Metastatic infection after hematogenous dissemination of Candida species is presumably dependent on the fungus traversing the vascular endothelium. An in vitro model of the earliest events of metastatic Candida infection was developed with whole vascular strips. Freshly obtained porcine blood vessels were secured in a perforated Lucite template that allowed the application of yeasts directly to the endothelial surface. Multiple wells allowed experimental and control observations on the same vascular segments. Adherence to endothelium was greatest with Candida albicans and Candida tropicalis, less with Candida krulsei, and least with Candida parapsilosis, Candida pseudotropicalis, and Torullopsis glabrata. This hierarchy of adherence parallels that in other in vitro systems employing mucosal epithelial. cells or fibrin-platelet matrixes and reflects the known virulence of the respective species and their potential for hematogenous dissemination. C. albicans and C. tropicalis yeasts that adhered were capable of directly traversing the endothelial surface before the production of germ tubes. Heat or Formalin-killed yeasts and viridans group streptococci, although adherent, were incapable of vascular penetration, a process presumably attributable to enzymatic digestion of host tissue. Loss of integrity of penetrated endothelial tissue was verified by loss of dye exclusion, lactic dehydrogenase release, and ultramicroscopic changes. These two steps, adherence and penetration, provide direct insight into the earliest events in hematogenous Candida species dissemination and suggest that C. albicans and C. tropicalis yeasts are capable of initiating tissue invasion before germ tubes have had the opportunity to form and participate in the invasive process.
The fungus, Coccidioides immitis, differs from other dimorphic pathogens in that its parasitic stage is a complex morphogenic cycle, raising the question that changes and composition during morphogenesis might influence host responses. As a prelude to examining the interaction of fungal morphogenesis and host responses, the life cycle of this fungus has been examined in greater detail than previously accomplished. During saprobic development, alternating enterothallic arthroconidia are formed as infectious propagules. The outer wall is broken and loosely adherent. Under in vitro conditions supporting the parasitic cycle, multinucleate arthroconidia transform into uninucleate round cells. Rapid, synchronous, nuclear replication is initiated, accompanied by increase in cell mass and deposition of new cell wall substance. As karyokinesis ceases, morphologic differentiation begins with invagination of the inner layers of the spherule wall and then is progressive, eventually segmenting the protoplasm into uninucleate endospores grouped in clusters within a hyaline membrane. Endospores, escaping through a break in the spherule wall, are held in aggregates by fibrils which are stretched and broken as endospores separate. It would seem that rapid production of hundreds of progeny from an original single cell, protected during development by an enclosing spherule wall and then released in clusters, should favor establishment of the fungus in a host, and dynamic changes in the cell wall during morphogenesis should influence the host response.
The adherence of Candida albicans yeasts to human umbilical vein endothelium to subendothelial extracellular matrix (ECM) was investigated. Yeasts added to confluent endothelium in citrated platelet-poor plasma adhered on the average of 1 colony forming unit (cfu) per culture well. When platelets were added as platelet-rich plasma, a significant increase of yeast adherence was not seen. However, when endothelium was contracted by treatment with 2 mM EDTA, resulting in exposure of ECM, yeast adherence was increased to 10 cfu/well. When platelets were added with these yeasts, the number of adhering yeasts was further increased to 23 cfu/well (P less than .01). This represented an increase in adherence of yeasts of 230%. When the endothelial cells were completely removed and ECM exposed, platelets were found to likewise augment yeast adherence. Platelets, when added to the ECM, formed aggregates to which the yeasts firmly adhered. Likewise, when platelets were aggregated by adenosine diphosphate and mixed with yeasts, yeasts were shown to bind avidly to aggregated platelets, whereas yeasts did not adhere to unactivated, discoid platelets. Thus, exposed subendothelial ECM induces the aggregation of platelets and yeasts bind avidly to these platelet aggregates.
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