Researchers from the University of East Anglia and Quadram Institute report that they have found how our immune cells use the body’s fat stores to fight infection. Their study (“Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection”), published in Nature Communications, may help develop novel approaches to treating people with bacterial infections, especially in vulnerable and older people.
The UEA team, which studied Salmonella, a bacterial infection which causes diarrhea, vomiting, abdominal pain, fever, and sepsis, collaborated with the Quadram Institute and colleagues at the Earlham Institute, to track fatty acid movement and consumption in live stem cells. They went on to analyze the immune response to Salmonella bacterial infection, by investigating liver damage.
The scientists, who uncovered how blood stem cells respond to infection by acquiring high energy fatty acids from the body’s fat stores, also found that in the bone marrow where blood stem cells are resident, infection signals drive adipocytes to release their fat stores as fatty acids into the blood. And they identified that these high energy fatty acids are then taken up by blood stem cells, effectively feeding the stem cells and enabling them to make millions of Salmonella-fighting white blood cells.
The researchers also identified the mechanism by which the fatty acids are transferred and discusses the potential impact this new knowledge could have on future treatment of infection.
“Acute infection is known to induce rapid expansion of hematopoietic stem cells (HSCs), but the mechanisms supporting this expansion remain incomplete. Using mouse models, we show that inducible CD36 is required for free fatty acid uptake by HSCs during acute infection, allowing the metabolic transition from glycolysis towards β-oxidation,” write the investigators.
“Mechanistically, high CD36 levels promote FFA uptake, which enables CPT1A to transport fatty acyl chains from the cytosol into the mitochondria. Without CD36-mediated FFA uptake, the HSCs are unable to enter the cell cycle, subsequently enhancing mortality in response to bacterial infection. These findings enhance our understanding of HSC metabolism in the bone marrow microenvironment, which supports the expansion of HSCs during pathogenic challenge.”
According to Stuart Rushworth, PhD, from UEA’s Norwich Medical School, “Our results provide insight into how the blood and immune system is able to respond to infection. Fighting infection takes a lot of energy and fat stores are huge energy deposits, which provide the fuel for the blood stem cells to power up the immune response.
“Working out the mechanism through which this ‘fuel boost’ works gives us new ideas on how to strengthen the bodies fight against infection in the future.”
With antibiotic resistance being such a present and widespread challenge for society, “there is an urgent need to explore novel ways like this to help the body’s immune system to fight infection,” notes Rushworth.
“Our results allow us to understand how our immune system uses fat to fuel the response to infection,” adds Naiara Beraza, PhD, from the Quadram Institute. “Defining these mechanisms will enable us to develop new therapeutics to treat infections in the liver.”