Periodic Reporting for period 1 - TANK_Sepsis (Targeting Amino acid uptake into NK cells to limit pathogenesis in sepsis)
Berichtszeitraum: 2023-10-01 bis 2025-09-30
Sepsis is a life-threatening condition where the immune system first becomes dangerously overactive, followed by prolonged immunosuppression. One of the key players in this process are natural killer (NK) cells, immune cells that help fight infection but can also worsen inflammation if they become too active. In the era of antimicrobial resistance, it is important to develop therapies that target over- or under-activated immune cells to balance and promote the natural immune response to the infection. However, currently there is a limited number of these therapies.
This project set out to understand how NK cells use nutrients—especially amino acids, the building blocks of proteins—when the body is fighting severe infection. The aim was to discover whether changes in nutrient availability could be used to control NK-cell activity and create new strategies to reduce harmful inflammation in sepsis.
The main objectives of the project were:
1. Investigate the dynamics of NK cell response in mouse models of sepsis
2. Test the importance of amino acid transporters Slc1a5 and Slc7a5 for NK cell function in sepsis using genetically modified mice
3. Test potential therapies altering amino acid availability for NK cells in sepsis
This project set out to understand how NK cells use nutrients—especially amino acids, the building blocks of proteins—when the body is fighting severe infection. The aim was to discover whether changes in nutrient availability could be used to control NK-cell activity and create new strategies to reduce harmful inflammation in sepsis.
The main objectives of the project were:
1. Investigate the dynamics of NK cell response in mouse models of sepsis
2. Test the importance of amino acid transporters Slc1a5 and Slc7a5 for NK cell function in sepsis using genetically modified mice
3. Test potential therapies altering amino acid availability for NK cells in sepsis
The project used mouse models of inflammation and bacterial infection to track what NK cells do from the first hours of illness to later stages. It found that NK cells respond in two waves. The first wave begins quickly (3-6 hours after the challenge), when NK cells release inflammatory molecules, such as interferon-γ and granzyme B, to fight infection. The second wave happens later (1-2 days after the challenge) and supports the growth and full activation of these cells, including production of cytotoxic molecule perforin.
A key discovery is that NK cells rely heavily on taking up certain amino acids from the bloodstream to function properly. One transporter, called Slc7a5, turned out to be essential. When NK cells lacked this transporter, they could no longer produce key factors, such as interferon-γ and granzyme B, or support inflammation. This transporter can also be targeted therapeutically using specific inhibitor to reach the similar effect. In contrast, genetic inactivation of Slc1a5 transporter did not substantially affect NK-cell response. However, therapeutic blocking of this transporter resulted in reduced production of granzyme B and perforin by NK cells.
The project also measured amino acids in the blood during inflammation and found that methionine, an amino acid needed for both energy and cell regulation, drops sharply early in sepsis. Experiments showed that lowering methionine levels weakens NK-cell activity, while adding extra methionine boosts some of their protective functions. Overall, the findings show that NK cells adjust their behaviour based on the nutrients available in the body during infection.
A key discovery is that NK cells rely heavily on taking up certain amino acids from the bloodstream to function properly. One transporter, called Slc7a5, turned out to be essential. When NK cells lacked this transporter, they could no longer produce key factors, such as interferon-γ and granzyme B, or support inflammation. This transporter can also be targeted therapeutically using specific inhibitor to reach the similar effect. In contrast, genetic inactivation of Slc1a5 transporter did not substantially affect NK-cell response. However, therapeutic blocking of this transporter resulted in reduced production of granzyme B and perforin by NK cells.
The project also measured amino acids in the blood during inflammation and found that methionine, an amino acid needed for both energy and cell regulation, drops sharply early in sepsis. Experiments showed that lowering methionine levels weakens NK-cell activity, while adding extra methionine boosts some of their protective functions. Overall, the findings show that NK cells adjust their behaviour based on the nutrients available in the body during infection.
The project offers new insight into how the body’s immune response during sepsis is linked to changes in metabolism. Until now, most research focused on immune cells in laboratory dishes, not in living organisms during infection. This work reveals that NK cells have specific nutrient needs at different stages of sepsis and that limiting or enhancing certain amino acids can change how strongly they respond.
By showing that NK cells depend on amino acid transporters (Slc7a5 and Slc1a5), the project identifies a new possible target for treatments aimed at calming excessive inflammation. The discovery that methionine levels in the blood strongly influence NK-cell behaviour also opens new directions for research on nutritional or metabolic support during sepsis.
By showing that NK cells depend on amino acid transporters (Slc7a5 and Slc1a5), the project identifies a new possible target for treatments aimed at calming excessive inflammation. The discovery that methionine levels in the blood strongly influence NK-cell behaviour also opens new directions for research on nutritional or metabolic support during sepsis.