|Knowles, Donald - Don|
Submitted to: Veterinary Immunology and Immunopathology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/21/2007
Publication Date: 4/15/2008
Citation: Lawrence, P.K., Nelson, W.R., Liu, W., Knowles Jr, D.P., Foreyt, W.J., Srikumaran, S. 2008. Beta(2) integrin Mac-1 is a receptor for Mannheimia haemolytica leukotoxin on bovine and ovine leukocytes. Veterinary Immunology and Immunopathology. 122(3-4):285-294. Interpretive Summary: Pneumonia is a population limiting disease in big horn sheep. One cause of this population limiting pneumonia in big horn sheep is Mannheimia haemolytica. One of the parts of the M. haemolytica bacterium that is important in the disease process is the leukotoxin (Lkt) which causes lysis of immune response cells. This study identified a molecule on the immune cells (Mac-1) which serves as a receptor (binds to) leukotoxin. Identification of the molecules involved the disease process will provide for novel methods to control and/or treat disease causing bacteria such as M. haemolytica.
Technical 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 b subunit of b2 integrins, mediates Lkt-induced cytolysis of leukocytes, whether CD18 of all three b2 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 b2 integrins, and they are the leukocyte subset that is most susceptible to Lkt. Therefore we hypothesized that all three b2 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 [Ca2+]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.