Lipid droplets as innate immunity hubs

Successful defence against invaders is critical for survival of eukaryotic cells.

Microbes have developed many strategies to subvert host organisms which, in turn, evolved several innate immune responses to counterattack.

As major lipid storage organelles of eukaryotes, lipid droplets (LDs) are an attractive source of nutrients for invaders.

Pathogens induce and physically interact with LDs and the current view is that they hijack LDs to draw on substrates for host colonisation.

We recently challenged this dogma by demonstrating that LDs are endowed with a regulated protein-mediated antibiotic activity.

Our work intro-duced the new concept that dependence on host nutrients is a generic Achilles heel of intracellular pathogens and LDs a chokepoint harnessed by innate immunity to organise a front-line defence.Here, we have formed a multidisciplinary group combining complementary knowledge and transdiscipli-nary expertise to investigate the hypothesis that LDs are innate immunity hubs sensing infection and di-rectly confronting invaders.

We will characterise, in cells and animals, how LDs efficiently coordinate and precisely execute a plethora of immune responses such as killing, signalling and inflammation.

High-throughput proteomics and lipidomics will identify defensive players. 3D electron tomography and confo-cal microscopy will be combined with proximity labelling strategies and biochemical methods to get un-precedented understanding of host LD-pathogen dynamics.

The successful pathogen Mycobacterium tuber-culosis will be used to test the medical significance of our findings and unravel bacterial mechanisms of resistance to LD-mediated defences.Characterisation of these novel innate immune systems will be paradigm-shifting in immunology, physiol-ogy and cell biology.

In the age of antimicrobial resistance and viral pandemics, unravelling how eukaryot-ic LDs fight and defeat dangerous microorganisms will inspire new anti-infective therapies.