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Modifying bacterial flagellin to evade Nod-like Receptor CARD 4 recognition enhances protective immunity against Salmonella

Nature Microbiology volume 5, pages 1588–1597 (2020)Cite this article

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Abstract

Pattern recognition receptors (PRRs) expressed in antigen-presenting cells are thought to shape pathogen-specific immunity by inducing secretion of costimulatory cytokines during T-cell activation, yet data to support this notion in vivo are 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 notably increases protection against lethal rechallenge. This finding suggests flagellin modification to reduce NLRC4 activation enhances protective immunity, which could have important implications for vaccine development against flagellated microbial pathogens.

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Fig. 1: NLRC4 restricts bacterial spread in vivo and Th1 CD4+ T-cell-mediated memory responses ex vivo.
Fig. 2: NLRC4 restricts the magnitude of effector CD4+ T-cell responses during microbial clearance of a primary infection.
Fig. 3: NLRC4 restricts the potency of CD4+ T-cell-mediated memory responses against Salmonella in a NLRP3-dependent manner.
Fig. 4: NLRC4 restricts NLRP3-dependent secretion of IL-18 and IFN-γ.
Fig. 5: Salmonella expressing flagellin from non-pathogenic E. coli largely escapes NLRC4-mediated detection in vivo.
Fig. 6: Primary challenge with Salmonella expressing flagellin from non-pathogenic E. coli improves protection against lethal rechallenge.

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Data availability

All data used to generate the figures presented in this work are available in Cambridge Research Repository Apollo with the identifier https://doi.org/10.17863/CAM.41575. Source data are provided with this paper.

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Acknowledgements

This work was supported by grants from Biotechnology and Biological Sciences Research Council (BBSRC) (nos. BB/H003916/1 and BB/K006436/1), Zoetis UK (no. BB/K006436/1) and Wellcome Trust (no. 108045/Z/15/Z) to C.E.B. A.S.B was supported by a Wellcome Trust 4-year PhD studentship. We thank K. A. Fitzgerald and D. Golenbock for suppling the gene-deficient mouse strains, S. M. Man for critical review of the manuscript and helpful discussions, and A. Cooke and members of her group, especially P. Zaccone and S. Newland, for sharing their expertise with P.T. and helpful discussions.

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Author notes

  1. Duncan J. Maskell

    Present address: The University of Melbourne, Parkville, Victoria, Australia

  2. These authors contributed equally: John A. Wright, Alessandra S. Bittante.

Authors and Affiliations

  1. Department of Veterinary Medicine, University of Cambridge, Cambridge, UK

    Panagiotis Tourlomousis, John A. Wright, Alessandra S. Bittante, Lee J. Hopkins, Steven J. Webster, Pietro Mastroeni, Duncan J. Maskell & Clare E. Bryant

  2. Department of Pathology, University of Cambridge, Cambridge, UK

    Owain J. Bryant

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Contributions

P.T. designed, performed and analysed all in vivo, ex vivo and in vitro experiments. P.M., J.A.W., L.J.H., A.S.B. and S.J.W performed part of some in vivo experiments. O.J.B. performed the bacterial motility assays. J.A.W supervised all bacterial mutagenesis work. A.S.B. performed all bacterial mutagenesis work. P.M., D.J.M. and C.E.B. conceived the study and secured the funding. C.E.B. and P.T. supervised the study. P.T., J.A.W. and C.E.B. wrote the manuscript.

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Correspondence to Clare E. Bryant.

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Extended data

Extended Data Fig. 1 NLRC4 is required to restrict microbial spread during an oral sub-lethal but not an oral lethal infection with S. Typhimurium.

a, Wild-type and nlrc4−/− mice were challenged orally with 4.4 × 109 CFU S. Typhimurium M525P to establish a sub-lethal infection and microbial burden was determined in the spleen and liver at 5 days (n = 6 for wild-type and Nlrc4−/−) and 14 days (n = 7 for wild-type and n = 6 for Nlrc4−/−) post-challenge. b, Wild type and Nlrc4−/− mice were challenged orally 8 × 108 CFU S. Typhimurium SL1344 to establish a lethal infection and microbial burden was determined in the spleen and liver at 4 days post-challenge. Each symbol represents one mouse and horizontal lines delineate the mean. Statistical significance was calculated by 2-way ANOVA followed by Sidak’s multiple comparisons test for a and two-tailed Mann Whitney test for b. Data are representative of two independent experiments.

Source data

Extended Data Fig. 2 The effect of infection dose on the potency of ex vivo CD4+ T cell-mediated responses.

Wild-type mice were challenged with either 1.58 × 105 CFU, 1.72 × 104 CFU or 1.53 × 103 CFU S. Typhimurium M525P. Mice were euthanised 104-125 days after challenge and their splenic CD4+ T cells were stimulated with medium only (w/o stim.), anti-mouse CD3e (anti-CD3e) or whole bacterial cell extract (extract). a, IFN-γ measured by ELISA in the cell culture supernatant after 72 hours. b, IL-2 measured by ELISA in the cell culture supernatant after 24 hours. Data are shown as mean ± s.e.m. Statistical significance was calculated by a one-way ANOVA. Data were generated from one experiment.

Source data

Extended Data Fig. 3 Flow cytometric analysis reveals that CD4+ T cells secreting IFN-γ ex vivo have the profile of effector memory, rather than central memory, CD4+ T cells.

CD4+ T cells isolated from the spleen of wild-type and Nlrc4−/− mice 100 days after primary challenge with 1.24 × 104 CFU S. Typhimurium M525P were stimulated ex vivo with whole bacterial cell extract and phenotypically characterised via flow cytometry. Viable cells were first selected using a fixable viability dye (FVD) and single cells only were further included in the analysis based on their forward scatter area vs. forward scatter height. Single viable cells expressing CD4 were then separated to IFN-γ- and IFN-γ+ with both groups analysed for expression of CD44 and CD62L. For CD4+IFN-γ- cells, the phenotype CD44+CD62−represents effector T cells, while the phenotype CD44−CD62+ represents naïve T cells. For CD4+IFN-γ+ cells, the phenotype CD44+CD62−represents effector memory T cells, while the phenotype CD44+CD62+ represents central memory T cells. Percentages shown in the respective quadrants are mean values ± SD from N = 5 wild-type and N = 6 Nlrc4−/− mice. Data were generated from one experiment.

Extended Data Fig. 4 NLRC4 does not affect protection against lethal re-challenge.

Wild-type and Nlrc4−/− mice were challenged with either sterile PBS (naïve) or 1-1.15 × 104 CFU S. Typhimurium M525P and allowed to clear the primary infection for 90-106 days. They were then re-challenged orally with 1.37-7.2 × 107 CFU S. Typhimurium SL1344 to establish a lethal infection and inspected twice daily. They were euthanized upon detection of adverse signs and a humane end point curve was constructed for a, naïve mice and b, mice ‘immunised’ with Salmonella. Data has been pooled from 2 independent experiments. Statistical significance was calculated by a two-sided log-rank test.

Source data

Extended Data Fig. 5 Data variation between independent trials comparing CD4+ T cell-mediated responses in wild-type, Nlrc4-/-, Nlrp3-/- and Nlrp3-/-Nlrc4-/- mice is not statistically significant.

Levels of IFN-γ produced by CD4+ T cells stimulated ex vivo with whole bacterial cell extract were compared between wild-type mice used in three independent trials shown in Fig. 1c, Fig. 3a and Fig. 3b. Each symbol represents one mouse and horizontal lines delineate the mean. The data was tested for statistical significance by one-way ANOVA.

Source data

Extended Data Fig. 6 In the absence of NLRC4, Salmonella-infected macrophages do not undergo early cell death enabling them to survive longer and secrete IL−1β via activation of NLRP3.

Unprimed bone marrow derived macrophages (BMDMs) from wild-type, Nlrc4−/−, Nlrp3−/− and Nlrc4−/−Nlrp3−/− mice were infected with S. Typhimurium M525P in logarithmic growth at the MOI=50. a, Cytotoxicity was determined by measuring levels of LDH released in the cell culture supernatant. b, Levels of IL-1β were determined by ELISA in the cell culture supernatant. Data are shown as mean of triplicate wells ± s.e.m. Data are representative of two independent experiments.

Source data

Extended Data Fig. 7 Pairwise Sequence Alignment of FliC from E. coli K-12 MG1655 and S. Typhimurium M525P.

Comparison of the predicted FliC proteins from S. Typhimurium M525P and E. coli K-12 MG1655 by Clustal Omega (EMBL-EBI).

Extended Data Fig. 8 Salmonella expressing flagellin from non-pathogenic E. coli (M525P fliCMG1655) is motile but impaired at activating the NLRC4 inflammasome in macrophages.

a, Comparison of the motility diameter between S. Typhimurium M525P, M525P fliCMG1655 and SL1344. Data are expressed as % of the diameter achieved by the SL1344. b–d, Unprimed bone marrow derived macrophages from wild-type and Nlrc4−/− mice were infected for 1 h, 2 h, 6 h and 24 h with S. Typhimurium M525P or M525P fliCMG1655 in logarithmic growth. b, Cytotoxicity was determined by measuring levels of LDH released in the cell culture supernatant at an MOI of 50. c, Levels of IL-1β and d, TNF-α were determined by ELISA in the cell culture supernatant at an MOI of 1. Data has been pooled from 6 independent experiments and shown as mean ± s.e.m. in a. Data are representative of two independent experiments in b–d and shown as mean of triplicate wells ± s.e.m.

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Tourlomousis, P., Wright, J.A., Bittante, A.S. et al. Modifying bacterial flagellin to evade Nod-like Receptor CARD 4 recognition enhances protective immunity against Salmonella. Nat Microbiol 5, 1588–1597 (2020). https://doi.org/10.1038/s41564-020-00801-y

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