Haemophilus influenzae type b (Hib), a Gram-negative bacterium belonging to Pasteurellaceae, remains a significant cause of invasive bacterial disease. The virulence of Hib has been attributed to a variety of potential factors associated with its cell surface, including lipopolysaccharides and major outer membrane proteins (OMPs). A better understanding of the structure-function relationships of Hib components and of the molecular mechanisms related to its pathogenesis may provide opportunities to develop new therapeutic strategies for Hib disease prevention and treatment.P2 porin, the most abundant OMP in Hib, has been shown to possess proinflammatory activity. To characterize the role played by bacterial surface components in Hib disease onset and development, the in vitro and in vivo studies using Hib P2 porin and its most active surface-exposed loop L7 was performed.The proteomic analysis of Hib P2 and L7-exposed U937 cells provided a list of qualitative and quantitative changes with potential relevance in the host immune and inflammatory response. Based on this observation, we also explored cytokine production and adhesion molecules (ICAM-1, VCAM-1 and E-selectin) by human astroglioma cells stimulated with Hib surface components demonstrating a direct ERK1/2 and p38 pathways involvement. These putative virulence-related functions for Hib P2 porin and L7 has been confirmed analyzing the in vivo effect of the synthetic peptide L7 on the coagulative/fibrinolytic cascade and the circulating markers of endothelial injury; the results indicate that L7 plays an essential role in pathophysiological events observed during Gram-negative infection.Finally, we report a novel use of the complementary peptide approach to design a specific antagonist of loop L7 that is able to bind selectively to the protein P2, thereby reducing its activity.Our findings may be of interest in understanding the specific intermolecular interactions between pathogens bacteria and their eukaryotic hosts, which underlie life-threatening disease, such as septic shock.