Predicting cross reactivity between the fire ant venom allergen Sol i 3 and the antigen 5 from vespid venoms based on molecular modeling computing

The fire ant Solenopsis invicta is an aggressive invasive species whose venom frequently triggers hypersensitivity reactions, including severe anaphylaxis. In endemic regions, its stings represent a significant cause of Hymenoptera-related allergy. Four venom allergens have been identified – phospholipase A1 (Sol i 1), antigen 2 (Sol i 2), antigen 3 (Sol i 3), and antigen 4 (Sol i 4) – with Sol i 3 recognized as the predominant sensitizer. However, the molecular determinants that drive Sol i 3 allergenicity and its potential cross-reactivity with other Hymenoptera venoms remain insufficiently understood. This study identified the linear immunoglobulin E (IgE) epitopes of Sol i 3 and examined their recognition by sera from yellow jacket venom (YJV) – and Polistes wasp–allergic patients. Two linear epitopes were mapped: Sol i 3_e1 (ELRQRVASGKEMRG) and Sol i 3_e2 (WAKTTKIGCGRIMF). Although Sol i 3 exhibits limited sequence and structural similarity to other antigen 5 proteins, it contains a conserved immunoreactive core (WAKTTK), analogous to the WAKTKE motif described for the allergen Poly p 5 from Polybia paulista. This conserved region may represent a shared epitope contributing to cross-reactivity among Hymenoptera venoms. Consistently, sera from P. dominula–sensitized patients and YJV-sensitized patients recognized Sol i 3_e2. These findings define key B-cell epitopes of Sol i 3 and reveal a conserved motif that may underlie cross-reactivity, offering implications for improved diagnosis and immunotherapy.