title: Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-SiglecG interaction.
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.
authors.affiliation: Division of Immunotherapy, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Guo-Yun
authors.initials: GY
authors.lastname: Chen
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Samantha
authors.initials: S
authors.lastname: King
authors.forename: Karen A
authors.initials: KA
authors.lastname: Cavassani
authors.forename: Jiansong
authors.initials: J
authors.lastname: Cheng
authors.forename: Xincheng
authors.initials: X
authors.lastname: Zheng
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Cao
authors.forename: Hai
authors.initials: H
authors.lastname: Yu
authors.forename: Jingyao
authors.initials: J
authors.lastname: Qu
authors.forename: Dexing
authors.initials: D
authors.lastname: Fang
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Bai
authors.forename: Jin-Qing
authors.initials: JQ
authors.lastname: Liu
authors.forename: Shireen A
authors.initials: SA
authors.lastname: Woodiga
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005434:Flow Cytometry; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000032:analysis; D037102:Lectins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000097:blood; D054730:Protein Interaction Domains and Motifs; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D013296:Streptococcus pneumoniae / Q000201:enzymology / Q000472:pathogenicity; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D051927:CD24 Antigen; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D037102:Lectins; D011947:Receptors, Antigen, B-Cell; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C522403:Siglecg protein, mouse; D014409:Tumor Necrosis Factor-alpha; D009439:Neuraminidase