R01AI182247

Role of IGE in human disease and immunity to ticks - 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 FCE 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.

Rector & Visitors Of The University Of Virginia

NOT APPLICABLE

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

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-24-254)

Amendment Since initial award the total obligations have increased 406% from $690,832 to $3,496,216.