Role of the pleiotropic effects of plasminogen deficiency in infection experiments with plasminogen-deficient mice

Plasminogen-deficient mice hold great promise as tools for analyzing the co ntribution of plasminogen activators produced by infectious agents to patho genesis. However, the pathology caused by congenital plasminogen deficiency complicates the interpretation of infection experiments conducted with the se animals. This pathology, the most prominent features of which are poor w eight gain, wasting after about 60 days of age, and shortened lifespan, res ults from the inability of the mice to clear small fibrin thrombi. This art icle describes strategies for distinguishing the contribution of this patho logy from the direct effects of depriving infectious agents of plasminogen. These strategies depend on the use of mouse genotypes in which the correla tion of plasminogen deficiency with fibrin-dependent pathology is broken. M ice with plasminogen activator deficiencies are unable to generate plasmin and develop pathologies identical to those seen in plasminogen-deficient mi ce. However, unlike plasminogen-deficient mice, they do make plasminogen av ailable to the infectious agent. Fibrinogen-deficient mice also deficient f or plasminogen do not develop the pathology typical of plasminogen deficien cy. These mice allow examination of plasminogen deficiency in the absence o f fibrin-dependent pathology. Use of fibrinogen-deficient mice is complicat ed by the possibility that fibrin may be the key substrate of plasmin gener ated by the infectious agent. (C) 2000 Academic Press.