Amelioration of Sepsis by Inhibiting Sialidase-mediated Disruption of the CD24-SiglecG Interaction

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2011 Apr 12

PMID 21478876

Citations 113

Authors

Guo-Yun Chen

Xi Chen

Samantha King

Karen A Cavassani

Jiansong Cheng

Xincheng Zheng

Hongzhi Cao

Hai Yu

Jingyao Qu

Dexing Fang

Wei Wu

Xue-Feng Bai

Jin-Qing Liu

Shireen A Woodiga

Chong Chen

Lei Sun

Cory M Hogaboam

Steven L Kunkel

Pan Zheng

Yang Liu

Affiliations

Soon will be listed here.

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 [corrected] 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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References

Dombrovskiy V, Martin A, Sunderram J, Paz H . Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007; 35(5):1244-50. DOI: 10.1097/01.CCM.0000261890.41311.E9. View

Blixt O, Collins B, van den Nieuwenhof I, Crocker P, Paulson J . Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein. J Biol Chem. 2003; 278(33):31007-19. DOI: 10.1074/jbc.M304331200. View

Yu H, Huang S, Chokhawala H, Sun M, Zheng H, Chen X . Highly efficient chemoenzymatic synthesis of naturally occurring and non-natural alpha-2,6-linked sialosides: a P. damsela alpha-2,6-sialyltransferase with extremely flexible donor-substrate specificity. Angew Chem Int Ed Engl. 2006; 45(24):3938-44. PMC: 2728590. DOI: 10.1002/anie.200600572. View

Liu Y, Chen G, Zheng P . CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns. Trends Immunol. 2009; 30(12):557-61. PMC: 2788100. DOI: 10.1016/j.it.2009.09.006. View

Hoffmann A, Kerr S, Jellusova J, Zhang J, Weisel F, Wellmann U . Siglec-G is a B1 cell-inhibitory receptor that controls expansion and calcium signaling of the B1 cell population. Nat Immunol. 2007; 8(7):695-704. DOI: 10.1038/ni1480. View

Rittirsch D, Flierl M, Ward P . Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 2008; 8(10):776-87. PMC: 2786961. DOI: 10.1038/nri2402. View

Carlin A, Uchiyama S, Chang Y, Lewis A, Nizet V, Varki A . Molecular mimicry of host sialylated glycans allows a bacterial pathogen to engage neutrophil Siglec-9 and dampen the innate immune response. Blood. 2009; 113(14):3333-6. PMC: 2665898. DOI: 10.1182/blood-2008-11-187302. View

Brocker T, Riedinger M, Karjalainen K . Driving gene expression specifically in dendritic cells. Adv Exp Med Biol. 1997; 417:55-7. DOI: 10.1007/978-1-4757-9966-8_9. View

Janeway C . Immunogenicity signals 1,2,3 ... and 0. Immunol Today. 1989; 10(9):283-6. DOI: 10.1016/0167-5699(89)90081-9. View

10.

Lemaitre B, Nicolas E, Michaut L, Reichhart J, Hoffmann J . The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996; 86(6):973-83. DOI: 10.1016/s0092-8674(00)80172-5. View

11.

Chen G, Tang J, Zheng P, Liu Y . CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science. 2009; 323(5922):1722-5. PMC: 2765686. DOI: 10.1126/science.1168988. View

12.

Medzhitov R, Preston-Hurlburt P, Janeway Jr C . A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997; 388(6640):394-7. DOI: 10.1038/41131. View

13.

Peck-Palmer O, Unsinger J, Chang K, Davis C, McDunn J, Hotchkiss R . Deletion of MyD88 markedly attenuates sepsis-induced T and B lymphocyte apoptosis but worsens survival. J Leukoc Biol. 2008; 83(4):1009-18. DOI: 10.1189/jlb.0807528. View

14.

Lee L, Howe C . Pneumococcal neuraminidase. J Bacteriol. 1966; 91(4):1418-26. PMC: 316058. DOI: 10.1128/jb.91.4.1418-1426.1966. View

15.

Hornung V, Bauernfeind F, Halle A, Samstad E, Kono H, Rock K . Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008; 9(8):847-56. PMC: 2834784. DOI: 10.1038/ni.1631. View

16.

Tracey K, Fong Y, Hesse D, Manogue K, Lee A, Kuo G . Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987; 330(6149):662-4. DOI: 10.1038/330662a0. View

17.

Favre D, Lederer S, Kanwar B, Ma Z, Proll S, Kasakow Z . Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog. 2009; 5(2):e1000295. PMC: 2635016. DOI: 10.1371/journal.ppat.1000295. View

18.

Rittirsch D, Hoesel L, Ward P . The disconnect between animal models of sepsis and human sepsis. J Leukoc Biol. 2006; 81(1):137-43. DOI: 10.1189/jlb.0806542. View

19.

Chen M, Wang Y, Wang Y, Huang L, Sandoval H, Liu Y . Dendritic cell apoptosis in the maintenance of immune tolerance. Science. 2006; 311(5764):1160-4. DOI: 10.1126/science.1122545. View

20.

Tettelin H, Nelson K, Paulsen I, Eisen J, Read T, Peterson S . Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science. 2001; 293(5529):498-506. DOI: 10.1126/science.1061217. View