Exploring the induction of trained immunity by anti-infective antibodies delivered directly to the respiratory tract, as a protective response against respiratory infection

Therapeutic antibodies (Abs), have become crucial drugs in modern medicine, showing success in treating various diseases, including the global COVID-19 pandemic. Although anti-infective Abs are usually administered parenterally, recent findings demonstrated that local administration into the respiratory tract of an Ab neutralizing Pseudomonas aeruginosa (Pa) not only blocks primary infection but also offers prolonged protection against secondary infections. However, the molecular mechanisms supporting the immunomodulatory features of the Ab and establishment of long-lasting protection remain unknown. Preliminary data from the host laboratory indicate that murine macrophages primed with Ab+Pa immune complexes (ICs) display an antimicrobial pro-inflammatory phenotype, further enhanced after exposure to Toll-like receptor ligands, suggesting the induction of immune memory. This capacity termed trained immunity (TI) depicts a type of immune memory within innate immune cells that recall previous epigenetically-encoded information under heterologous stimulation. Using a combination of molecular, metabolic, and epigenetic approaches in conjunction with omics-based techniques, TI-LAB (Trained immunity Induced in the Lungs by therapeutic AntiBodies) will define the capacity of ICs to induce TI. Furthermore, TI-LAB will provide a detailed analysis of the intracellular signaling pathways involved in IC-mediated TI. Finally, the protective effects of IC-mediated TI will be assessed using an in vivo model of respiratory infection. This proof of concept will be extended to other respiratory pathogens to determine if TI induced by ICs is a conserved mechanism across pathogens. Overall, our findings will reveal a new function of anti-infective Abs in immune memory and reprogramming of the innate immune system, which should help design new treatments against respiratory pathogens.