Detecting ADP-heptose during bacterial infection: what for? – ADPH-WHAT4

Innate immunity constitutes the first line of defense against pathogens and conditions the onset of acquired immunity. The molecular mechanisms underlying its activation and regulation are therefore of particular interest for understanding the determinants that impact the outcome of infections, and for identifying targets for new treatments. During bacterial infection, bacteria are detected by Pathogen Recognition Receptors (PRRs) on immune cells and on “non-professional” immune cells, such as epithelial cells, which act as sentinels. Following binding to Pathogen-Associated Molecular Patterns (PAMPs), PRRs trigger pro-inflammatory signaling pathways that result in the secretion of a broad range of immune effectors such as cytokines, chemokines and antimicrobial peptides.
ADP-heptose was recently described as a new bacterial PAMP. It is a soluble metabolite of the lipopolysaccharide inner core biosynthetic pathway of most Gram-negative bacteria. Once in the host cell cytoplasm, it binds to alpha-protein kinase 1 (ALPK1), an atypical kinase which acts as a PRR. In turn, ALPK1 phosphorylates adaptor TIFA proteins, a process that triggers their oligomerization in large structures called TIFAsomes, the activation of TRAF6 and NF-kB and the expression of pro-inflammatory genes. Although the ADPH/ALPK1/TIFA pathway is activated by a growing number of pathogenic bacteria, it remains very poorly characterized. The goals of the ADPH-WHAT4 project are to determine how ADP-heptose is delivered into cells during infection, understand its potential contribution to the spread of inflammation within the infected epithelium, and to characterize its impact on the anti-infectious activities of neutrophils.