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Non-typeable Haemophilus influenzae (NTHi) is an emerging respiratory pathogen that causes a significant disease burden worldwide, yet an effective vaccine is still lacking. The focus of this thesis is to elucidate the critical molecular interactions governing NTHi pathogenesis and host immunity. We identified Elongation Factor Tu (EF-Tu) as a surface-exposed protein on NTHi, demonstrating its immunogenicity and potential as a vaccine candidate by showing that anti-EF-Tu antibodies mediate bacterial killing and provide protection in preclinical models. Concurrently, we uncovered a novel role for the innate receptor Dectin-1 in defence against bacterial pneumonia – a finding supported by human genetic associations and mouse infection studies and identifying bacterial EF-Tu as its conserved ligand. Complementing these findings, we identified Outer Membrane Protein P5 (OMP P5) as the key NTHi factor mediating recruitment of the human complement inhibitor C4BP, establishing a crucial mechanism for NTHi immune evasion and serum resistance. This research advances our understanding of specific bacterial molecules (EF-Tu, P5) and host pathways (Dectin-1) central to NTHi infection, and possibly important for future vaccines and therapeutics against this pathogen.