Abstract
Cryptococcus gattii is a resurgent fungal pathogen that primarily infects immunocompetent hosts. Thus, it poses an increasingly significant impact on global public health; however, the mechanisms underlying its pathogenesis remain largely unknown. We conducted a detailed characterization of the deubiquitinase Ubp5 in the biology and virulence of C. gattii using the hypervirulent strain R265, and defined its properties as either distinctive or shared with C. neoformans. Deletion of the C. gattii Ubp5 protein by site-directed disruption resulted in a severe growth defect under both normal and stressful conditions (such as high temperature, high salt, cell wall damaging agents, and antifungal agents), similar to the effects observed in C. neoformans. However, unlike C. neoformans, the C. gattii ubp5Δ mutant displayed a slight enhancement of capsule and melanin production, indicating the evolutionary convergence and divergence of Ubp5 between these two sibling species. Attenuated virulence of the Cg-ubp5Δ mutant was not solely due to its reduced thermotolerance at 37°C, as shown in both worm and mouse survival assays. In addition, the assessment of fungal burden in mammalian organs further indicated that Ubp5 was required for C. gattii pulmonary survival and, consequently, extrapulmonary dissemination. Taken together, our work highlights the importance of deubiquitinase Ubp5 in the virulence composite of both pathogenic cryptococcal species, and it facilitates a better understanding of C. gattii virulence mechanisms.
Highlights
Cryptococcosis is one of most prominent invasive fungal diseases; it can invade both immunocompromised and immunocompetent hosts and often manifests as life-threatening meningoencephalitis
C. neoformans var. grubii and C. neoformans var. neoformans belonged to the same species, which was distinct from C. gattii
We conducted a detailed characterization of the deubiquitinase Ubp5 in the biology and virulence of C. gattii using the hypervirulent strain R265, and we defined its properties as either distinctive or shared with C. neoformans
Summary
Cryptococcosis is one of most prominent invasive fungal diseases; it can invade both immunocompromised and immunocompetent hosts and often manifests as life-threatening meningoencephalitis. C. gattii yields both round and bacilliform cells, and it is consistently found inhabiting decaying trees but not bird droppings like C. neoformans[6, 7]. These pathogens are not routinely discriminated in clinical practice, their interspecific differences are significant for the clinical manifestation and management of infection. From the remaining DUBs, we further identified Ubp, which is essential for sexual reproduction, the stress response, and the virulence composite in C. neoformans[23]. Our study demonstrates the functional convergence and divergence of Ubp among pathogenic Cryptococcus species, facilitating a better understanding of C. gattii virulence mechanisms
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