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The old name of this Gram-negative opportunistic pathogen of cattle, sheep and other ruminants is Pasteurella haemolytica. This pathogen produces a variety of virulence factor thought to play an important role during the pathogenesis of bovine pneumonic pasteurellosis.
Mannheimia haemolytica leukotoxin abbr. Lkt) is a secreted cytolytic toxin encoded by an operon with a complex mosaic structure (Davies et al, 2002). The genes are homologous to the Escherichia coli hemolysin locus (hlyCABD).
The toxin specifically lyses bovine leukocytes. Low affinity binding that does not result in lysis has been demonstrated also for equine, porcine, canine lymphocytes, and human lymphoid Raji cells (Sun et al, 1999). Leukocytes from cattle, sheep and goats are susceptible to leukotoxin -induced lysis. Neutrophils obtained from three white-tailed deer, four Saiga antelope, a Grant's gazelle and a Sable antelope are also susceptible to the lytic effects of P. haemolytica leukotoxin (Confer et al, 1990). Susceptible cells undergo cell death by apoptosis (Sun et al, 1999; Wang et al, 1998). Sun et al (2000) have reported that low concentrations of the toxin induce cell death by apoptosis whereas high concentrations induce oncosis in bovine lymphocytes. Apoptosis of bovine lymphocytes and monocytes correlates with the expression of p53 and myc, which are activated by the leukotoxin (Marcatili et al, 2002).
Czuprynski et al (1991) and Maheswaran et al (1992) have reported that the toxin causes cell activation of neutrophils and stimulates the release of granule constituents and an respiratory burst.
Hughes et al (1994) have reported that the leukotoxin induces a marked downregulation of MHC class 2 expression on bovine monocytes, which is not observed when the cells are preactivated by IFN-gamma. Adusu et al (1994) have reported that the leukotoxin induces histamine release from bovine pulmonary mast cells.
Nyarko et al (1998) have reported that the toxin enhances platelet aggregation. This is observed also in vivo (Cheryk et al, 1998). Clinkenbeard and Upton (1991) have characterized a platelet lytic factor that causes rapid lysis of isolated bovine platelets. This activity behaves like the leukotoxin and is neutralized with an antileukotoxin rabbit serum.
Czuprynski and Ortiz-Carranza (1992) have reported that Pasteurella haemolytica leukotoxin inhibits mitogen-induced bovine peripheral blood mononuclear cell proliferation in vitro. Majury and Shewen (1991) have reported that the toxin inhibits proliferation induced by Con A or pokeweed mitogen of human and dog lymphocytes. At high doses, proliferation of pig lymphocytes stimulated with Con A is reduced also. These effects are not observed with rabbit lymphocytes.
The toxin binds to bovine integrin-beta-2 CD18 which, together with CD11a, forms the lymphocyte function-associated antigen 1, LFA-1 (CD11a) (Deshpande et al, 2002; Jeyaseelan et al, 2000). The toxin itself, and also IL1-beta, TNF-alpha, and IFN-gamma have been shown to increase expression of LFA-1 (CD11a) on bovine peripheral blood neutrophils. This enhances binding of the toxin and cytotoxicity and may be one mechanism to amplify the lung inflammation that characterizes bovine pasteurellosis (Leite et al, 2002, 2003).
Hsuan et al (1999) have reported that the toxin induces NF-kappa-B activation and calcium ion elevation in bovine alveolar macrophages but not in bovine pulmonary artery endothelial cells and porcine alveolar macrophages. Chelation of calcium ions blocks NF-kappa-B activation and IL1-beta, TNF-alpha, and IL8 mRNA expression. The tyrosine kinase inhibitor herbimycin A blocks expression of all three cytokine genes in bovine alveolar macrophages stimulated with the toxin. Yoo et al (1995) have reported that subcytolytic concentrations of the toxin induce TNF-alpha and IL1-beta gene expression and secretion of these cytokines in bovine alveolar macrophages.
For other examples of microbial or parasitic gene products interfering with host cell functions see also: Modulins. For virus-encoded proteins with immunomodulatory/immune evasion activities and/or functions of cytokines or cytokine receptors see also the Virulence Factors Dictionary section of this encyclopedia.
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ENTRY LAST MODIFIED: September 2003
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