MKP1 modulating host defence: pathogen-specific innate immune regulation

Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP1) plays a crucial role in the regulation of immune responses and the body’s defence mechanisms against infections. MKP1 is involved in modulating the activity of MAPKs, which are vital for transducing signals from microbial pathogens. During infection, MKP1 acts as a ‘regulatory brake’ on the inflammatory response, as excessive or prolonged inflammation can lead to tissue damage and chronic inflammatory diseases. MKP1 fine-tune’s this response by deactivating MAPKs, thereby reducing the production of pro-inflammatory cytokines. This action is critical for preventing tissue damage and promoting resolution of inflammation, demonstrating a dual role for MKP1 in infections acting as a critical modulator of the immune response. While the functional role of MKP1 has been studied in bacterial infections, no studies have investigated its role in fungal infections.
Fungi kill ~2.5 million individuals each year, five times more than malaria or influenza, and are deadlier than most bacterial infections. Candida spp. cause ~1 million deaths from invasive/bloodstream infections and >150 million mucosal infections annually. As such, Candida infections are a serious medical problem and an immense burden to human health. Given this, the World health Organisation recently cited C. albicans in the ‘critical’ group (highest) in the ‘fungal priority pathogens’ list. Thus, identifying biological and immunological mechanisms that advance our understanding of C. albicans infection and lead to disease prevention is now a recognised priority.
MKP1 is strongly activated in epithelial cells and neutrophils during C. albicans infection. Importantly, using a MKP1 knockout (KO) mouse, MKP1 deletion resulted in protection against mucosal and systemic C. albicans infection. These findings are in stark contrast to bacterial studies, where the MKP1 KO dramatically increases morbidity and mortality. This dichotomy between fungal and...