Dietary cholesterol exacerbates inflammation, disease in mice with influenza

A new study from the University of Illinois found that high cholesterol in food makes mice sick when they are infected with the flu. The study is the first to link cholesterol in the diet to an exacerbation of a viral infection.

Previously, scientists have linked diets high in fat and high blood cholesterol with increased susceptibility to infections and reduced immune response. For example, obesity is a well-known risk factor for severe disease in COVID and flu. But few studies have highlighted the contribution of cholesterol to these infections, and none have outlined the effects of cholesterol in food.

“We knew that high serum cholesterol could increase the risk sepsis in influenza infections and that statins – cholesterol-lowering drugs – can improve survival during influenza pneumonia, SARS-CoV-2 infection and sepsis. But it was unclear whether cholesterol was involved in food and how, ”said Alison Louis, lead author. Journal of Immunology is also studying for a doctorate in neurology in Illinois.

Cholesterol is needed by the body. It is part of our cell membranes, helps us produce hormones and vitamin D, and ensures the proper function of immune cells. Our bodies produce it for us, requiring little to come from dietary sources. In fact, for healthy people, cholesterol in food does not significantly affect circulating cholesterol levels and does not increase the risk of cardiovascular disease. This is one of the reasons why cholesterol restrictions were lifted from the 2015 Dietary Guidelines for Americans.

But when it comes to infectious diseases in mice, Louis’s study shows that cholesterol in food can make a difference, even without increasing the amount of fat.

Louis, along with co-authors Andrew Stillman and Joseph Tingling, fed mice standard rodent food or an identical diet supplemented with 2% cholesterol. After five weeks of dieting, mice were infected with human-adapted influenza A virus. The research team monitored disease progression, including weight loss, food intake, and disease behavior. They also monitored serum cholesterol and immune responses and measured viral load in the lungs at several time points during infection.

“In the four cohorts of mice fed cholesterol, they consistently had higher rates of disease,” says Louis. “They showed more weight loss and disease.”

Because viruses also need cholesterol to enter cells and replicate, it was likely that a diet high in cholesterol would increase the viral load in the lungs. But this is not what the researchers found.

“Our plaque analysis did not show a significant difference in viral load in the lungs of the two groups of mice,” says Tingling, a doctoral student in the Illinois Department of Animal Sciences. “It’s important to consider not only the infectious agent but also the host’s immune system.”

Speaking of the host, the researchers found that mice fed a high-cholesterol diet were sicker because their immune systems went wrong. Fat can have an immunosuppressive effect, which is detrimental during infection. But an insufficiently active immune system is not something that researchers observed in mice fed cholesterol. Instead, cholesterol increased the number of immune cells that produce cytokines in the lungs.

“The so-called cytokine storm during severe illness leads to excessive inflammation which may harm the host. Accordingly, we found that more cytokine-producing cells entered the lungs of cholesterol-fed mice, which may have led to them becoming sicker, says Louis. “It’s a double-edged sword.” You want to be able to build an effective immune response, but excessive inflammation is harmful. ”

Unfortunately, the effect of dietary cholesterol on influenza continued long after mice stopped eating it. The researchers took mice that first ate a high-cholesterol diet and then gave them a normal diet for five weeks. When these mice were exposed to the flu, they were still sicker than mice who had never eaten a high-cholesterol diet.

“We thought this dietary ingredient was a very variable factor. Perhaps this will only have a transient effect. But in the end, we found that five extra weeks of the regular diet was not enough time to completely change the harmful effects of cholesterol, ”says Louis. .

Surprisingly, inflammatory changes in the lungs were found in mice with high cholesterol even before they were infected with the flu.

“Some changes in the immune function of the lungs were already before the infection. It would be interesting to see exactly how cholesterol in food increased inflammation before infection, ”says correspondent Stillman, Associate Professor of Animal Science, Neurology. Program and Department of Nutrition Science in Illinois.

“However, our data combined show that dietary nutrition cholesterol increase the incidence of influenza-infected mice. The reaction seemed to be the result of an aberrant immune response in the lungs rather than the effect of the virus itself. These results demonstrate the need to consider how host factors contribute to disease outcome. ”