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

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 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 beta2 integrin CD11a/CD18 (LFA-1) on the leukocyte surface. In vitro exposure to proinflammatory cytokines (i.e. interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma) 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.

A Review of Hypothesized Determinants Associated with Bighorn Sheep (Ovis canadensis) Die-Offs

“…This is similar to the shipping fever model of respiratory disease in domestic livestock. The shipping fever model views pasteurellosis as an opportunistic disease that results when endogenous Pasteurellaceae colonize the lungs of livestock compromised by different combinations of infectious agents, host and environmental determinants [23, 24, 208–210]. This model arose subsequent to the failure of single-agent experiments to provide an explanation for shipping fever.…”

Genome Sequence of a Spontaneous Nonhemolytic Mutant of Mannheimia haemolytica 16041065 GH

“…Studies have shown that several characteristics or activities of this bacterium contribute to its virulence. An exotoxin, leukotoxin, is considered the most important virulence factor associated with M. haemolytica (6). Leukotoxin is responsible for M. haemolytica hemolysis on blood agar and causes leukocyte necrosis and apoptosis in vivo , thus allowing the bacterium to escape phagocytosis and killing by neutrophils and macrophages (7, 8).…”

Genome Sequence of Mannheimia haemolytica Serotype 1 Strain 16041065 BH

“…Bacterial species include Pasteurella multocida , Mannheimia haemolytica , Histophilus somni , and Mycoplasma bovis . Studies suggest that it is the interaction of these pathogens and the failure of the animal’s immune system that produce full-blown disease (1–3). These same sources point to the possibility that bacterial pathogens cause the acute syndrome by invading the bovine respiratory tract that has been compromised by viral infections, environmental conditions, and/or other stress factors such as comingling, dehydration, and crowding during shipping (4, 5).…”