Modifying bacterial flagellin to evade Nod-like Receptor CARD 4 recognition enhances protective immunity against Salmonella.
Bittante, Alessandra S
Hopkins, Lee J
Bryant, Owain J
MetadataShow full item record
Tourlomousis, P., Wright, J. A., Bittante, A. S., Hopkins, L. J., Webster, S., Bryant, O. J., Mastroeni, P., et al. (2020). Modifying bacterial flagellin to evade Nod-like Receptor CARD 4 recognition enhances protective immunity against Salmonella.. Nature microbiology, 5 (12), 1588-1597. https://doi.org/10.1038/s41564-020-00801-y
Pattern recognition receptors (PRRs) expressed in antigen-presenting cells are thought to shape pathogen-specific immunity by inducing secretion of co-stimulatory cytokines during T-cell activation, yet data to support this notion in vivo is surprisingly scarce. Here we show that the cytosolic PRR Nod-like Receptor CARD 4 (NLRC4) suppresses, rather than facilitates, effector and memory CD4+ T-cell responses against Salmonella in mice. NLRC4 negatively regulates immunological memory by preventing delayed activation of the cytosolic PRR NLR pyrin domain 3 (NLRP3) that would otherwise amplify the production of cytokines important for the generation of Th1 immunity such as intereukin-18. Consistent with a role for NLRC4 in memory immunity, primary challenge with Salmonella expressing flagellin modified to largely evade NLRC4 recognition significantly increases protection against lethal re-challenge. This finding suggests flagellin modification to reduce NLRC4 activation enhances protective immunity which could have important implications for vaccine development against flagellated microbial pathogens.
T-Lymphocytes, Th1 Cells, Macrophages, Animals, Mice, Inbred C57BL, Humans, Mice, Salmonella typhimurium, Salmonella Infections, Flagellin, Calcium-Binding Proteins, Interleukin-18, Female, Male, Apoptosis Regulatory Proteins, Host-Pathogen Interactions, Immunity, Innate, NLR Family, Pyrin Domain-Containing 3 Protein
Is supplemented by: https://doi.org/10.17863/CAM.41575
WELLCOME TRUST (108045/Z/15/Z)
External DOI: https://doi.org/10.1038/s41564-020-00801-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/310548
All rights reserved