Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

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.Fil: Grewal, Prabhjit K.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados UnidosFil: Aziz, Peter V.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados UnidosFil: Uchiyama, Satoshi. University of California at San Diego; Estados UnidosFil: Rubio, Gabriel R.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados UnidosFil: Lardone, Ricardo Dante. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Le, Dzung. University of California at San Diego; Estados UnidosFil: Varki, Nissi M.. University of California at San Diego; Estados UnidosFil: Nizet, Victor. University of California at San Diego; Estados UnidosFil: Marth, Jamey D.. University of California; Estados Unidos. Sanford-burnham Medical Research Institute; Estados Unido

Normally occurring human Anti-GM1immunoglobulin M antibodies and the Immune response to bacteria

Fil: Alaniz, María E. Universidad Nacional de Córdoba. Departamento de Química Biológica Dr. Ranwel Caputto; Argentina.Fil: Lardone, Ricardo D. Universidad Nacional de Córdoba. Departamento de Química Biológica Dr. Ranwel Caputto; Argentina.Fil: Yudowski, Silvia L. Hospital Infantil Municipal. Servicio de Bacteriología; Argentina.Fil: Farace, María Isabel. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio Bacteriología Sanitaria; Argentina.Fil: Nores, Gustavo A. Universidad Nacional de Córdoba. Departamento de Química Biológica Dr. Ranwel Caputto; Argentina.Anti-GM1 antibodies of the immunoglobulin M (IgM) isotype are normal components of the antibody repertoire of adult human serum. Using a sensitive high-performance thin-layer chromatography (HPTLC) immunostaining assay, we found that these antibodies were absent in the umbilical vein and children <1 month of age but could be detected after 1 month of age. Although most of the children older than 6 months of age were positive, there were still a few negative children. The appearance of anti-GM1 IgM antibodies showed a perfect concordance with two well-characterized antibacterial antibodies, anti-Forssman and anti-blood group A, which indicates a similar origin. We also studied IgM reactivity with lipopolysaccharides (LPSs) from gram-negative bacteria isolated from stool samples from healthy babies and from Escherichia coli HB101 in serum from individuals of different ages. We found a positive reaction with both LPSs in all the children more than 1 month of age analyzed, even in those that were negative for anti-GM1 antibodies. Anti-GM1 IgM antibodies were purified from adult serum by affinity chromatography and tested for the ability to bind LPSs from different bacteria. This highly specific preparation showed reactivity only with LPS from a strain of Campylobacter jejuni isolated from a patient with diarrhea. We conclude that normally occurring IgM antibodies are generated after birth, probably during the immune defense against specific bacterial strains

Normally occurring human Anti-GM1immunoglobulin M antibodies and the Immune response to bacteria

Fil: Alaniz, María E. Universidad Nacional de Córdoba. Departamento de Química Biológica Dr. Ranwel Caputto; Argentina.Fil: Lardone, Ricardo D. Universidad Nacional de Córdoba. Departamento de Química Biológica Dr. Ranwel Caputto; Argentina.Fil: Yudowski, Silvia L. Hospital Infantil Municipal. Servicio de Bacteriología; Argentina.Fil: Farace, María Isabel. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio Bacteriología Sanitaria; Argentina.Fil: Nores, Gustavo A. Universidad Nacional de Córdoba. Departamento de Química Biológica Dr. Ranwel Caputto; Argentina.Anti-GM1 antibodies of the immunoglobulin M (IgM) isotype are normal components of the antibody repertoire of adult human serum. Using a sensitive high-performance thin-layer chromatography (HPTLC) immunostaining assay, we found that these antibodies were absent in the umbilical vein and children <1 month of age but could be detected after 1 month of age. Although most of the children older than 6 months of age were positive, there were still a few negative children. The appearance of anti-GM1 IgM antibodies showed a perfect concordance with two well-characterized antibacterial antibodies, anti-Forssman and anti-blood group A, which indicates a similar origin. We also studied IgM reactivity with lipopolysaccharides (LPSs) from gram-negative bacteria isolated from stool samples from healthy babies and from Escherichia coli HB101 in serum from individuals of different ages. We found a positive reaction with both LPSs in all the children more than 1 month of age analyzed, even in those that were negative for anti-GM1 antibodies. Anti-GM1 IgM antibodies were purified from adult serum by affinity chromatography and tested for the ability to bind LPSs from different bacteria. This highly specific preparation showed reactivity only with LPS from a strain of Campylobacter jejuni isolated from a patient with diarrhea. We conclude that normally occurring IgM antibodies are generated after birth, probably during the immune defense against specific bacterial strains

Normally Occurring Human Anti-GM(1) Immunoglobulin M Antibodies and the Immune Response to Bacteria

Anti-GM(1) antibodies of the immunoglobulin M (IgM) isotype are normal components of the antibody repertoire of adult human serum. Using a sensitive high-performance thin-layer chromatography (HPTLC) immunostaining assay, we found that these antibodies were absent in the umbilical vein and children <1 month of age but could be detected after 1 month of age. Although most of the children older than 6 months of age were positive, there were still a few negative children. The appearance of anti-GM(1) IgM antibodies showed a perfect concordance with two well-characterized antibacterial antibodies, anti-Forssman and anti-blood group A, which indicates a similar origin. We also studied IgM reactivity with lipopolysaccharides (LPSs) from gram-negative bacteria isolated from stool samples from healthy babies and from Escherichia coli HB101 in serum from individuals of different ages. We found a positive reaction with both LPSs in all the children more than 1 month of age analyzed, even in those that were negative for anti-GM(1) antibodies. Anti-GM(1) IgM antibodies were purified from adult serum by affinity chromatography and tested for the ability to bind LPSs from different bacteria. This highly specific preparation showed reactivity only with LPS from a strain of Campylobacter jejuni isolated from a patient with diarrhea. We conclude that normally occurring IgM antibodies are generated after birth, probably during the immune defense against specific bacterial strains