Immune Dysregulation Predicts Severe Infection Risk
A common gene signature of immune health or dysfunction predicts severe outcomes from infection.
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At the start of the COVID-19 pandemic, information began to trickle in about who was at higher risk of a dangerous outcome from infection. Men. Those over 65. Smokers. Those with obesity.
It turns out these seemingly unrelated categories of people have one thing in common: a signature of immune dysregulation. A new study led by researchers at Stanford Medicine, published June 17 in Immunity, shows that a common gene signature of immune health or dysfunction predicts severe outcomes from infection. This signature of poor immune health is present in people with known risk factors such as being a smoker or having a high body mass index, even before they encounter a virus or bacteria. And it appears to be modifiable.
“We don’t know what a healthy immune system looks like. How do you quantify it?” said Purvesh Khatri, PhD, a professor of biomedical informatics at the Institute for Immunity, Transplantation and Infection and senior author on the study. “This work is a step toward being able to quantify immune health.”
The gene signature discovered by Khatri and his colleagues also predicts treatment response in patients with bacterial sepsis, burns or asthma, they found. Knowing if a person’s immune system is healthy or dysregulated could help providers choose medications most likely to help.
The researchers discovered a set of immune-related genes more than a decade ago, when they were looking for changes in gene expression that occur after people are infected with different viruses. When COVID-19 emerged, they found that expression levels of a subset of 42 of those same genes similarly predicted how people responded to the novel virus — whether they were likely to have a mild or severe infection.
Finding immune dysregulation
In their new study, the researchers used several existing public datasets that included information on patients’ infections and outcomes as well as gene expression data. The largest of these datasets, the Framingham Heart Study, included gene expression data from more than 5,000 adults with a range of different health conditions and demographics. The data from that study showed that immune dysregulation was present even in the absence of infection in people with risk factors for severe immune responses such as smoking, being older or male, having a higher BMI, or having diabetes. The Framingham study data also showed that immune dysregulation was associated with a higher likelihood of dying from any cause — even when the researchers took into account that many of the risk factors also raise mortality rates.
Of the 42 immune-related genes that make up this panel of immune health or dysregulation, the researchers classify them into four groups. Two of these groups are protective against severe infection outcomes, and two exacerbate poor outcomes. It’s the ratio between those bad and good immune responses that seems to matter, Khatri said.
The bad immune response clusters include genes expressed in immune cells known as neutrophils, which play many roles in the immune system. Some kinds of neutrophils seem to be bad actors, Khatri said, doing things like suppressing the action of other helpful immune cells such as T cells. The good immune response genes include those expressed in T cells, monocytes and NK cells, all different forms of immune cells.
“This underlying biology is telling us that different arms of the immune system contribute to overall health in different ways,” Khatri said.
Improving immune health
Khatri and his colleagues also found that this immune signature can be changed. Looking at subsets of people from the Framingham study, they found that immune health improved in former smokers who had quit smoking five or more years prior as compared with current or more recent smokers, and in people with diabetes whose blood sugar levels were controlled as compared with those who have higher blood sugar levels. They also looked at data from a different study in which overweight people were randomized to eat a calorie-restricted diet. They found that those who reduced calories in their diet had lowered immune dysregulation than those who did not eat reduce calories in their diet.
Currently, the researchers are looking at the immune signature in patients with chronic conditions such as heart disease. They also want to explore how exercise and different kinds of foods modify the signatures. Ultimately, Khatri said, he hopes this signature could be used in the clinic to capture a snapshot of a person’s immune health and point to ways it could be improved.
“This is a metric for immune health,” he said. “Now we have a way to measure: Is my immune system healthy? Is it dysregulated?”
Researchers at the Institute for Systems Biology contributed to the work.
Reference: Ganesan A, Moore AR, Zheng H, et al. A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response. Immunity. 2025. doi: 10.1016/j.immuni.2025.05.020
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