Ovis aries CR4 is involved in Mannheimia haemolytica leukotoxin-induced cytotoxicity.

Pneumonia caused by Mannheimia haemolytica is an important disease of domestic sheep (DS, Ovis aries) and cattle (BO). M. haemolytica is a normal commensal of the upper respiratory tract in ruminants, but during stress and viral infection it breaches the host innate mucosal defense and descents into lungs causing fibrinous pleuropneumonia. Leukotoxin (Lkt) produced by M. haemolytica is cytolytic to all subsets of ruminant leukocytes. Earlier, we and others have shown that DS and BO LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) can mediate Lkt-induced cytolysis. It is not clear whether CR4 (CD11c/CD18), which is involved in chemotaxis, phagocytosis and regulates host immune response can also mediate Lkt-induced cytolysis in ruminants. The host innate immune response to M. haemolytica is poorly understood and the involvement of CR4 in M. haemolytica pathogenesis is one of the most understudied. This problem is further compounded by the lack of cd11c genes from any ruminant species. Therefore, the objectives of this study were to clone cd11c and determine whether CR4 can serve as a receptor for Lkt. In this direction we cloned two alleles of cd11c gene from leukocytes isolated from DS blood by RT-PCR. Transfectants developed expressing functional DS CR4 were found to be cytotoxic to Lkt from four different isolates of M. haemolytica. This is the first report confirming the ability of a recombinant ovine CR4 to bind to M. haemolytica Lkt and mediate concentration-dependent lysis of host cells, thus, confirming their role in M. haemolytica pathogenesis. This is a critical step in understanding host innate immunity and the management of pneumonia in sheep.