Cryptococcal Virulence in Humans: Learning From Translational Studies With Clinical Isolates

Abstract

Cryptococcosis, an invasive mycosis caused by Cryptococcus spp, kills between 20% and 70% of the patients who develop it. There are no vaccines for prevention, and treatment is based on a limited number of antifungals. Studying fungal virulence and how the host responds to infection could lead to new therapies, improving outcomes for patients. The biggest challenge, however, is that experimental cryptococcosis models do not completely recapitulate human disease, while human experiments are limited due to ethical reasons. To overcome this challenge, one of the approaches used by researchers and clinicians is to: 1) collect cryptococcal clinical isolates and associated patient data; 2) study the set of isolates in the laboratory (virulence and host-pathogen interaction variables, molecular markers); 3) correlate the laboratory and patient data to understand the roles fungal attributes play in the human disease. Here we review studies that have shed light on the cryptococcosis pathophysiology using these approaches, with a special focus on human disease. Isolates that more effectively evade macrophage responses, that secrete more laccase, melanize faster and have larger capsules in the cerebrospinal fluid are associated with poorer patient outcomes. Additionally, molecular studies have also shown that cryptococcal clades vary in virulence, with clinical impact. Limitations of those studies include the use of a small number of isolates or retrospectively collected clinical data. The fact that they resulted in very important information is a reflection of the impact this strategy has in understanding cryptococcosis and calls for international collaboration that could boost our knowledge.

Use of Clinical Isolates to Establish Criteria for a Mouse Model of Latent Cryptococcus neoformans Infection

“…The use of C. neoformans (serotype A, var. grubii) clinical isolates allows more accurate comparisons between the mouse latent infection model and the reactivation of latent infections that occurs in the vast majority of human patients (De Sousa et al, 2021). Although C57BL/6 mice have a truncated CXCL11 gene (Groom and Luster, 2011), we observed very similar infection trajectories between C56BL/6 mice and A/JCr mice with only subtle differences between the two inbred backgrounds (Mukaremera et al, 2019).…”

“…C. deneoformans only accounts for 4% of all infections caused by the pathogenic Cryptococcus species complex; whereas C. neoformans accounts for 95% of all infections (Maziarz and Perfect, 2016). Ideally, the development of a latent animal model of C. neoformans infection should use clinically relevant strains to recapitulate human disease (De Sousa et al, 2021).…”

Three models of vaccination strategies against cryptococcosis in immunocompromised hosts using heat-killedCryptococcus neoformansΔsgl1

“…In fact, clinical cases can occur due to the reactivation of granuloma-contained fungal cells from either immunosuppression or comorbidities (HIV/AIDS progression) [27, 69]. Because of this, we tested our vaccination strategy in this mouse model during prolonged corticosteroid-induced immunosuppression as well as CD4-deficiency.…”

“…In fact, clinical cases can occur due to the reactivation of granuloma-contained fungal cells from either immunosuppression or comorbidities (HIV/AIDS progression) [27,69].…”

“…One of these fungal pathogens is Cryptococcus neoformans , a basidiomycetous yeast ubiquitously found in environmental sources such as avian habitation, trees, and soil [3, 5, 26]. C. neoformans is a main etiological agent of cryptococcosis, a life-threatening invasive fungal infection that originates in the respiratory tract [27–29]. Upon inhalation of the environmental fungal propagules, immunocompetent hosts often remain asymptomatic while they either clear the initial infection eliminating the yeast from the lungs or control fungal proliferation by enclosing the persistent yeast in lung granulomas where the fungal cells remain dormant [30–32].…”