People with obesity may have increased risk from severe COVID-19 because they have a poorer inflammatory immune response – not because of excessive inflammation in their blood, according to a “surprising” study.
After SARS-CoV-2 infection, cells in the lining of the lungs, nasal cells and immune cells in the blood have a reduced inflammatory response in obese patients, according to researchers at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) and Wellcome Sanger Institute.
This results in those patients producing lower levels of molecules that are needed to fight the infection.
Obesity is one of the major risk factors for severe COVID-19, although until now, the reasons why have not been clear, the researchers say.
Studies have shown people who are obese already have higher levels of key molecules associated with inflammation in their blood, but the Cambridge researchers looked to see if an overactive inflammatory response could explain the connection.
Professor Menna Clatworthy, a clinician scientist at the University of Cambridge, said: “During the pandemic, the majority of younger patients I saw on the COVID wards were obese. Given what we know about obesity, if you’d asked me why this was the case, I would have said that it was most likely due to excessive inflammation. What we found was the absolute opposite.”
Professor Clatworthy and her team analysed blood and lung samples from 13 obese COVID-19 patients who needed mechanical ventilation and intensive care treatment and also from 20 controls, who were non-obese COVID-19 patients and ventilated non-COVID-19 patients.
They used transcriptomics to study activity of cells in these key tissues and writing in the American Journal of Respiratory and Critical Care Medicine, they say obese patients had underactive immune and inflammatory responses in their lungs.
When compared to non-obese patients, cells in the lining of their lungs and some of their immune cells had lower levels of activity among genes responsible for the production two interferons (INF) – interferon-alpha and interferon-gamma – and of tumour necrosis factor (TNF).
When the team looked at immune cells in the blood of 42 adults from an independent cohort, they found a similar, but less marked, reduction in the activity of interferon-producing genes as well as lower levels of IFN-alpha in the blood.
Professor Clatworthy said: “This was really surprising and unexpected. Across every cell type we looked at, we found that the genes responsible for the classical antiviral response were less active. They were completely muted.”
The team replicated its findings in nasal immune cells taken from obese children with COVID-19 and again found lower levels of activity among the genes that produce IFN-alpha and IFN-gamma. They say this is important because the nose is one of the entry points for the virus.
One possible explanation for the finding involves the hormone leptin, which plays a role in the immune response.
In individuals who are in the normal weight range, levels of the hormone increase in response to infection and it directly stimulates immune cells.
But obese people already have chronically increased levels of leptin, and Professor Clatworthy says it is possible they no longer produce sufficient additional leptin in response to infection, or are insensitive to it, which leads to inadequate stimulation of their immune cells.
Co-author Dr Andrew Conway Morris, from the Department of Medicine at the University of Cambridge, said: “What we’ve shown is that not all patients are the same, so we might need to tailor treatments. Obese subjects might need less anti-inflammatory treatments and potentially more help for their immune system.”
Guo, SA, Bowyer, GS, Ferdinand, JR, Maes, M & Tuong, ZK et al. Obesity associated with attenuated tissue immune cell responses in COVID-19. Am J Resp Critical Care Med; 1 Mar 2023; DOI: 10.1164/rccm.202204-0751OC
Leave a Reply