title: Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor.
abstract: The endocytic Ashwell-Morell receptor (AMR) of hepatocytes detects pathogen remodeling of host glycoproteins by neuraminidase in the bloodstream and mitigates the lethal coagulopathy of sepsis. We have investigated the mechanism of host protection by the AMR during the onset of sepsis and in response to the desialylation of blood glycoproteins by the NanA neuraminidase of Streptococcus pneumoniae. We find that the AMR selects among potential glycoprotein ligands unmasked by microbial neuraminidase activity in pneumococcal sepsis to eliminate from blood circulation host factors that contribute to coagulation and thrombosis. This protection is attributable in large part to the rapid induction of a moderate thrombocytopenia by the AMR. We further show that neuraminidase activity in the blood can be manipulated to induce the clearance of AMR ligands including platelets, thereby preactivating a protective response in pneumococcal sepsis that moderates the severity of disseminated intravascular coagulation and enables host survival.
authors.affiliation: Center for Nanomedicine, University of California, Santa Barbara, CA 93106.
authors.forename: Prabhjit K
authors.initials: PK
authors.lastname: Grewal
authors.forename: Peter V
authors.initials: PV
authors.lastname: Aziz
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uchiyama
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Rubio
authors.forename: Ricardo D
authors.initials: RD
authors.lastname: Lardone
authors.forename: Dzung
authors.initials: D
authors.lastname: Le
authors.forename: Nissi M
authors.initials: NM
authors.lastname: Varki
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Jamey D
authors.initials: JD
authors.lastname: Marth
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000276:immunology* / Q000378:metabolism; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009439:Neuraminidase / Q000008:administration & dosage / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013296:Streptococcus pneumoniae / Q000276:immunology*
chemical_list: D037263:Asialoglycoprotein Receptor; D009439:Neuraminidase