The molecular mechanism of Siglec-E in bacterial clearance

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Principal Investigator: Guoyun  Chen
Organization: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
Fiscal Year: 2024
Award: $462,000
Funding agency: National Institute of Allergy and Infectious Diseases

Sepsis is a systemic inflammatory response syndrome initiated by infection. Most cases of septic shock are
caused by Gram-negative bacteria, including Escherichia coli (E. coli), which remains one of the most common
pathogens leading to sepsis. Understanding the mechanisms by which the mammalian immune system
differentially responds to infection by Gram-negative and Gram-positive bacteria will place us in a better
position to treat or prevent sepsis. Members of the sialic acid-binding immunoglobulin-like lectin family
(Siglecs) are cell surface receptors that negatively regulate the response to infection by binding or taking up
sialylated pathogens; however, most pathogens are not sialylated. We previously published a study in which
we used nonsialylated bacteria to show that Siglec-E knockout (SiglecE-/-) mice exhibited higher mortality than
wild-type (WT) mice following infection by Gram-negative but not Gram-positive bacteria. Better survival in WT
mice depended on more efficient clearance of Gram-negative than Gram-positive bacteria. Moreover, infection
with Gram-negative E. coli strains 25922 and DH5α induced the expression of Siglec-E, which promoted
production of reactive oxygen species (ROS). In contrast, infection with Gram-positive bacteria Staphylococcus
aureus or Listeria monocytogenes reduced expression of Siglec-E, which inhibited production of ROS. Based
on these findings, we designed this project to: 1) Elucidate the molecular mechanisms of Siglec-E in bacterial
clearance; 2) Dissect the molecular mechanisms underlying differential regulation of innate immune response
during infection with Gram-positive and Gram-negative bacteria by controlling Siglec-E; 3) Evaluate Siglec-E
as a therapeutic target for the treatment of bacterial sepsis by using CLP. These studies will not only reveal the
molecular mechanisms of the novel role of Siglec-E in bacterial clearance but also provide novel approaches
toward treatment of bacterial induced-sepsis.

Terms: <Abbreviations><Active Oxygen><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Bacteremia><Bacteria><Bacterial Infections><Binding><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><CLP model><CLP mouse model><COVID-19><CV-19><Cause of Death><Cecal ligation perforation><Cell Surface Receptors><Cessation of life><Clinical><Coronavirus Infectious Disease 2019><Death><Death Rate><Development><E coli><E. coli><Elderberry><Escherichia coli><Exhibits><Family><Fluorescence><Gram-Negative Bacteria><Gram-Positive Bacteria><Hospital Admission><Hospitalization><Human><IP injection><ITIM><Immune><Immune Globulins><Immune Precipitation><Immune response><Immune system><Immunes><Immunoglobulins><Immunological response><Immunoprecipitation><Immunoreceptor Tyrosine-Based Inhibitory Motif><Incidence><Infection><Innate Immune Response><Intraperitoneal Injections><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><L monocytogenes><L. monocytogenes><Lectin><Lectin Receptors><Link><Lipopolysaccharides><Listeria monocytogenes><Maackia amurensis><Marrow Neutrophil><Mediating><Mice><Mice Mammals><Miscellaneous Antibiotic><Modern Man><Molecular><Molecular Interaction><Murine><Mus><N-Acetylneuraminic Acids><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Null Mouse><Ortholog><Orthologous Gene><Oxygen Radicals><Patients><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Position><Positioning Attribute><Predisposition><Pro-Oxidants><Production><Publishing><Reactive Inhibition><Reactive Oxygen Species><Regulation><Reporting><Role><S aureus><S. aureus><Sambucus><Sambucus nigra><Sepsis><Septic Shock><Sialic Acids><Site><Staph aureus><Staphylococcus aureus><Susceptibility><Systemic Inflammatory Response Syndrome><TLR protein><Testing><Toll-Like Receptor Family Gene><Toll-like receptors><Tyrosine><United States><Wild Type Mouse><anti-microbial><antimicrobial><bacteraemia><bacteria infection><bacterial disease><bacterial sepsis><blood infection><bloodstream infection><cecal ligation and perforation><cecal ligation and puncture><cecal ligation puncture><cecum ligation and puncture><cecum ligation puncture><clinical relevance><clinically relevant><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><design><designing><developmental><effective therapy><effective treatment><extracellular><host response><immune system response><immunoresponse><lipo-teichoic acid><lipoteichoic acid><member><migration><model of animal><mortality><mortality rate><mortality ratio><mouse model><murine model><neutrophil><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pathogen><prevent><preventing><response><sialic acid binding Ig-like lectin><sialylation><siglec><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><wildtype mouse>