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.Pathogens in the host bloodstream often induce a hyperactive coagulation cascade that can progress to disseminated intravascular coagulation with severe thrombosis, organ failure, and death (1–3). With current limited understanding of pathogen–host interactions, sepsis remains a debilitating and deadly syndrome with few treatment options (4, 5). An unexpected protective host response that reduces coagulopathy during sepsis caused by Streptococcus pneumoniae (SPN) was recently discovered in studies of the endocytic Ashwell-Morell receptor (AMR) (6, 7). Host protection by the AMR is linked to the hydrolysis of sialic acids from blood glycoproteins by the neuraminidase A (NanA) of SPN. Sialic acids are posttranslational glycan modifications often attached to underlying galactose on many cell surface and secreted glycoproteins (8, 9).Neuraminidases (aka sialidases) produced by microbial pathogens hydrolyze sialic acids on glycoproteins to establish infection and facilitate host colonization (10). For example, NanA remodels mucosal cell surface glycoproteins to promote bacterial colonization of the upper respiratory tract (11, 12) and contributes to pulmonary inflammation along with the development of SPN pneumonia (13, 14). However, the host has adapted to counteract the pathological effects of this SPN virulence factor by the clearance from blood circulation of host factors bearing AMR ligands that have been unmasked by NanA desialylation.In this study we have identified multiple blood components that are removed from circulation by the AMR and have determined which of these are primarily responsible for diminishing the lethal coagulopathy of SPN sepsis. We have further used this information to develop and assess a prophylactic approach that preactivates AMR function in the early phases of sepsis to reduce the severity and lethality of the ensuing coagulopathy.