Our knowledge of pathogenesis has benefited from a better understanding of the roles of specific virulence factors in disease. To determine the role of the virulence factor ZapA, a 54-kDa metalloproteinase of Proteus mirabilis, in prostatitis, rats were infected with either wild-type (WT) P. mirabilis or its isogenic ZapA ؊ mutant KW360. The WT produced both acute and chronic prostatitis showing the typical histological progressions that are the hallmarks of these diseases. Infection with the ZapA ؊ mutant, however, resulted in reduced levels of acute prostatitis, as determined from lower levels of tissue damage, bacterial colonization, and inflammation. Further, the ZapA ؊ mutant failed to establish a chronic infection, in that bacteria were cleared from the prostate, inflammation was resolved, and tissue was seen to be healing. Clearance from the prostate was not the result of a reduced capacity of the ZapA ؊ mutant to form biofilms in vitro. These finding clearly define ZapA as an important virulence factor in both acute and chronic bacterial prostatitis.Proteus mirabilis can be an important infectious agent of the urinary tract that can lead to pyelonephritis or renal calculus, especially in those who are catheterized or who have anomalies in their urinary tract (16,24,31). ZapA, which is an extracellular metalloprotease, is one of many well-characterized virulence factors important in urinary tract infections caused by P. mirabilis (3,16,26,27). ZapA is a broad-spectrum protease which degrades a number of substrates, including immunoglobulin A (IgA) and defensins of the host's immune system (26, 27). Swarmer cell formation, which is important in the pathogenesis of this organism, results in the upregulation of many P. mirabilis virulence factors, including ZapA (1,27). This appears to be influenced by the ability of P. mirabilis to sense surfaces (4), and, not surprisingly, swarmer cell formation is also seen in biofilm formation in artificial urine (12), which may explain the link of pathogenesis to catheterization and anomalies in the urinary tract, where biofilm formation will be encouraged.Prostatitis is the leading cause for men under 50 years of age to seek treatment from a urologist. The etiology of this disease remains confusing, as bacteria are isolated from only 5 to 10% of clinical cases; however, this is believed to represent a gross underestimation of infection (18,20). Bacterial prostatitis occurs both as an acute febrile disease that as often responsive to antibiotic treatment and as a chronic infection that is too often nonresponsive to antibiotic treatment and is believed to involve bacterial biofilm formation. Bacterial prostatitis is believed to be the leading cause of recurrent urinary tract infections in men (18,20). Our lab has established models of bacterial and nonbacterial prostatitis in rats (7,13,19) and has demonstrated biofilm formation at the mucosal surface of the prostatic acini in this model (5).It has been well established that distinct virulence factors are important in bo...