Tick Intrastadial Feeding and Its Role on IgE Production in the Murine Model of Alpha-gal Syndrome: The Tick “Transmission” Hypothesis

Abstract

Recent studies have provided strong evidence indicating that lone star tick bites are a cause of AGS (alpha-gal syndrome, also known as red meat allergy RMA) in humans. AGS is characterized by an increase in IgE antibody production against galactose-alpha-1,3-galactose (aGal), which is a common glycan found in mammalian tissue, except in Old World monkeys and humans. The main causative factor of AGS, the lone star tick (Amblyomma americanum), is broadly distributed throughout the east and midwest of the United States and is a vector of a wide range of human and animal pathogens. Our earlier glycomics study of the salivary glands of partially fed male and female ticks revealed relatively high levels of aGal epitopes. In this study, we found that partially fed males of A. americanum on bovine blood, which engage in multiple intrastadial feedings, carry a large amount of aGal in the salivary glands. In our current work, we aimed to test whether ticks mediate the transmission of the aGal sensitizer acquired from nonhuman blood to humans in the intrastadial host switch (referred to as the “transmission” hypothesis). To test this hypothesis, we used an alpha-galactosyltransferase knockout mutant mouse (aGT-KO) model system infested with ticks that were unfed or partially fed on bovine blood. Based on the levels of total IgE and specific IgG and IgE antibodies against aGal after tick feedings, aGT-KO mice significantly responded to tick feeding and injection of aGal (Galα1-3Galβ1-4GlcNAc) conjugated to human serum albumin or mouse serum albumin (aGal-HSA or aGal-MSA) by increasing total IgE and aGal-specific IgE levels compared to those in C57BL/6 control mice. All of the treatments of aGT-KO mice involving the feeding of partially fed and unfed ticks functioned as sensitizers that increased the levels of specific IgE against aGal, with large individual variations. The data in this study do not support the “transmission” component of AGS, although they confirmed that aGT-KO mice can be used as a model for RMA studies.

High levels of alpha-gal with large variation in the salivary glands of lone star ticks fed on human blood

“…This study also supports the previous study rejecting the aGal transmission hypothesis in AGS where the source of aGal in tick saliva was hypothesized from prior feeding on non-human mammalian hosts 14 . In our previous study using the mouse model with tick infestation, we observed that aGal levels in the mouse-fed ticks were low (Fig.…”

“…In our previous study using the mouse model with tick infestation, we observed that aGal levels in the mouse-fed ticks were low (Fig. S1 ) (see Supplementary Information) with highly varying levels of mouse antibodies specific to aGal 14 . While the alpha-1,3-galactosyltransferase orthologue gene has not been detected in ticks 23 , earlier research has indicated the potential involvement of other tick galactosyltransferases in the decoration of saliva with aGal.…”

“…A growing number of cases in the Southeast and Midwest regions of the United States, which overlap with the endemic areas of the lone star tick, have been reported 3 , 12 . This was demonstrated in the alpha-galactosyltransferase knockout mouse model system (αGT-KO) lacking aGal 13 , 14 . While this condition has been associated to tick bites from different species worldwide, including Ixodes spp.…”

The Meat of the Matter: Understanding and Managing Alpha-Gal Syndrome

“… 96 Meat from these animals is also believed to be safe for individuals with AGS to consume ( https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-intentional-genomic-alteration-line-domestic-pigs-both-human-food , accessed 11 April 2022). However, pre-clinical trials examining the safety of this meat using currently available animal models of alpha-gal syndrome 21 , 28 , 97 and clinical trials of this meat in human subjects need to be conducted.…”

“…fda.gov/news-events/press-announcements/fda-approves-first-its-kind-intentional-genomic-alteration-line-domestic-pigsboth-human-food, accessed 11 April 2022). However, pre-clinical trials examining the safety of this meat using currently available animal models of alpha-gal syndrome 21,28,97 and clinical trials of this meat in human subjects need to be conducted. Alpha-gal sensitization has also been linked to coronary artery disease (CAD) with increased atherosclerotic burden and plaque instability.…”