Does impaired adipose tissue B cell function lead to loss of natural antibody secretion and increase susceptibility to infection in obesity?

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Obesity affects nearly 30% of adults in the UK. The effect of obesity on increased risk of cardiovascular diseases, diabetes and cancer is well recognised. Obesity also affects the immune system leading to increased susceptibility to infections. This has become dramatically apparent with COVID-19; obesity is one of the main risk factors of hospitalisation and death with COVID-19. Obesity also increases the risk of pneumonia and post-operative infections, raising important clinical challenges in hospitals.Antibodies are a critical tool in the fight against infections. They are produced by a type of white blood cell called B cells. During infection with bacteria or a virus, antibodies specific to the bacteria or virus are produced leading to the elimination of the infection. These are the type of antibodies induced by vaccination. However, the production of these antibodies can take up to 3 weeks. Another type of antibody exists called natural antibodies. These recognise generic components found on all microbes. They are constantly made and their production increases during infection, providing blanket protection at the beginning of infections. Animal studies show that natural antibodies are key for protection early during infection. Lower levels of natural antibodies are found in obese and old individuals, which could partly explain their increased susceptibility to infections. Thus, it could be very helpful to be able to make B cell produce more natural antibodies to increase resistance to infection. Or we could manufacture a natural antibody product to treat patients with bad infections. To develop such treatments, we need to better understand the B cells that produce natural antibodies in human.We have discovered that the fat that surrounds our internal organs is an important place for the production of natural antibodies. B cells are found in our abdominal fat (known as the omentum) and in the fat tissue that surrounds the heart (known as the pericardium). We found that B cells from obese patients produce far fewer natural antibodies than those from non-obese patients and they fail to increase production of natural antibodies during infection. In this project, we will work with surgeons performing abdominal surgery and heart operations to obtain fat samples from omentum and pericardium from consenting patients. We will work out exactly how B cells within these fat tissues are making natural antibodies and why they lose the ability to do so in obese people. We want to identify molecules or drugs that can boost the protective function of these B cells to restore natural antibody production and increase resistance to infection in obese people. Using the genetic sequence of the B cells found in the fat biopsies, we want to produce a natural antibody with high anti-microbial properties. The efficacy of this natural antibody will then be test in animal models of infection.