C-type lectin receptors and their implication in the innate response against respiratory pathogens

Respiratory pathogens are known for giving rise to periodic pandemic outbreaks. The innate immune system senses these pathogens via different receptors, among which, the C-type lectin receptors recognize specific pathogen-associated carbohydrates. Previous studies have demonstrated that one of these receptors, SIGN-R1, has exquisite pathogen-recognition capacities, detecting not only viruses, but also bacteria and fungi. In addition, SIGN-R1 plays a crucial role in the activation of the initial inflammatory response, which is instrumental in the pathogenesis of these diseases.Therefore, the main goal of this project is to study how the C-type lectin-mediated inflammatory response initiated against the respiratory pathogens influenza, Streptococcus pneumoniae (Objective 1) and SARS- CoV-2 (Objective 2), affect the outcome of the disease. In addition, we will investigate new approaches aimed at using C-type lectins as therapeutic targets (Objective 3). Amongst them, we will develop SIGN- R1 chimeric molecules, such as SIGN-R1-C3d or SIGN-R1-Fc, intended to opsonize the pathogen and direct it towards a specific type of immune cells. Moreover, we will design and evaluate different therapies intended to promote or inhibit the SIGN-R1-mediated inflammatory response in the course of an infection or during vaccination. Finally, we will also develop nanocarriers specifically targeted towards SIGN-R1- expressing cells.In the last five years, our group has published a series of papers characterizing the innate response to respiratory pathogens. During these studies we have developed a unique toolbox of in vivo and in vitro microscopy techniques, including intravital 2-photon microscopy, as well as other immunology and microbiology-based methods that will be used in this project. Additionally, we will take advantage of our network of international experts in pharmacology and molecular biology to design the new compounds with a potential therapeutic use against influenza, S. pneumoniae and SARS-CoV-2. The successful completion of this project will provide significant benefits to the fields of vaccinology and infectious diseases, especially regarding the modification of the inflammatory and humoral responses against a specific antigen as well as the neutralization of the pathogen. Moreover, our results will be valuable to understand the role of the early inflammatory process in the immune cell-pathogen dynamics in other major respiratory diseases.