Cryptococcus neoformans, a global threat to human health

Abstract

Background: Emerging fungal pathogens pose important threats to global public health. The World Health Organization has responded to the rising threat of traditionally neglected fungal infections by developing a Fungal Priority Pathogens List (FPPL). Taking the highest-ranked fungal pathogen in the FPPL, Cryptococcus neoformans, as a paradigm, we review progress made over the past two decades on its global burden, its clinical manifestation and management of cryptococcal infection, and its antifungal resistance. The purpose of this review is to drive research efforts to improve future diagnoses, therapies, and interventions associated with fungal infections.

Methods: We first reviewed trends in the global burden of HIV-associated cryptococcal infection, mainly based on a series of systematic studies. We next conducted scoping reviews in accordance with the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews using PubMed and ScienceDirect with the keyword Cryptococcus neoformans to identify case reports of cryptococcal infections published since 2000. We then reviewed recent updates on the diagnosis and antifungal treatment of cryptococcal infections. Finally, we summarized knowledge regarding the resistance and tolerance of C. neoformans to approved antifungal drugs.

Results: There has been a general reduction in the estimated global burden of HIV-associated cryptococcal meningitis since 2009, probably due to improvements in highly active antiretroviral therapies. However, cryptococcal meningitis still accounts for 19% of AIDS-related deaths annually. The incidences of CM in Europe and North America and the Latin America region have increased by approximately two-fold since 2009, while other regions showed either reduced or stable numbers of cases. Unfortunately, diagnostic and treatment options for cryptococcal infections are limited, and emerging antifungal resistance exacerbates the public health burden.

Conclusion: The rising threat of C. neoformans is compounded by accumulating evidence for its ability to infect immunocompetent individuals and the emergence of antifungal-resistant variants. Emphasis should be placed on further understanding the mechanisms of pathogenicity and of antifungal resistance and tolerance. The development of novel management strategies through the identification of new drug targets and the discovery and optimization of new and existing diagnostics and therapeutics are key to reducing the health burden.

Keywords: Antifungal resistance; Antifungal tolerance; Cryptococcal meningitis; Cryptococcus neoformans; Fungal infections.

Fig. 1

Clinical manifestation of cryptococcal infection. The most common clinical manifestation of cryptococcal infection are CNS infections, which cause cryptococcal meningitis (Left in the upper panel). Pulmonary infections are the result of initial infection through inhalation of infectious propagules (Right in the upper panel). Another manifestation is cryptococcomas (Lower panel), which is formed by an inflammatory response in brain, lungs, skin, and other organs, thus it is more common in immunocompetent hosts. It may subsequently appear in a complex granuloma, including various macrophages. CNS Central nervous system

Fig. 2

Flow diagram of the scoping review process for case reports of cryptococcosis

Fig. 3

Diagnosis of cryptococcal infections. India ink microscopy, cerebrospinal fluid (CSF) culture, and detection of cryptococcal antigen in serum or CSF are three protocols for diagnosis of cryptococcal infections. India ink microscopy remains the primary diagnostic tool for identifying Cryptococcus in CSF. CSF fungal culture is the gold standard for diagnosis of cryptococcal meningitis. The detection of cryptococcal antigens, the capsular polysaccharide glucuronoxylomannan (GXM), is a very sensitive, specific, and effective test to detect cryptococcal infections. The antigen test was mainly performed through the Latex agglutination test (LAT), Enzyme Immunoassay (EIA) and Lateral flow assay (LFA).

Fig. 4

Antifungals, targets, and antifungal resistance mechanism. Three main classes of drugs are used in the treatment of cryptococcal infections: polyenes (AmB), azoles (fluconazole), flucytosine. C. neoformans is intrinsic resistant to echinocandins (shown in dotted lines). AmB binds to ergosterol in the cell membrane, which forming pores and exerting fungicidal activity. Fluconazole targets the ergosterol biosynthetic enzyme Erg11. Flucytosine blocks DNA synthesis. C. neoformans cells develop resistance to different drugs through different mechanisms. The exact mechanism leading to AmB resistance is not yet clear. Fluconazole resistance has been reported to be associated with aneuploidy, heteroresistance and mutations in the ERG11 gene. Flucytosine resistance may be associated with mutations in genes related to flucytosine conversion, hypermutation, and transposon mutagenesis. The echinocandins resistance is attributed to the interaction of Cdc50 and Crm1, and preventing drug uptake could also arise echinocandins resistance