Illuminating neutrophils dark microproteome against fungal pathogens

The human genome contains thousands of unannotated short open reading frame (sORF) encoded microproteins, which are potential functional peptides waiting to be discovered.

Despite the increasing body of work in identifying the microproteome in different model organisms and cell lines, only a few have been functionally studied showing diverse regulatory roles in multiple cellular pathways.

Moreover, while some studies show microproteins´ potential in innate immunity, no research has focused on neutrophils, despite being the most abundant innate immune cell in circulation, and essential against pathogen invasion such as fungi.In this proposal, I present a 4-year plan to pursue a 3-aim workflow combining computational and synthetic biology, protein and genetic engineering approaches designed to systematically uncover the microproteome in neutrophils and its functional role in the context of the antifungal response.I aim to:Comprehensively identify microproteins expressed in neutrophils upon fungal stimulation.Elucidate the functional role of microproteins differentially expressed upon fungal stimulation.Determine the molecular mechanism of specific microproteins used in the antifungal response.Understanding the role of microproteins in the neutrophil-mediated response against fungi can impact our understanding of the immune response at a fundamental level and open new avenues for therapeutic interventions in which new antifungal peptides or druggable targets could be discovered.