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 bacterial responses is highly intriguing and highlights the complexity of MKP1's role in immune regulation. Therefore, our objectives are twofold. First, to determine why MKP1 deletion is protective in fungal disease but detrimental in bacterial disease. Second, to determine the cell-type specific functional role of MKP1 in C. albicans infection, which will reveal new mechanisms by which fungal diseases outcome could be improved through targeted immunostimulatory therapy. The work will considerably enhance our understanding of immune regulation during fungal and bacterial infection and will identify new therapeutic opportunities that may arise from manipulating MKP1 pathways to improve microbial infection resolution, especially as adjunctive therapy during antimicrobial resistance. This work will have multiple academic beneficiaries in the fields of general and innate immunology, fungal and bacterial pathogenesis, cellular signalling, and host-pathogen interactions. An integral part of this research proposal involves the creation of conditional MKP1 knockout mouse models, which will create invaluable and powerful research tools that will enhance the impact and significance of this research proposal and be of considerable value to the wider scientific community (broader ranging infection studies, immunology, MAPK biology). In addition, this proposal has potential commercial beneficiaries, as our findings could be exploited at several levels in the longer term to improve human health and quality of life.