gene expression—the levels of messenger RNA (mRNA), which codes for proteins—shortly after the patients were admitted to the hospital, they found that 10 genes were expressed at either higher or lower levels in the sicker patients. OLAH stood out: Its expression level was about 82 times higher.
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The team then found that three seasonal influenza patients on ventilators at U.S. hospitals had far higher OLAH mRNA levels than two healthy controls. And OLAH expression levels were also elevated in the most severely ill group in a cohort of 143 COVID-19 patients at U.S. pediatric hospitals. Finally, analyzing blood from 23 children in a Memphis, Tennessee, hospital revealed a correlation between high OLAH levels and severe disease from RSV. “It was such a striking signal,” Kedzierska says.
Several factors determine how ill people become from infections with respiratory viruses, including other health conditions they may have, their innate immune responses, and immunity from previous infections. To better understand the role of OLAH, the researchers engineered mice to cripple the OLAH gene and inoculated them with levels of an influenza virus high enough to kill them.
The virus killed fewer than 7% of these knock-out animals, compared with 50% of control mice with intact OLAH genes. “I think what we managed to identify here is something quite major,” says immunologist Brendon Chua, who co-led the studies. “It’s sort of the gatekeeper that kickstarts the [inflammation] process.”
Seeking to explain how OLAH might cause harm, the researchers found that high levels of the enzyme prompted an increase in lipid droplets in the blood that, in turn, led to damaging levels of inflammation-causing cytokines. OLAH also helps viruses copy themselves.
Why some people have such high OLAH expression levels remains unclear.
Although oleic acid is found in high levels in many foods, especially olive oil, it’s unlikely that reducing consumption would lower our risk of a severe respiratory infection, Kedzierska stresses, because the amount we ingest pales in comparison to the amount our bodies naturally make.
Chua is now trying to find compounds that inhibit OLAH and might be used as a therapeutic for patients who show up with respiratory infections and high levels of oleic acid. The team also hopes to develop a diagnostic test that can measure levels of the enzyme and, ultimately, predict disease severity. “When patients are admitted to the hospital, it’s really hard to know which patients will survive and which patients will die,” Kedzierska says.
Peter Openshaw, an immunologist at Imperial College London who specializes in lung diseases, shares the enthusiasm for the study, yet adds a word of caution. “It’s interesting and exciting science, but there’s a long and unpredictable path to clinical use,” he says.
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