Complexities of the pathogenesis ofMannheimia haemolyticaandHaemophilus somnusinfections: challenges and potential opportunities for prevention?

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Abstract
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 haemolyticaandHaemophilus somnus, which illustrate some of the complexities that must be confronted. Susceptibility toM. haemolyticais 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 theM. haemolyticaleukotoxin by increasing the expression of or activating the β2integrin CD11a/CD18 (LFA-1) on the leukocyte surface.In vitroexposure 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 leukotoxinex vivothan leukocytes from uninfected cattle. Likewise,in vitroincubation of bovine leukocytes with bovine herpesvirus 1 (BHV-1) potentiates LFA-1 expression and makes the cells more responsive to leukotoxin. A striking characteristic ofH. somnusinfection is its propensity to cause vasculitis. We have shown thatH. somnusand its lipo-oligosaccharide (LOS) trigger caspase activation and apoptosis in bovine endothelial cellsin 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 ofH. somnusLOS 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 toH. somnusmight help in the development of new preventive or therapeutic regimens. A more thorough understanding ofM. haemolyticaandH. somnusvirulence factors and their interactions with the host might identify new targets for prevention of bovine respiratory disease.

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