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Principal Investigator: Mary Ann Comunale
Organization: DREXEL UNIVERSITY
Fiscal Year: 2024
Award: $187,033
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract: Lyme disease (LD) leads to lifelong health problems if standard antibiotic therapy is not initiated
during the first 2-3 weeks after infection. Diagnosis for LD currently relies on seroconversion and is unreliable
during acute disease. Cases of suspected acute LD should be confirmed using clinical diagnostic assays. N-
linked glycosylation is one of the most abundant post-translational modifications of serum proteins. While it is
dynamic in nature, it is also highly consistent in a healthy state. N-linked glycosylation of serum immunoglobulins
(Igs) are known to change in a disease specific manner and can direct the host immune response toward a pro-
or an anti-inflammatory response. We previously observed that Ig N-glycans produced during acute LD contain
specific alterations in the abidance of galactose and sialic acid. We hypothesize that these Ig alterations are
antigen-specific, and that the glycosylation patterns present will negatively impact downstream immune
responses. This hypothesis is based on our preliminary data, known LD B-cell perturbations, and reports of IgG
N-glycans altering the immune response to COVID-19, tuberculosis, multiple sclerosis, and HIV.
This proposal is novel and unique because it is the only study that examines the role of glycosylation
during the human immune response to LD. This proposal is built on our preliminary work where we identified
aberrant glycosylation on the total serum IgG and IgM in acute LD patients prior to seroconversion. In this
proposal, we examine the glycosylation of Igs specific to LD antigens and determine if acute LD infection will
alter B-cell responses to produce antigen specific Igs with the same unique glycosylation changes seen in our
preliminary data. Additionally, we examine how the glycosylation pattern on antigen specific Igs effect the
immune response to LD.
In Aim 1, we isolate Igs specific to the LD antigen VlsE and establish the IgG and IgM N-glycan profiles.
The result will determine if antigen specific Igs contain the same aberrant glycosylation found in the total Ig
population of acute LD patients. In Aim 2, we quantify the impact of LD antigen-specific IgG glycosylation on the
promotion of ADCC and complement deposition. The result will determine if there is a link between IgG
glycosylation and the inability of the patients to clear the Borrelia burgdorferi spirochete that causes LD. In Aim
3, we quantify the impact of antigen-specific IgM glycosylation on the complement deposition rate. Complement
deposition leads to rapid clearance of Lyme disease pathogens. Altered glycosylation of IgM could impair
complement deposition and impede the ability of the human host to clear the infection.
This work will establish a new mechanism of Borrelial immune evasion, characterize the host-response
to LD pathogenesis in humans. Additionally, the results will potentiate the use of Ig N-glycans to serve as
multiplexed biomarkers in a novel Lyme disease diagnostic assay and guide the glycoengineering of
antibodies for use in intravenous therapy in hard-to-treat disseminated Lyme disease cases.
Terms: <19S Gamma Globulin><7S Gamma Globulin><AIDS Virus><Ab-dependent cellular cytotoxicity><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Acute Disease><American><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibiotic Therapy><Antibiotic Treatment><Antibodies><Antibody Therapy><Antigen Binding Fragment><Antigen Variation><Antigenic Variability><Antigenic Variation><Antigens><Assay><Atrophic Arthritis><B blood cells><B burgdorferi><B burgdorferi sensu lato><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><B. burgdorferi><B. burgdorferi sensu lato><Bacterial Infections><Binding><Bioassay><Biological Assay><Biological Markers><Blood Serum><Borrelia><Borrelia burgdorferi><Borrelia burgdorferi Group><Borrelia burgdorferi sensu lato><Borrelia burgdorferi sensu stricto><Borreliella><Borreliella burgdorferi><Brain><Brain Nervous System><C1 q><C1q><COVID-19><CV-19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical><Complement><Complement 1q><Complement Activation><Complement C1q><Complement Proteins><Complex><Contracting Opportunities><Contracts><Coronavirus Infectious Disease 2019><Cytolysis><D-Galactose><Data><Deposit><Deposition><Development><Diagnostic tests><Disease><Disorder><Disseminated Sclerosis><Dysfunction><Early Diagnosis><Early treatment><Encephalon><Enzyme Gene><Enzymes><Exoglycosidases><Fab Fragments><Fab Immunoglobulins><Fab domain><Fc Receptor><Fc domain><Functional disorder><Future><Galactopyranose><Galactopyranoside><Galactose><Germinal Center><Glycans><Glycoengineering><Goals><HIV><Health><Heart><Human><Human Immunodeficiency Viruses><IGIV><IV Immunoglobulins><IVIG><IgG><IgM><Immune><Immune Evasion><Immune Globulins><Immune Targeting><Immune globulin IV><Immune response><Immune signaling><Immunes><Immunoglobulin Alterations><Immunoglobulin G><Immunoglobulin M><Immunoglobulin, F(ab) Fragment><Immunoglobulins><Immunological response><Immunology procedure><Immunomodulation><Impairment><Incidence><Incubated><Infection><Inflammation><Inflammatory><Inflammatory Response><Intracellular Communication and Signaling><Intravenous><Intravenous Antibodies><Intravenous IG><Intravenous Immune Globulin><Intravenous Immunoglobulins><Joints><Kawasaki Disease><LAV-HTLV-III><Label><Link><Lyme Borreliosis><Lyme Disease><Lyme Disease Spirochete><Lyme disease diagnosis><Lyme disease diagnostic><Lyme disease pathogenesis><Lymphadenopathy-Associated Virus><Lysis><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Masks><Measures><Mediating><Metabolic Glycosylation><Modern Man><Molecular Interaction><Mucocutaneous Lymph Node Syndrome><Multiple Sclerosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><N-Acetylneuraminic Acids><Nature><Order Spirochaetales><Organ><Patients><Pattern><Peptides><Physiopathology><Polysaccharides><Population><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Protein Modification><Receptor Protein><Reporting><Research><Rheumatoid Arthritis><Role><Sampling><Serum><Serum Proteins><Sialic Acids><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Spirochaetales><Spirochetes><Structure of germinal center of lymph node><TB infection><Testing><Tuberculosis><Virus-HIV><Work><acute disease/disorder><acute disorder><antibody based therapies><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody mediated cellular cytotoxicity><antibody receptor><antibody treatment><antibody-based therapeutics><antibody-based treatment><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-dependent cellular phagocytosis><antibody-mediated cytotoxicity><bacteria infection><bacterial disease><bacterial disease treatment><bacterial infectious disease treatment><bio-markers><biologic marker><biological signal transduction><biomarker><borrelial><clinical diagnostics><complement pathway regulation><complementation><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><developmental><diagnostic assay><disseminated TB><disseminated tuberculosis><early detection><early therapy><glycosylated IgG><glycosylated IgM><glycosylated immunoglobulin G><glycosylated immunoglobulin M><glycosylation><host response><immune evasive><immune modulation><immune regulation><immune system response><immunogen><immunologic assay><immunologic assay/test><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><in vitro Assay><infection due to Mycobacterium tuberculosis><insular sclerosis><lyme pathogenesis><lyme spirochete><medical diagnostic><neutravidin><novel><pathogen><pathophysiology><potential biological marker><potential biomarker><prevent><preventing><receptor><response><rheumatic arthritis><seroconversion><social role><sugar><tuberculosis infection><tuberculous spondyloarthropathy>