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Pseudomonas aeruginosa quorum-sensing metabolite induces host immune cell death through cell surface lipid domain dissolution

Nature Microbiology volume 4, pages 97–111 (2019)Cite this article

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Abstract

Bacterial quorum-sensing autoinducers are small chemicals released to control microbial community behaviours. N-(3-oxo-dodecanoyl) homoserine lactone, the autoinducer of the Pseudomonas aeruginosa LasI–LasR circuitry, triggers significant cell death in lymphocytes. We found that this molecule is incorporated into the mammalian plasma membrane and induces dissolution of eukaryotic lipid domains. This event expels tumour necrosis factor receptor 1 into the disordered lipid phase for its spontaneous trimerization without its ligand and drives caspase 3–caspase 8-mediated apoptosis. In vivo, P. aeruginosa releases N-(3-oxo-dodecanoyl) homoserine lactone to suppress host immunity for its own better survival; conversely, blockage of caspases strongly reduces the severity of the infection. This work reveals an unknown communication method between microorganisms and the mammalian host and suggests interventions of bacterial infections by intercepting quorum-sensing signalling.

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Fig. 1: 3oc induces TNFR1 pathway-mediated apoptosis.
Fig. 2: 3oc disrupts the structure of the plasma membrane.
Fig. 3: 3oc induces TNFR1 autotrimerization.
Fig. 4: 3oc alters the motion pattern of TNFR1 on the plasma membrane.
Fig. 5: 3oc-induced neutrophil apoptosis promotes P. aeruginosa infection.
Fig. 6: Proposed mechanism for the role of 3oc in Pseudomonas aeruginosa infection.

Data availability

The data that support the findings of this study are available from the corresponding author upon request. Complete western blot images of all figures in the manuscript are provided as Supplementary Figures.

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Acknowledgements

We thank P. Greenberg of University of Washington for his expert advice and his gift of P. aeruginosa strains, J. Yuan of Institute of Chemistry of CAS for his assistance on single-molecule imaging data analysis, J. Harrison and H. Almblad for their expert advice on P. aeruginosa mutagenesis and L. Yu of Tsinghua University for DNA constructs. X.F. is supported by the National Natural Science Foundation of China (21735006 and 91413119). Y.S. is supported by the joint Peking-Tsinghua Center for Life Sciences, the National Natural Science Foundation of China General Program (31370878), and by grants from the US NIH (R01AI098995), the Natural Sciences and Engineering Research Council of Canada (RGPIN-355350/396037) and the Canadian Institutes for Health Research (MOP-119295).

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Authors and Affiliations

  1. Institute for Immunology, Department of Basic Medical Sciences, Center for Life Sciences, Tsinghua University, Beijing, China

    Dingka Song, Junchen Meng, Hefei Ruan, Ning Kang, Ying Xu, Xiaobo Wang, Fei Shu, Libing Mu, Tengfei Li, Wenran Ren, Xin Lin, Tie Xia & Yan Shi

  2. Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China

    Jie Cheng & Junhong Lü

  3. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, China

    Zheng Fan & Weihui Wu

  4. Key Laboratory of Advanced Materials (MOE), Department of Chemical Engineering, Tsinghua University, Beijing, China

    Pengyu Chen & Li-Tang Yan

  5. Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute, University of Calgary, Calgary, Alberta, Canada

    Zhongyuan Tu & Yan Shi

  6. Key Laboratory of Molecular Nanostructure and Nanotechnology, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China

    Nan Li & Xiaohong Fang

  7. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Jun Zhu

  8. Department of Microbiology, Nanjing Agricultural University, Nanjing, China

    Jun Zhu

  9. Departments of Cell Biology and Anatomy, Snyder Institute, University of Calgary, Calgary, Alberta, Canada

    Matthias W. Amrein

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  1. Dingka Song
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Contributions

D.S. performed all of the experiments and data analyses unless otherwise specified with assistance from J.M., Z.T., Y.X., X.W., F.S., N.L., W.R. and L.M. N.K. and J.C. performed the AFM analysis. J.L., T.X. and M.W.A. proposed and supervised the AFM experiments. X.L. helped to design the TNFR1 signalling assays. X.F. helped to design the single-molecule imaging experiments. J.Z. helped to design the quorum-sensing mutant experiments. H.R. designed and performed the GUV experiments. T.L. performed the TLC analysis. Z.F. and W.W. designed and constructed the vector-based lasI overexpression version of ΔlasR P. aeruginosa. P.C. and L-T.Y. designed and performed the TNFR1 simulation work. T.X. designed and supervised all imaging work. Y.S. conceptualized the work and wrote the manuscript with assistance from D.S.

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Correspondence to Yan Shi.

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Supplementary information

Supplementary Information

Supplementary Figures 1–6, uncropped gels, Supplementary Tables 1 and 2, Supplementary References, Supplementary Video legends.

Reporting Summary

Supplementary Video 1

Sample movie of TNFR1 multiple-step fluorescence quenching.

Supplementary Video 2

Sample movie of AFM scanning of lipid membrane treated with DMSO.

Supplementary Video 3

Sample movie of AFM scanning of lipid membrane treated with 3oc.

Supplementary Video 4

Sample movie of TNFR1 single-particle tracking treated with DMSO.

Supplementary Video 5

Sample movie of TNFR1 single-particle tracking treated with 3oc.

Supplementary Video 6

Coarse-grained model of TNFR1’s dynamics on plasma membrane.

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Song, D., Meng, J., Cheng, J. et al. Pseudomonas aeruginosa quorum-sensing metabolite induces host immune cell death through cell surface lipid domain dissolution. Nat Microbiol 4, 97–111 (2019). https://doi.org/10.1038/s41564-018-0290-8

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