Mice lacking CCL3 have a reduced inflammatory response to influenza virus and are resistant to coxsackievirus-induced myocarditis. Although these chemokines can play positive roles in resolving acute inflammation, they are increasingly recognized as detrimental for chronic inflammation, and therapeutic inhibitors of MIP1inflammatory chemokines are being developed to treat diseases associated with chronic inflammation. The increased expression of these chemokines in kidneys infected with WT C. albicans, therefore, could play a role in the strong inflammatory responses we observed. In the absence of Dur1,2p activity, inflammation and expression of CCL3 and, more reproducibly, CCL4 was markedly decreased. Altered expression of MIP1 chemokines was recently associated with virulence in a different C. albicans mutant. Both chemokines showed decreased circulating levels in mice infected with C. albicans lacking HMX1, and their expression was regulated by the immunosuppressive carbon monoxide produced by Hmx1p. Decreased kidney expression of CCL3 and CCL4 was also noted in mice infected with a pmr1D mutant of C. albicans with decreased virulence. Determining how Dur1,2p expression increases CCL3 and CCL4 expression in infected kidneys, therefore, is an important topic for future research. Given the importance of the kidney for concentrating and excreting urea, we propose that urea metabolism to ammonia and CO2 by Dur1,2p plays a role in the persistence of C. albicans in this organ. CO2 is known to inhibit macrophage clearance of C. albicans, and so may limit the efficacy of the macrophages recruited into infected kidneys. NH3 has been considered as a virulence factor for C. albicans, and its importance for virulence is well established for Helicobacter pylori. NH3 produced by this bacterial pathogen via urease plays a critical role in controlling local pH and facilitating invasion through the gastric mucosa. A second enzymatic pathway that produces NH3 by deamidation of asparagine or glutamine is also essential for colonization of the stomach environment by H. pylori. NH3 plays an additional role in virulence of H. pylori by enhancing host cell apoptosis through its modulation of endocytic vesicle trafficking. Furthermore, NH3 is increasingly recognized as an important signaling molecule in cellular responses to LOUREIRIN-B stress. In the context of inflammation, elevated NH3 levels inhibit neutrophil chemotaxis, phagocytosis, and degranulation while also stimulating spontaneous oxidative bursts. NH3 also inhibited the capacity of neutrophils to engulf bacteria. Notably, the latter study implicated the p38 pathway in this neutrophil dysfunction, and we observed differential expression 4 MAP kinases that are direct or indirect activators of p38. Therefore, NH3 production by Dur1,2p may mediate some of the changes in host gene expression and neutrophil recruitment between mice infected with WT and the dur1,2 mutant. Our results are also compatible with the specific requirement of DUR1,2 for germ tube formation in the macrophage and evidence that that urea metabolism via Dur1,2p provides ammonia for external alkalinization of the C. albicans environment, thus permitting germ tube formation and escape from the phagolysosome. Despite its Albaspidin-AA defect in hyphal-dependent escape from macrophages, the dur1,2 mutant can make hyphae except when driven exclusively by arginine in macrophages or in response to urea in vitro. This selective defect in hyphal differentiation may contribute to the lower abundance 
of filaments in kidneys infected with the mutant strain at 3 and 5 days PI. Taken together, our present and previous results strongly indicate that expression of Dur1,2p enhances kidney neutrophil infiltration but limits phagocytic clearance of C. albicans.