Dataset Information

Tick salivary gland extract induces alpha-gal syndrome in alpha-gal deficient mice.

ABSTRACT:

Introduction

Alpha-gal syndrome (AGS) is characterized by delayed hypersensitivity to non-primate mammalian meat in people having specific immunoglobulin E (sIgE) to the oligosaccharide galactose-alpha-1,3-galactose. AGS has been linked to tick bites from Amblyomma americanum (Aa) in the U.S. A small animal model of meat allergy is needed to study the mechanism of alpha-gal sensitization, the effector phase leading to delayed allergic responses and potential therapeutics to treat AGS.

Methods

Eight- to ten-weeks old mice with a targeted inactivation of alpha-1,3-galactosyltransferase (AGKO) were injected intradermally with 50 μg of Aa tick salivary gland extract (TSGE) on days 0, 7, 21, 28, 42, and 49. Total IgE and alpha-gal sIgE were quantitated on Day 56 by enzyme-linked immunosorbent assay. Mice were challenged orally with 400 mg of cooked pork kidney homogenate or pork fat. Reaction severity was assessed by measuring a drop in core body temperature and scoring allergic signs.

Results

Compared to control animals, mice treated with TSGE had 190-fold higher total IgE on Day 56 (0.60 ± 0.12 ng/ml vs. 113.2 ± 24.77 ng/ml; p < 0.001). Alpha-gal sIgE was also produced in AGKO mice following TSGE sensitization (undetected vs. 158.4 ± 72.43 pg/ml). Further, sensitized mice displayed moderate clinical allergic signs along with a drop in core body temperature of ≥2°C as an objective measure of a systemic allergic reaction. Interestingly, female mice had higher total IgE responses to TSGE treatment but male mice had larger declines in mean body temperature.

Conclusion

TSGE-sensitized AGKO mice generate sIgE to alpha-gal and demonstrate characteristic allergic responses to pork fat and pork kidney. In keeping with the AGS responses documented in humans, mice reacted more rapidly to organ meat than to high fat pork challenge. This mouse model establishes the central role of tick bites in the development of AGS and provides a small animal model to mechanistically study mammalian meat allergy.

SUBMITTER: Choudhary SK

PROVIDER: S-EPMC8342229 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This study provides a multi-omics approach to determine the effect on the transcriptome and proteome gut profiles of zebrafish inoculated with tick saliva followed by mammalian meat consumption. With bioinformatics analysis using the R software, we sought for significant biological and metabolic pathway changes, in order to fill up some of the current knowledge gaps associated with the alpha-Gal syndrome (AGS). In addition, ortholog mapping allowed to obtain highly concordant biological 1:1 human ortholog genes for the detection of gene-disease associations (GDAs) and disease enriched pathways. Further data validation was performed using reverse transcriptase quantitative PCR (RT-qPCR) and Western Blot (WB) analysis on target differentially expressed genes (DEGs) and differentially represented proteins (DRPs), respectively. We found that treatment with tick saliva increased mortality and caused significant higher incidence of hemorrhagic type allergic reactions, changes in behavior and feeding patterns. Transcriptomics analysis showed downregulation of biological and metabolic pathways correlated with anti-Gal IgE and allergic reactions to tick saliva such as blood circulation, cardiac and vascular smooth muscle contraction, behavior and sensory perception. Disease enrichment analysis revealed that downregulated orthologous genes were mostly associated with human disorders affecting the nervous, musculoskeletal, and cardiovascular systems. Proteomics analysis predominantly revealed suppression of biological and metabolic pathways associated with the immune system production of reactive oxygen species (ROS) and cardiac muscle contraction. The underrepresented proteins were mainly linked to nervous and nutritional/metabolic human disorders. Furthermore, 12 DEGs were found to have concomitant protein-level representation. Lastly, the integration of transcriptomics and proteomics layers through multi-omics pathway enrichment revealed inhibition of pathways associated with adrenergic signaling in cardiomyocytes, as well as heart and muscle contraction. This research contributed to the discovery of AGS-related biological pathways, reinforcing disease multisystemic organ involvement and linking α-Gal sensitization with other illnesses. Furthermore, our results shed light on novel bioinformatic strategies for the identification of key genes and proteins that may serve as potential disease biomarkers.