Cutaneous cryptococcosis in athymic and beige-athymic mice

Abstract

The dermotropism of Cryptococcus neoformans SLHA in congenitally athymic (nu/nu) and doubly immunodeficient beige-athymic (bg/bg-nulnu) mice is described. Both bg/bg-nulnu and nulnu mice developed cutaneous cryptococcosis within 7 to 12 days following intravenous challenge with 104 encapsulated yeast cells. Macroscopically, cutaneous lesions appeared as small subcutaneous nodules without ulceration. Cryptococcal skin lesions were observed primarily on the flank of nu/nu mice, whereas skin lesions in bg/bg-nulnu mice were distributed over the trunk, abdomen, and face. While bg/bg-nulnu mice had four times as many macroscopic skin lesions as nulnu mice on day 14 after intravenous challenge, the skin lesions in nu/nu mice were larger. Histopathology revealed large foci of encapsulated yeasts extending from the basement membrane of the epidermis through the dermis to the underlying musculature. Yeasts in these lesions evoked a minimal inflammatory response that consisted primarily of macrophages. Interestingly, yeast cells appeared to be degrading collagen bundles located in the dermis. The dermotropic strain used in this study produced gelatinase and other proteases in vitro. These results indicate that C. neoformans can be dermotropic in a T-cell-deficient host and that proteases may be a virulence factor(s).

Extracellular proteinase activity of Cryptococcus neoformans

“…Collagen fibril and extracellular matrix degradation has been observed in experimental murine cryptococcal infections (34). These in vivo observations are suggestive of and consistent with the elaboration of tissue-degrading enzymes, such as extracellular proteinases, by C. neoformans (12,34). In this article, we report C. neoformans extracellular proteinase activity and demonstrate that this fungus can grow in the presence of immunoglobulin or complement proteins as the sole sources of carbon and nitrogen.…”

“…Rapid tissue invasion by C. neoformans has been observed in experimental rat pulmonary infections (12). Collagen fibril and extracellular matrix degradation has been observed in experimental murine cryptococcal infections (34). These in vivo observations are suggestive of and consistent with the elaboration of tissue-degrading enzymes, such as extracellular proteinases, by C. neoformans (12,34).…”

“…Studies of experimental infection in rats have shown that C. neoformans can penetrate the lung parenchyma within hours after being deposited in the alveolar space (12), suggesting that the fungus produces tissue-disrupting substances, such as proteolytic enzymes. A suggestion of in vivo protease production was obtained from histopathological studies of C. neoformans infection in beige mice in which collagen fibrils were degraded in infected tissues (34). However, the literature contains conflicting reports on the ability of C. neoformans to produce extracellular proteolytic activity: Staib (35) studied 32 strains on human serum agar plates and found no proteolytic activity; Federici (11) studied 7 strains and found proteolytic activity in only 2; Ahearn et al (1) studied 8 isolates and found proteolytic activity in only 3; and Brueske (5) studied 1 strain and described extracellular proteolytic activity.…”

Role of Amino Acid Metabolism in the Virulence of Human Pathogenic Fungi

“…Generally, proteinase activity also appears to be important during C. neoformans infection, since degradation of extracellular matrix and collagen has been observed in murine infection models and is viewed as a facilitator for establishing infections in the central nervous system via permeabilization of epithelial barriers [71][72][73]. Further, C. neoformans produces several secreted proteases involved in the utilization of immunoglobulin and complement proteins as the sole nitrogen and carbon source in vitro [74].…”

Extracellular Protease and DNase Activities in Clinical and Environmental Isolates of Cryptococcus neoformans Species Complex from Central India

“…neoformans infection commonly acquires from the environment 12 , the mechanism includes tissue invasion and is disseminated to other organs via the bloodstream from the lung [13][14][15] . Studies of experimental infection in rats suggested C. neoformans produces tissue disrupting substances such as proteolytic enzymes through which it can penetrate the lung parenchyma and histopathological studies suggested in-vivo protease production which degrades collagen fibrils in infected tissues 16 .…”