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Principal Investigator: Geoffrey Mueller
Organization: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Fiscal Year: 2023
Award: $753,852
Funding agency: National Institute of Environmental Health Sciences
I. Origins of Allergic Disease
Nothing to report this year.
II. Characterization of Allergens
The NMR Structure of the vicillin buried peptide (VBP) domains of Ana o 1 and Pis v 3 were determined. The NMR structure showed 4 of the cysteine residues are disulfide bonded and hold together two parallel alpha helices. IgE binding was mapped to common regions on the peanut VBP and walnut VBP. The results indicate that cysteine residues known to confer high structural stability to allergens may also coincide with areas of increased IgE binding frequency and intensity in Ara h 1 VBP. The leader sequence contain multiple immunodominant epitopes and may be important in cross-reactivity and nut allergy. At NIEHS we continue to characterize more leader sequence allergens from hazlenut, sesame, and macadamia nuts to better understand patient cross-reactivity.
A common general question about allergens is whether or not there are common properties. The cockroach allergen Bla g 1 is known to bind hydrophobic ligands, but why the protein is an important allergen is unknown. We investigated a homolog of Bla g 1 from mosquitos called AZ1. This protein is upregulated in mosquitos following a blood feed, and is upregulated in response to viral infections. We have discovered that AZ1 can facilitate red blood cell lysis, and blocks infections of flaviviruses and corona viruses related to the COVID-19 virus. The common mechanism of action is a lipid exchange, whereby AZ1 loaded with fatty acids will strip a PC molecule from either a red blood cell, or an enveloped virus and deliver the fatty acid, destabilizing the target membrane. This has important implications as a possible broad spectrum anti-viral agent. During this review period we examined the ability of AZ1 to deliver non-natural anti-viral ligands to prevent infection of SAR-COV-2. In returning to the question of Bla g 1 related allergy, lung surfactant also contains a high concentration of PC. Therefore we propose in the future to investigate if the lipid exchange properties of Bla g 1, facilitate lung damage that encourages allergic disease, or asthma exacerbations.
III. Adaptive Immune response
The defining characteristic of allergy is the generation of IgE antibodies, which leads to patient symptoms. We wish to probe more fundamental properties of the antibody response. It is suggested that by better understanding and characterizing the antibodies of all types new treatment modalities, or safer therapies can be developed.
Previously, we determined the first structure of the major peanut allergen Ara h 2. Ara h 2 is recognized by more than 90% of peanut allergic patients and sensitivity to Ara h 2 is measurable risk factor for peanut induced anaphylaxis. We have initiated a collaboration with researchers at Harvard University who have been studying the antibody production of peanut allergic patients in response to oral immunotherapy. By isolating B-cells from the patients and sequencing immunoglobulin genes, they found evidence that separate patients were honing in on similar regions of Ara h 2. We have received antibody clones and determined structures of antibody fragments in complex with Ara h 2. The epitope information derived from these complexes will be useful in understanding the targets of the adaptive immune response of patients during peanut immunotherapy. We have discovered that certain epitopes appear important for patients that have durable efficacy after immunotherapy. These results suggest certain biomarkers of successful peanut oral immunotherapy. The results also suggest ways to develop a hypoallergen of Ara h 2 that may have improved safety in immunotherapy.
Directly examining human IgE in complex an allergen is technically challenging for a number of reasons. First of all, the memory cells that make IgE are extremely rare in sera. Scott Smith at Vanderbilt University has recently developed a technique to clone these rare cells and produce full length human IgE. We have acquired human monoclonal IgE antibodies against the VBP allergens mentioned above. In the past year we have been measuring the interactions of the human IgE with Can f 1 and Fel d 7 via NMR technologies. The results will help us better understand the human immune response to allergens like Der p 2 with a hope using the information to design hypo-allergens that will improve allergy immunotherapy, better known as allergy-shots.
This project involves research on human coronavirus, novel coronavirus, COVID-19, Severe Acute Respiratory Syndrome coronavirus disease, SARS coronavirus, SARS-coronavirus-2, SARS-cov-2, SARS-cov2, SARS-related coronavirus 2, Severe acute respiratory syndrome coronavirus 2, SARS-Associated Coronavirus, SARS-cov, or SARS-Related Coronavirus.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Ab response><Allergen Immunotherapy><Allergens><Allergic><Allergic Disease><Allergy><Allergy Shot><Allergy immunotherapy><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Antibodies><Antibody Formation><Antibody Fragments><Antibody Production><Antibody Response><Antigenic Determinants><Antiviral Agents><Antiviral Drugs><Antivirals><Area><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Biological Markers><Bla g 1><Blood><Blood Reticuloendothelial System><Blood erythrocyte><COVID-19><COVID-19 virus><COVID19><COVID19 virus><CV-19><CV19><Cell Body><Cells><Characteristics><CoV emergence><CoV-2><CoV2><Collaborations><Complex><Coronaviridae><Coronavirus><Culicidae><Cysteine><Cytolysis><Der p 2><Der p 2 allergen><Der p II><Der p II allergen><Dermatophagoides pteronyssinus antigen p 2><Diagnosis><Environmental Health><Environmental Health Science><Epitopes><Erythrocytes><Erythrocytic><Exposure to><Fatty Acids><Flavivirus Infections><Frequencies><Future><GeneHomolog><Generations><Goals><HCoV><Half-Cystine><Health><Homolog><Homologous Gene><Homologue><Hu-mABs><Human><Hydrophobicity><Hypersensitivity><Ig Genes><IgE><Immune mediated therapy><Immune response><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><Immunoglobulin E><Immunoglobulin Fragments><Immunoglobulin Genes><Immunological response><Immunologically Directed Therapy><Immunotherapy><Infection prevention><Investigators><Juglans><L-Cysteine><Length><Ligands><Lipids><Lung Surfactant><Lung damage><Lysis><Macadamia><Maps><Marrow erythrocyte><Measurable><Measures><Membrane><Memory><Modality><Modern Man><Molecular><Molecular Interaction><Mosquitoes><Motivation><NIEHS><National Institute of Environmental Health Sciences><Nut Allergy><Nut Hypersensitivity><Nuts><Patients><Peptide Domain><Peptides><Prevent infection><Property><Protein Domains><Proteins><Pulmonary Surfactants><Red Blood Cells><Red Cell><Reporting><Research><Research Personnel><Researchers><Risk Factors><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV disease><SARS-CoV-1><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Sesame><Sesame - dietary><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Source><Structure><Symptoms><Techniques><Technology><Tertiary Protein Structure><Tree Nut Allergy><Tree Nut Hypersensitivity><Universities><Viral><Viral Diseases><Virus><Virus Diseases><Walnut><Wuhan coronavirus><adaptive immune response><allergen Bla g 1><allergen response><allergic response><allergic to nuts><allergy response><allergy to nuts><alpha helix><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antibody biosynthesis><antiviral compound><antiviral medication><antiviral therapeutic><asthma attack><asthma exacerbation><bio-markers><biologic marker><biomarker><blood corpuscles><cockroach allergen><corona virus><corona virus disease 2019><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><cross reactivity><design><designing><disulfide bond><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><exacerbation in asthma><exacerbation prone asthma><exacerbation prone asthmatic><exposed human population><hCoV19><host response><humAbs><human CoV><human corona virus><human coronavirus><human exposure><human mAbs><human monoclonal antibodies><human monoclonals><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoglobulin biosynthesis><immunoresponse><improved><interest><lung injury><membrane structure><mite allergen Der p 2><mite group 2 allergen Der p 2><molecular diagnostics><nCoV><nCoV2><new CoV><new corona virus><new coronavirus><novel CoV><novel corona virus><novel coronavirus><oral immunotherapy><patient response><patient specific response><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><response><responsive patient><severe acute respiratory syndrome-CoV><viral infection><virus infection><virus-induced disease><α-helix>