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Principal Investigator: Scott Alan Smith
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $763,421
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
There is a growing body of evidence that the allergic immune response is directed toward ectoparasites,
like it is helminths (endoparasites), possibly playing a central role in the phenomenon known as acquired
tick resistance. We hypothesize that human immunity naturally develops following recurrent tick bites,
involves IgE antibodies that target tick salivary proteins, and can result in either IgE-mediated disease
(alpha-gal syndrome) and/or protection from subsequent bites. At the center of the IgE-mediated immune
response is the IgE antibody molecule. In sensitized individuals, re-exposure to the offending antigen
results in IgE engagement, causing Fcε receptor cross-linking and activation of mast cells and basophils.
This triggers the release of mediators into the local tissue, resulting in the mass influx of basophils and
eosinophils. A novel way to study allergic immunity is to use naturally occurring human IgE monoclonal
antibodies (mAbs), isolated from allergic or parasite exposed subjects. We have established a method to
grow, identify and immortalize ultra-rare IgE encoding memory B cells by making human hybridomas
from the peripheral blood of allergic and parasitized individuals. Using our technology, we will generate
IgE mAbs from human subjects with alpha-gal syndrome and/or have received numerous recurrent tick
bites in Aim 1. We believe that IgE expressing B cell clones targeting tick salivary antigens are present
and can be captured from human subjects exposed to tick bites as part of their natural defense against
parasites. Already our preliminary data shows this to be the case, humans exposed to tick bites develop
IgE antibodies to tick salivary antigens. We will in Aim 2 identify, express, and validate the specific tick
salivary protein targeted by each tick-specific human IgE antibody through immunoprecipitation and
proteomics analyses using partially fed tick salivary extracts. We believe that alpha-gal is a very small
fraction of the antigens that the human IgE antibody response is targeting when one is bitten repeatably
by ticks and exposed to their salivary proteins. We will use these human mAbs and their tick salivary
antigens in Aim 3 to characterize the role IgE plays in immunity to tick bites using murine models of
passive systemic anaphylaxis and active tick feeding challenges. Analyses of the bite wound infiltrates
and rates of tick feeding success will allow for careful direct measures of the IgE-mediated immune
response between experimental and control animals. To begin studies to understand human immunity to
ticks, we first must define the dominant immune targets that could allow for interruption of tick feeding
and perhaps pathogen transmission. This work will have tremendous implications in studies of
pathogenesis and immunity of tickborne diseases, such as establishing correlates of protection against tick
feeding in humans, and indirectly, the transmission of infectious pathogens and disease.
Terms: <A americanum><A. americanum><Adaptive Immune System><Allergic><Allergic Disease><Allergic Reaction><Allergy><Ambylomma americanum><Amines><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Animal Experiments><Antibodies><Antibody Response><Antigen Presentation><Antigen Targeting><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Basophilic Granulocyte><Basophils><Binding><Binding Determinants><Biological Markers><Bite><Black-legged Tick><Blood Basophil><Blood Eosinophil><Blood Serum><Body Tissues><Cell Body><Cells><Clinical Treatment Moab><Clone Cells><Control Animal><Coupling><Data><Deer Tick><Development><Diagnostic><Disease><Disorder><E coli><E. coli><ELISA><Effector Cell><Enzyme-Linked Immunosorbent Assay><Eosinophilic Granulocyte><Eosinophilic Leukocyte><Epitopes><Escherichia coli><Evaluation><Exposure to><Farm Animal><Foundations><Generations><Glycans><Glycoproteins><Helminths><Histologic><Histologically><History><Hu-mABs><Human><Hybridomas><Hypersensitivity><I scapularis><I. scapularis><IRB><IRBs><IgE><Immobilization><Immune><Immune Precipitation><Immune Targeting><Immune response><Immunes><Immunity><Immunoblotting><Immunochemical Immunologic><Immunoglobulin E><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunoprecipitation><Individual><Infection><Infiltration><Innate Immunity><Institutional Review Boards><Interruption><Ix scalpularis><Ix. scapularis><Ixodes dammini><Ixodes scapularis><Ixodida><Livestock><Lone Star tick><Marrow Eosinophil><Marrow Mast Cell><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Measures><Meat Hypersensitivity><Mediating><Mediator><Memory B Cell><Memory B-Lymphocyte><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Outcome><PBMC><Parasites><Parasitic Worms><Pathogenesis><Pathologic><Peripheral Blood Mononuclear Cell><Persons><Play><Polysaccharides><Proteins><Proteomics><Reaction><Receptor Protein><Recombinants><Recording of previous events><Recurrence><Recurrent><Research Subjects><Resistance><Role><Salivary><Salivary Gland Proteins><Salivary Proteins><Serum><Site><Specificity><Techniques><Technology><Testing><Therapeutic Uses><Tick-Borne Diseases><Ticks><Time><Tissue Basophils><Tissues><Transmission><Vaccination><Western Blotting><Western Immunoblotting><Work><acquired immune system><allergic to meat><allergy to meat><alpha-gal allergic><alpha-gal allergy><alpha-gal syndrome><amine><animal experiment><arm><bio-markers><biologic marker><biomarker><blacklegged tick><cohort><crosslink><developmental><enzyme linked immunoassay><eosinophil><experiment><experimental animal><experimental animals><experimental research><experimental study><experiments><exposed human population><feeding><histories><host response><humAbs><human disease><human exposure><human mAbs><human monoclonal antibodies><human monoclonals><human subject><immune system response><immunogen><immunoresponse><in vivo><insight><mAbs><mast cell><mastocyte><meat allergy><memory encoding><monoclonal Abs><mouse model><murine model><novel><orthopedic freezing><pathogen><peripheral blood><protein blotting><receptor><recruit><resistant><social role><success><superparamagnetic><superparamagnetism><tick bite><tick blood feeding><tick blood meal><tick bloodmeal><tick fed><tick feeding><tick imbibes><tick mediated transmission><tick saliva><tick transmission><tick transmitted><tick-borne illness><tick-borne pathogen><tickborne disease><tickborne illness><tickborne pathogen><tissue wound><tool><transmission process><wound><wounding><wounds><α-gal allergic><α-gal allergy><α-gal syndrome>