COVID-19 News: Obesity Linked to Weakened Immune Response in COVID-19 Patients, Often Leading To Disease Severity

COVID-19 News: A new study led by researchers from University of Cambridge-United Kingdom has found that obesity linked to weakened immune response in COVID-19 patients, often leading to disease severity.


 
The study was included scientists from Wellcome Sanger Institute-United Kingdom, Shenzhen Third People’s Hospital-China, University College London-United Kingdom, Newcastle University-United Kingdom, Northwestern University, Chicago-USA and Addenbrooke’s Hospital-United Kingdom.
 
Obesity which is prevalent in 40% of American adults, contributes to a proinflammatory state and poses a substantial risk for severe COVID-19. However, limited information exists on how obesity might influence immune cell responses during SARS-CoV-2 infection.
 
The study team’s aim was to assess the impact of obesity on respiratory tract immunity in COVID-19 patients across various age groups.
 
The team analyzed single-cell transcriptomes from bronchoalveolar lavage (BAL) samples in three ventilated adult groups with or without COVID-19, nasal immune cells in children with or without COVID-19, and peripheral blood mononuclear cells in an independent adult COVID-19 cohort, comparing obese and non-obese participants.
 
Surprisingly, obese adult patients exhibited reduced lung immune or inflammatory responses during SARS-CoV-2 infection, with lower expression of IFN-α, IFN-γ, and TNF-α response gene signatures in nearly all lung epithelial and immune cell subsets, as well as diminished expression of IFNG and TNF in specific lung immune cells. Peripheral blood immune cells from an independent adult cohort demonstrated a similar, albeit less pronounced, reduction in type-I IFN and IFNγ response genes, and decreased serum IFNα levels in obese individuals with SARS-CoV-2. Obese children with COVID-19 also displayed lower enrichment of IFN-α and IFN-γ response genes in nasal immune cells.
 
The study findings reveal dampened tissue immune responses in obese COVID-19 patients, which could have implications for treatment strategies, advocating for the targeted use of inhaled recombinant type-I IFNs in this high-risk group.
 
The study findings were published in the peer reviewed journal: American Journal of Respiratory and Critical Care Medicine.
https://www.atsjournals.org/doi/10.1164/rccm.202204-0751OC
 
The study findings show that individuals who are obese may be more susceptible to severe COVID-19 because of a poorer inflammatory immune response.
 
The study team showed that following SARS-CoV-2 infection, cells in the lining of the lungs, nasal cells, and immune cells in the blood show a blunted inflammatory response in obese patients, producing suboptimal levels of molecules needed to fight the infection.
 
It has been found since the early part of the COVID-19 pandemic that one of the major risk factors for severe COVID-19 is obesity, which is defined as a body mass index (BMI) of over 30. More than 40% of US adults and 28% of adults in England are classed as obese.
 
Although this correlation been shown in numerous epidemiological studies, until now, it has not been clear why obesity s hould increase an individual’s risk of severe COVID-19.
 
A possible explanation was thought to be that obesity is linked to inflammation: studies have shown that individuals who are obese already have higher levels of key molecules associated with inflammation in their blood.
 
Could an overactive inflammatory response explain the connection?
 
Corresponding author, Dr Menna Clatworthy, a professor and clinician scientist at the University of Cambridge, studying tissue immune cells at CITIID alongside caring for patients at Addenbrooke’s Hospital told COVID-19 News reporters at TMN, “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.”
 
The study team analyzed blood and lung samples taken from 13 obese patients with severe COVID-19 requiring mechanical ventilation and intensive care treatment, and 20 controls (non-obese COVID-19 patients and ventilated non-COVID-19 patients). These included patients admitted to the Intensive Care Unit at Addenbrooke’s Hospital.
 
The study team used a technique known as transcriptomics, which looks at RNA molecules produced by our DNA, to study activity of cells in these key tissues.
 
Interestingly, contrary to expectations, the study team found that the obese patients had underactive immune and inflammatory responses in their lungs.  In particular, 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 of two molecules known as interferons (INF) - interferon-alpha and interferon-gamma, which help control the response of the immune system, and of tumor necrosis factor (TNF), which causes inflammation.
 
Upon analyzing in detail, the immune cells in the blood of 42 adults from an independent cohort, the study team 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.
 
Dr Clatworthy commented, “This was really surprising and unexpected. Across every cell type we looked at, we found that that the genes responsible for the classical antiviral response were less active. They were completely muted.”
 
The study team was able to replicate its findings in nasal immune cells taken from obese children with COVID-19, where they again found lower levels of activity among the genes that produce IFN-alpha and IFN-gamma. This is important because the nose is one of the entry points for the virus and a robust immune response there could prevent the infection spreading further into the body, while a poorer response would be less effective.
 
A possible explanation for the finding involves leptin, a hormone produced in fat cells that controls appetite.
 
It is known that leptin also plays a role in the immune response….in individuals who are normal weight, levels of the hormone increase in response to infection and it directly stimulates immune cells.
 
However, obese people already have chronically higher levels of leptin, and the study team says it is possible that they no longer produce sufficient additional leptin in response to infection, or are insensitive to it, leading to inadequate stimulation of their immune cells.
 
The study findings could have important implications both for the treatment of COVID-19 and in the design of clinical trials to test new treatments.
 
As a result of an overactive immune and inflammatory response being associated with severe COVID-19 in some patients, doctors have turned to anti-inflammatory drugs to dampen this response. But anti-inflammatory drugs may not be appropriate for obese patients.
 
Dr Andrew Conway Morris from the Department of Medicine at the University of Cambridge and Honorary Consultant on the intensive care unit at Addenbrooke’s Hospital and a co-author of the study 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.”
 
Importantly, clinical trials for potential new treatments would need to involve stratifying patients rather than including both severe and normal weight patients, whose immune responses differ.
 
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