Klebsiella Autotransporter Repertoire in Microbial virulence and Antigenicity

Objective

Multidrug-resistant Klebsiella pneumoniae represents a major global health challenge causing severe infections like pneumonia and over 600 000 deaths per year. The World Health Organization has designated this pathogen as a critical priority due to limited medical options, underscoring the need for innovative preventive strategies. While capsular polysaccharides and lipopolysaccharides have been the primary vaccine targets, their variability poses limitation for vaccine development. Autotransporters (ATs) are conserved surface-exposed virulence factors with strong potential as vaccine antigens. ATs are central to adhesion, tissue colonization, and immune evasion, functioning through interactions with host receptors, complement factors and modulation of immune signalling pathways. While their value as vaccine antigens is supported in other Gram-negative pathogens, their role in K. pneumoniae infection remains unexplored. This project applies innovative structure-guided genomics and proteomics approaches, to define the repertoire of K. pneumoniae ATs and assess their contributions to virulence and immunogenicity. I will characterize their structure and function and evaluate the effect on neutrophils, macrophages and epithelial cells, including lung organoids as a physiologically relevant ex vivo system, to investigate their role in adhesion, invasion, phagolysosome escape, complement resistance and immune modulation. These studies will also establish assays to measure antibody-mediated impairment of AT function, informing rational vaccine design. My expertise in bacterial pathogenesis and ability to design and implement complex experimental strategies, combined with the outstanding experience of Prof. Pizza, uniquely position us to lead this innovative investigation. This fellowship represents a pivotal opportunity to advance my career as an independent researcher and to spearhead the conceptualization of effective vaccines to fight multidrug-resistant K. pneumoniae.