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Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction

Nature Biotechnology volume 29, pages 428–435 (2011)Cite this article

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An Erratum to this article was published on 08 February 2012

This article has been updated

Abstract

Suppression of inflammation is critical for effective therapy of many infectious diseases. However, the high rates of mortality caused by sepsis attest to the need to better understand the basis of the inflammatory sequelae of sepsis and to develop new options for its treatment. In mice, inflammatory responses to host danger-associated molecular patterns (DAMPs), but not to microbial pathogen-associated molecular patterns (PAMPs), are repressed by the interaction of CD24 and SiglecG (SIGLEC10 in human). Here we use an intestinal perforation model of sepsis to show that microbial sialidases target the sialic acid–based recognition of CD24 by SiglecG/10 to exacerbate inflammation. Sialidase inhibitors protect mice against sepsis by a mechanism involving both CD24 and Siglecg, whereas mutation of either gene exacerbates sepsis. Analysis of sialidase-deficient bacterial mutants confirms the key contribution of disrupting sialic acid–based pattern recognition to microbial virulence and supports the clinical potential of sialidase inhibition for dampening inflammation caused by infection.

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Figure 1: CD24 and SiglecG protect mice against inflammation and mortality associated with polybacterial sepsis.
Figure 2: Expression of CD24 predominantly on CD11c+ cells protects against sepsis.
Figure 3: The interaction of CD24 with SIGLEC10 depends on sialylation of CD24.
Figure 4: Increased circulating sialidase activity and reduction of SIGLEC10 binding of CD24 in CLP mice.
Figure 5: Sialidase inhibitors protect mice against sepsis.
Figure 6: S. pneumoniae sialidases exacerbate sepsis by a CD24− and SiglecG-dependent mechanism.

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  • 18 January 2012

    In the version of this article initially published, a line in the abstract read, “repressed by the t interaction….” It should have read, “repressed by the interaction….” The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank P.N. Boyaka for valuable advice, Y. Chen for critical reading of the manuscript and valuable discussions and D. Kroft for editorial assistance. This study is supported by grants from US National Institutes of Health.

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Authors and Affiliations

  1. Division of Immunotherapy, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA

    Guo-Yun Chen, Chong Chen, Pan Zheng & Yang Liu

  2. Department of Chemistry, University of California, Davis, Davis, California, USA

    Xi Chen, Jiansong Cheng, Hongzhi Cao, Hai Yu & Jingyao Qu

  3. Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA

    Samantha King & Shireen A Woodiga

  4. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Karen A Cavassani, Lei Sun, Cory M Hogaboam, Steven L Kunkel & Pan Zheng

  5. OncoImmune, Inc., Ann Arbor, Michigan, USA

    Xincheng Zheng, Dexing Fang & Wei Wu

  6. Department of Pathology, The Ohio State University, Columbus, Ohio, USA

    Xue-Feng Bai & Jin-Qing Liu

  7. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Yang Liu

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Contributions

G.-Y.C., K.A.C., J.C., H.C., H.Y., X.Z., D.F., W.W., J.Q., S.A.W., C.H., C.C. and L.S. performed experiments, C.M.H., and S.L.K. advised on CLP model, X.-F. B. and J.-Q.L. provided transgenic mice, Y.L., P.Z. and G.-Y.C. designed the overall study. X.C. supervised synthesis of sialosides and sialo-modifications of CD24Fc, while S.K. supervised production of mutant bacteria. Y.L., P.Z. and G.-Y.C. wrote the manuscript with input from other authors.

Corresponding authors

Correspondence to Pan Zheng or Yang Liu.

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Competing interests

Y.L., P.Z., G.-Y.C., X.C. and S.K. are co-inventors of a pending patent application that has been licensed to OncoImmune, Inc., of which Y.L. and P.Z. are among the co-founders and have equity interest.

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Chen, GY., Chen, X., King, S. et al. Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction. Nat Biotechnol 29, 428–435 (2011). https://doi.org/10.1038/nbt.1846

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