title: beta(2) integrin Mac-1 is a receptor for Mannheimia haemolytica leukotoxin on bovine and ovine leukocytes.
abstract: Pneumonia caused by Mannheimia haemolytica is an important disease of cattle (BO), domestic sheep (DS, Ovis aries) and bighorn sheep (BHS, Ovis canadensis). Leukotoxin (Lkt) produced by M. haemolytica is cytolytic to all leukocyte subsets of these three species. Although it is certain that CD18, the beta subunit of beta(2) integrins, mediates Lkt-induced cytolysis of leukocytes, whether CD18 of all three beta(2) integrins, LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18) and CR4 (CD11c/CD18), mediates Lkt-induced cytolysis of BO, DS and BHS leukocytes remains a controversy. Based on antibody inhibition experiments, earlier studies suggested that LFA-1, but not Mac-1 and CR-4, serves as a receptor for M. haemolytica Lkt. PMNs express all three beta(2) integrins, and they are the leukocyte subset that is most susceptible to Lkt. Therefore we hypothesized that all three beta(2) integrins serve as the receptor for Lkt. The objective of this study was to determine whether Mac-1 of BO, DS and BHS serves as a receptor for Lkt. cDNAs for CD11b of BO, DS and BHS were transfected into a Lkt-non-susceptible cell line along with cDNAs for CD18 of BO, DS and BHS, respectively. Transfectants stably expressing BO, DS or BHS Mac-1 specifically bound Lkt. These transfectants were lysed by Lkt in a concentration-dependent manner. Increase in intracellular [Ca(2+)](i) was observed in transfectants following exposure to low concentrations of Lkt indicating signal transduction through secondary messengers. Collectively, these results indicate that Mac-1 from these three species serves as a receptor for M. haemolytica Lkt.
authors.affiliation: Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040, USA.
authors.forename: Paulraj K
authors.initials: PK
authors.lastname: Lawrence
authors.forename: Whitney R
authors.initials: WR
authors.lastname: Nelson
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.forename: Donald P
authors.initials: DP
authors.lastname: Knowles
authors.forename: William J
authors.initials: WJ
authors.lastname: Foreyt
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Srikumaran
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D004351:Drug Resistance; D005098:Exotoxins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000502:physiology*; D016978:Mannheimia haemolytica / Q000378:metabolism*; D011485:Protein Binding; D012756:Sheep; D014162:Transfection
chemical_list: D000900:Anti-Bacterial Agents; D005098:Exotoxins; D016177:Macrophage-1 Antigen; C018579:leukotoxin; D002118:Calcium