IFITM3-expressing Lactobacillus plantarum (HA-r-LAB) as a probiotic vector for targeted immunotherapy against TGEV

Lactiplantibacillus plantarum, recognized for its potent probiotic functionality and advanced drug delivery capability, has emerged as a versatile platform for the heterologous expression of bioactive therapeutic proteins. In this study, we genetically engineered L. plantarum to express interferon-induced transmembrane protein 3 (IFITM3), an immunomodulatory protein that exhibits extensive antiviral efficacy by predominantly obstructing viral entry. To enhance gastrointestinal resilience and systemic bioavailability, the recombinant strain was encapsulated with hyaluronic acid (HA-r-LAB) through a precise nanoencapsulation methodology, generating stable nanoparticle-like constructs. In a piglet model challenged with transmissible gastroenteritis virus (TGEV), a prototypical coronavirus, oral administration of HA-r-LAB expressing IFITM3 substantially decreased viral titres and alleviated clinical manifestations. Furthermore, biochemical analyses confirmed a direct molecular interaction between IFITM3 and the TGEV nucleocapsid (N) protein, suggesting an unprecedented antiviral mechanism. These findings underscore the potential of HA-r-LAB as a probiotic-based nanodelivery vector for antiviral proteins and lay the groundwork for the development of combinatorial therapeutic strategies targeting coronaviruses.