Progress in producing improved vaccines against bacterial diseases of cattle is limited by an incomplete understanding of the pathogenesis of these agents. Our group has been involved in investigations of two members of the family Pasteurellaceae, Mannheimia haemolytica and Haemophilus somnus, which illustrate some of the complexities that must be confronted. Susceptibility to M. haemolytica is greatly increased during active viral respiratory infection, resulting in rapid onset of a severe and even lethal pleuropneumonia. Despite years of investigation, understanding of the mechanisms underlying this viral–bacterial synergism is incomplete. We have investigated the hypothesis that active viral infection increases the susceptibility of bovine leukocytes to the M. haemolytica leukotoxin by increasing the expression of or activating the β2 integrin CD11a/CD18 (LFA-1) on the leukocyte surface. In vitro exposure to proinflammatory cytokines (i.e. interleukin-1β, tumor necrosis factor-α and interferon-γ) increases LFA-1 expression on bovine leukocytes, which in turn correlates with increased binding and responsiveness to the leukotoxin. Alveolar macrophages and peripheral blood leukocytes from cattle with active bovine herpesvirus-1 (BVH-1) infection are more susceptible to the lethal effects of the leukotoxin ex vivo than leukocytes from uninfected cattle. Likewise, in vitro incubation of bovine leukocytes with bovine herpesvirus 1 (BHV-1) potentiates LFA-1 expression and makes the cells more responsive to leukotoxin. A striking characteristic of H. somnus infection is its propensity to cause vasculitis. We have shown that H. somnus and its lipo-oligosaccharide (LOS) trigger caspase activation and apoptosis in bovine endothelial cells in vitro. This effect is associated with the production of reactive oxygen and nitrogen intermediates, and is amplified in the presence of platelets. The adverse effects of H. somnus LOS are mediated in part by activation of endothelial cell purinergic receptors such as P2X7. Further dissection of the pathways that lead to endothelial cell damage in response to H. somnus might help in the development of new preventive or therapeutic regimens. A more thorough understanding of M. haemolytica and H. somnus virulence factors and their interactions with the host might identify new targets for prevention of bovine respiratory disease.

Haemophilus somnus (‘Histophilus somni’) is a Gram-negative bacterium and opportunistic pathogen associated with multisystemic diseases of bovines. Some strains of H. somnus are relatively avirulent, but are biochemically and antigenically similar to the virulent strains. Several virulence factors have been identified in H. somnus, of which lipo-oligosaccharide phase variation, induction of apoptosis, intraphagocytic survival and immunoglobulin Fc binding proteins have been well studied. The sequencing of the genomes of two strains of H. somnus has facilitated the identification of genes responsible for distinctive attributes within this species and related bacteria. The genetic characterization of this bacterium will enhance our understanding of H. somnus virulence factors and facilitate the development of new and improved vaccines. This review presents an overview of H. somnus virulence factors, their role in resistance to host defenses and pathogenesis, and the host immune response to this bacterium. Current areas of investigation in the post-genomic era and recent insights into new pathogenic mechanisms are also discussed.