Risk factors of alpha-gal syndrome: investigating the human genetic risk factors and the tick salivary sensitizer - Project Summary Alpha-Gal Syndrome (AGS), commonly known as red meat allergy, is a tick-borne allergic condition triggered by IgE antibodies against the glycan galactose-α-1,3-galactose (αGal), which is present in red meat and other animal-derived products. Clinically, AGS is associated with delayed anaphylaxis, urticaria, and, in severe cases, life-threatening reactions to common dietary items, pharmaceuticals, and medical procedures such as xenotransplantation and transfusion. An estimated 450,000 cases were reported in the U.S. between 2017 and 2022, underscoring a growing public health concern. In the U.S., the lone star tick (Amblyomma americanum) is the main vector responsible for sensitization, though only a small percentage (1–8%) of individuals bitten by these ticks develop AGS. This disparity suggests that both tick-related and human-specific factors contribute to disease onset. Our research has identified a strong correlation between AGS and reduced activity of the enzyme α-galactosidase in humans, indicating a potential protective role of this lysosomal enzyme. Furthermore, preliminary exome-wide association study with 13 AGS samples has revealed several candidate genetic variants that may confer susceptibility. On the vector side, the team discovered considerable variation in αGal levels in the salivary glands of ticks, especially, significantly high levels of αGal in those fed on human blood. This project is structured around two central aims. Specific Aim 1 focuses on identifying human risk factors, particularly low α-galactosidase activity and genetic variations associated with AGS. The team will expand the cohort of AGS and control subjects to analyze plasma α-galactosidase activity and characterize the causal enzyme. The team will also conduct exome-wide association studies to identify risk variants. Furthermore, in order to elucidate causal mechanisms of the associated factors, genetically modified mouse models will be used to examine the mechanistic role of enzyme deficiency in AGS sensitization and elicitation. Specific Aim 2 seeks to determine tick-related risk factors by investigating the mechanisms underlying the high αGal levels in the saliva of ticks that have fed on human blood. The team will identify differentially expressed genes in salivary glands of ticks fed on human blood with high αGal levels by transcriptomic sequencing. The team will also characterize αGal-containing proteins in salivary glands, the AGS sensitizers, of ticks fed on human blood using proteomic approaches. This hypothesis-driven research directly supports long-term goals in AGS management, including improved diagnostic tools, α-galactosidase-based therapeutic strategies, and targeted prevention.
