RESISTANCE TO PLATELET MICROBICIDAL PROTEIN RESULTS IN INCREASED SEVERITY OF EXPERIMENTAL CANDIDA-ALBICANS ENDOCARDITIS

Thrombin-induced platelet microbicidal protein (tPMP) exerts potent in vitro microbicidal activity against pathogens commonly found in the b loodstream, including Staphylococcus aureus, Staphylococcus epidermidi s, and Candida albicans, Localized platelet release of tPMP may be imp ortant in defense against infections involving the vascular endotheliu m caused by tPMP-susceptible organisms, In contrast, pathogens capable of surviving in the presence of tPMP could then exploit the platelet as an adhesive surface for attachment to damaged endothelium, To exami ne these hypotheses, we derived a tPMP-resistant (tPMP(r)) C. albicans strain from its tPMP-sensitive (tPMP(s)) parental strain ATCC 36082 b y serial passage in tPMP (5 mu g/ml), The tPMP(r) and tPMP(s) strains were equivalent in vitro as assessed by genotyping (electrophoretic ka ryotype and restriction endonuclease analysis of genomic DNA), biotypi ng, germination, platelet aggregation, adherence to vascular endotheli al cells, and growth characteristics. In addition, the tPMP(r) phenoty pe was stable following multiple in vitro and in vivo passages, We the n investigated the in vivo relevance of tPMP susceptibility on endovas cular infection using a rabbit model of endocarditis and hematogenous dissemination, Rabbits with transaortic catheters (n = 15 in each grou p) were challenged with either the tPMP(s) or tPMP(r) C. albicans stra in, All rabbits developed C. albicans-induced endocarditis, as determi ned by the presence of infected vegetations, In rabbits challenged wit h the tPMP(r) C. albicans strain, significantly higher mean vegetation fungal densities occurred than in animals challenged with the tPMP(s) strain (P < 0.001), These results were seen in the absence of differe nces in either initial adherence of strains to cardiac valves or veget ation weights, Furthermore, although these C. albicans strains induced equivalent rates and extent of hematogenous renal infection, only the tPMP(r) strain disseminated hematogenously to the spleen (15 of 15 ra bbits) versus 0 of 15 [tPMP(s) strain]; P < 0.0001), Thus, tPMP(r) C. albicans caused more-severe endocarditis and produced greater metastat ic sequelae than the tPMP(s) counterpart.