Bacterial sensing by human Natural Killer cells

The innate immune system is our first line of defence against pathogens and protective mechanisms against viruses, bacteria and yeast. Of these, the non-canonical inflammasome (NCI) is an essential cellular signalling platform that detects and responds to infection by Gram-negative bacteria such as E.coli and Salmonella. The NCI is involved with a range of infections and complications arising from these infections, including endotoxemia and sepsis.

Our lab is interested in identifying novel functions for the NCI in Caspase-4 to develop novel immunotherapies against a range of diseases with an immune component, such as cancer, sepsis, infections and inflammatory bowel disease.

The NCI's activation has been characterised by defined immune cells (macrophages) and at the body's physical barrier ( e.g., skin epithelium, intestinal epithelium). This leads to the activation of a signalling enzyme called caspase-4. Caspase-4 cleaves proteins to kill infected cells and release inflammatory messengers (cytokines) to recruit immune cells further and educate long-term immune response (adaptive immunity).

Inflammasome functions in white blood cells (lymphocytes, e.g., Natural Killer cells and T cells) are poorly defined.

Here, we hypothesise that a type of white blood cell, natural killer (NK) cells, activates inflammasomes in response to bacterial membrane components in humans but not in mice. Here, we are challenging the current dogma that suggests that NK cells do not use inflammasome against infection. Through this exciting project grant, we aim to:

1- Characterise how NK cells recognise the bacterial membrane component LPS to activate inflammasomes

Here, we will define the molecular actors that control bacterial detection by NK cells. As these proteins are conserved between mice and humans, we will likely unveil exciting new biology. 2- Determine how NK cells control inflammasome activity

NK cell's interactions with its environment (inflammatory cytokines, cells) influence its functions. Here, we will study how these also influence inflammasome functions in NK cells in different cellular environments. 3- Identify the consequence of inflammasome activation in NK cells

Here, we will study the consequences of the inflammasome on NK cells in circulation (blood) and in immune organs (tonsils). We will also assess the impact of inflammasome activation on controlling bacterial infections.

This fundamental proposal has the potential to unveil novel mechanisms controlling NK cell functions during bacterial infections. These cells have been studied in the context of viral infection and cancer. Here, we identified an active role of NK cells inflammasome activation in response to Gram-negative bacteria, fundamental knowledge that may develop into novel immunotherapies against infection.

Our study may better understand early changes in LPS-mediated sepsis in humans, which have been associated with a decrease in circulating NK cells. Moreover, NK cells are critical mediators in various anti-cancer therapies (e.g., NK-CAR, Salmonella immunotherapies), and new knowledge from our proposal may contribute to improving these therapies. Thus, besides providing exciting novel information about the role of NK cells in infections, our work has the potential to help engineer more efficient immunotherapies.