Virulence factors of Cryptococcus neoformans and Cryptococcus gattii: two sides of the same coin

Cryptococcus neoformans and Cryptococcus gattii are a globally distributed fungal pathogen that causes a significant number of cryptococcosis worldwide, especially among immunocompromised individuals, although immunocompetent may also be affected. This infection begins when Cryptococcus is inhaled from the environment into the lungs resulting in pneumonia. Critically, the fungus can disseminate systemically and cross the blood-brain barrier causing cryptococcal meningitis (CM), the severe clinical form of the disease. CM, when untreated, is fatal in a short period of time causing high mortality rates. This mortality is associated with immunosuppression, failures in treatment, diagnostic problems, and the virulence of Cryptococcus. We often attribute epidemiological and pathogenesis studies to knowledge acquired from C. neoformans; however, studies have shown that pathogenic differences exist between various Cryptococcus species complexes. In this review, we will present the literature about epidemiology and virulence factors of C. neoformans and C. gattii, emphasizing their differences and pointing out unexplored research. Moreover, we will demonstrate strategies aimed at inhibiting virulence factors that can become a valuable source for the development of new drugs.Literature search: PubMed, Scopus, and Web of Science (from database inception to June 2026).