Functional analysis of ADP-heptose sensing in bacterial infections and structural characterization of TIFAsomes – TIFAsomes

Bacterial infectious diseases are a major concern for human health. The use of antibiotics to treat them has been a major success in medicine. However, its efficacy has gradually decreased due to the rapid emergence of multi-drug-resistance mechanisms. The identification of new microbial targets is the major obstacle faced by academic and pharmaceutical laboratories, largely explaining the current lack of new antibiotic treatments. It is critical to identify new virulence determinants associated with human pathogens and to characterize the cellular pathways that can respond or interact with these determinants. This knowledge will be paramount to design novel therapeutic approaches that target the pathogen, host response or both.

Innate immunity is the first line of defense against pathogens and contributes to the initiation of adaptive immunity, which confers long-lasting protection and immunological memory. We hypothesize that a deep understanding of the host-pathogen molecular interactions controlling the activation of innate immunity and its regulation during infection is crucial to identify promising target mechanisms for therapeutic intervention.

The team of C. Arrieumerlou recently identified a new pathway of innate immunity that induces inflammation in response to infection by several Gram-negative bacteria, including Shigella flexneri, Salmonella Typhimurium and Neisseria meningitidis. They showed that the proteins ALPK1, TIFA and TRAF6 act sequentially to activate the transcription factor NF-?B and induce the secretion of inflammatory cytokines. They identified ADP-heptose, an intermediate of LPS biosynthesis, as a new bacterial PAMP and showed that the ALPK1/TIFA/TRAF6 axis is activated in response to ADP-heptose recognition. They discovered that recognition of ADP-heptose induces the formation of multi-protein structures called TIFAsomes, which, like inflammasomes, regulate innate immunity during infection. ADP-heptose is shared by most Gram-negative bacteria and thus by important human pathogens. Yet, the functional impact of ADP-heptose detection during bacterial infections in vivo is largely unknown. Furthermore, the in vivo existence and regulation of TIFAsomes, which have so far been observed only in cell lines overexpressing TIFA, remain unsolved questions.

The TIFAsomes project combines single-cell immune signaling analysis, cryo-electron microscopy, genomics and real-time imaging of zebrafish infection to determine the spatio-temporal dynamics and the structural organization of TIFAsomes in infected cells, and to characterize the functional consequences of detecting ADP-heptose during a bacterial infection in vivo.