Active Infection & Immunity Genetics & Molecular Biology

Regulation of innate immune responses by the TPL-2/ABIN-2/NF-κB1 p105 complex

Funder Wellcome Charity-funded
Recipient organisation Imperial College London
Funding £1.6M
Period Jan 2022 — Jan 2027

In plain English

AI plain-English summary

A protein complex that helps immune cells swallow and destroy bacteria is doing more than scientists thought—it also controls the process directly, not just through the signals that trigger it. This matters because the body’s first line of defence against bacterial infections relies on immune cells called macrophages, neutrophils, and dendritic cells engulfing and digesting invading microbes inside compartments called phagosomes. The TPL-2/ABIN-2/NF-κB1 p105 complex was already known to switch on inflammatory signals, but the researchers recently discovered it also drives phagosome maturation—the step that actually kills the bacteria—independently of those signals. No one knows how it does this, or whether it works the same way in different immune cell types and against different bacteria. If the team succeeds, they will reveal a new mechanism of bacterial killing that could be targeted to boost immune responses. The work has direct relevance to inflammatory bowel disease, where a genetic link between TPL-2 and gut inflammation suggests faulty phagosome function may allow intestinal bacteria to trigger abnormal immune reactions. Understanding this pathway could eventually point toward treatments that restore normal bacterial clearance in the gut.

View original technical description
The TPL-2/ABIN-2/NF-κB1 p105 complex is essential for transmitting Toll-like receptor (TLR) signals, turning on inflammatory responses via TPL-2 kinase activation of ERK1/2 and p38alpha MAP kinases. This proposal will investigate the roles in innate immunity of the newly discovered functions of the TPL-2 complex in stimulating phagosome maturation in macrophages independently of MAP kinase activation. 1) TPL-2 and ABIN-2 regulation of phagosome function in professional phagocytes. Mechanisms of TPL-2 and ABIN-2 regulation of phagosome maturation in mouse and human macrophages will be established. Roles of TPL-2 and ABIN-2 regulation of phagosome function in mouse neutrophils and dendritic cells will be investigated. 2) TPL-2 and ABIN-2 regulation of innate immune responses to pathogenic bacteria. Roles of TPL-2 and ABIN-2 regulation of phagosome function in mouse immune responses to Staphylococcus aureus will be determined. 3) TPL-2 induction of phagosome maturation in inflammatory bowel disease (IBD). The human MAP3K8 gene encoding TPL-2 is linked genetically to the development of IBD, an auto-inflammatory disease that involves an abnormal mucosal immune response to intestinal bacteria. The role of TPL-2 regulation of phagosome function in gut inflammation will be investigated, using human monocyte-derived macrophages from IBD patients/control individuals, and the Citrobacter rodentium mouse model of colitis.

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Researchers

Steven Ley (EPMC Awardee)

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Original classification

Investigator Award in Science

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