R01AI172112

Project Abstract

Increased total serum IgE levels are associated with coronary artery disease (CAD). However, the causal role of antigen-specific IgE in CAD remains largely unexplored. Recent work from our group and others provide evidence that humans with IgE sensitization to the mammalian oligosaccharide allergen alpha-gal have larger coronary artery plaques and unstable plaque features, signifying increased CAD compared to those without IgE to alpha-gal. Yet, whether IgE to alpha-gal directly promotes atherosclerotic plaque development and the molecular and cellular mechanisms mediating IgE sensitization to alpha-gal linked to atherosclerosis formation are unknown.

Bites from the lone star tick induce IgE sensitization to alpha-gal and a subsequent severe allergic response when the subject ingests alpha-gal-containing foods such as red meat. However, the vast majority of individuals with IgE to alpha-gal do not manifest with delayed anaphylaxis and frequently have no outward identifying symptoms. As such, they continue to consume alpha-gal-containing food products (meat, dairy, etc.) which have the capacity to continue to stimulate IgE responses and inflammation in the vessel wall.

Preliminary data provide the first evidence that humans with IgE sensitization to alpha-gal had a higher frequency of CCR6+ switched memory (SWM) B cells. Notably, consistent with the association of the IgE sensitization to alpha-gal and CAD, the amount of CCR6 on SWM B cells was associated with CAD severity. Transcriptomic analysis demonstrated that CCR6+ SWM B cells expressed higher IL-4R and STAT6 in subjects that were IgE alpha-gal+ compared to IgE alpha-gal-. Interestingly, IL-4 and STAT6 are important for B cell class switch recombination to IgE, suggesting that cells that make IL-4 may be important in IgE alpha-gal production.

Studying IgE sensitization to alpha-gal in conventional murine models of atherosclerosis is not feasible as mice, like all lower mammals but unlike humans, express the enzyme galactosyltransferase, produce alpha-gal, and do not develop an IgE response to alpha-gal. We have obtained a novel alpha-gal-/- mouse that mimics the human condition to study the role of IgE sensitization to alpha-gal in atherosclerosis. Comparing alpha-gal-/- mice to mice wildtype (WT) for alpha-gal, we show a significant induction of IgE to alpha-gal after exposure to lone star tick-derived lipids in the alpha-gal-/- but not the WT mouse. Moreover, preliminary data from mice deficient in NKT cells implicates iNKT cells in the regulation of IgE antibody production to lipids from lone star ticks.

Based on these human and murine data, the overarching objective of this proposal is to investigate whether these factors and cells play a causal role in atherosclerosis development due to IgE sensitization to alpha-gal. We will use loss and gain of function studies in murine atherosclerosis models to define novel mechanisms of alpha-gal IgE production and the impact of tick-induced alpha-gal sensitization on diet-induced atherosclerosis. We will also test a larger cohort of humans with CAD qualitatively and quantitatively by intravascular ultrasound virtual histology (IVUS-VH), allowing for more robust multivariate analysis and deeper interrogation of immune cell phenotypes that mark those at greatest risk.

Rector & Visitors Of The University Of Virginia

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Charlottesville, Virginia 229044195 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 431% from $817,754 to $4,344,077.