Classification & Structure
Taxonomy & Morphology
| Kingdom / Phylum | Fungi · Basidiomycota · Tremellomycetes; teleomorph Filobasidiella neoformans |
| Species complex | C. neoformans (serotypes A, D, AD hybrid) — predominantly HIV/immunosuppressed hosts; C. gattii (serotypes B, C) — immunocompetent hosts |
| Environmental reservoir | Pigeon (Columba livia) guano (alkaline high-creatinine substrate); soil; eucalyptus trees (C. gattii) |
| Yeast morphology | 5–10 µm encapsulated yeast; reproduces by unipolar budding; polysaccharide capsule 1–100 µm thick |
| Polysaccharide capsule | Glucuronoxylomannan (GXM) 88%; galactoxylomannan (GalXM/GXMGal) 10%; mannoproteins 2%; MW up to 10⁷ Da; anti-phagocytic; main virulence factor |
| Melanin / cell wall | Laccase enzymes (LAC1, LAC2) oxidise exogenous catecholamines (dopamine, DOPA) → melanin deposited in cell wall; particularly active in brain (high dopamine) |
| Titan cells | Polyploid cells up to 100 µm diameter in vivo; too large to phagocytose; form by endoreplication; bystander immune modulation |
| Mating type | MATα dominant in clinical isolates; MATa necessary for sexual reproduction → basidiospores (infective propagules) |
| Identification | India ink CSF smear (capsule as clear halo); CrAg latex agglutination/LFA (serum and CSF); mucicarmine staining of capsule in tissue |
Pathogenesis Mechanisms
- GXM capsule — master immune suppressor Glucuronoxylomannan (GXM) is shed copiously into surrounding tissue and bloodstream. Free GXM: (1) blocks phagocytosis by steric hindrance and complement factor displacement; (2) induces IL-10, IL-4 in macrophages → Th2/Treg polarization, suppressing Th1/Th17; (3) binds Fc receptors non-productively, blocking IgG-mediated opsonisation; (4) captures anti-cryptococcal antibodies as decoy antigen; (5) inhibits leukocyte migration. Capsule size correlates with virulence and inversely with immune competence.
- Laccase / melanin — oxidative protection and neurotropism LAC1/LAC2 laccase enzymes use L-DOPA and dopamine as substrates, found in abundance in the CNS. Melanin: scavenges reactive oxygen species from macrophage oxidative burst; confers resistance to amphotericin B; acts as cation chelator reducing antifungal penetration. CNS dopamine availability explains preferential CNS colonisation (brain tropism) beyond immune privilege alone.
- Urease (URE1) — phagosome alkalinisation and neurotropism Urease hydrolyses urea → NH₃ + CO₂. NH₃ alkalinises the macrophage phagolysosome, blunting acidification-dependent killing. Urease also promotes crossing of the blood-brain barrier by altering endothelial tight junctions. Urease-deficient mutants show reduced brain invasion in animal models.
- Trojan horse mechanism — macrophage-mediated CNS entry C. neoformans survives inside alveolar macrophages after pulmonary inhalation. Infected macrophages transmigrate across the blood-brain barrier in a paracellular fashion (Trojan horse) or by directly traversing endothelial cells. Intracellular yeast avoid complement and antibody; macrophages serve as protected transport vehicles. Also enters CNS by direct transcytosis through endothelium (fungus binds CD44 on brain endothelium).
- Vomocytosis — non-lytic macrophage escape After phagocytosis, C. neoformans can be expelled from macrophages without killing the host cell (non-lytic exocytosis / vomocytosis). Yeast replicate within vacuoles, acidify the phagosome via V-ATPase inhibition, and are expelled in a polarised manner. Expelled cells disseminate while macrophage continues to circulate — maintaining the Trojan horse reservoir.
- Latent pulmonary infection — reactivation model Primary infection in childhood via inhalation of desiccated yeast/basidiospores; controlled in immunocompetent hosts by granuloma formation. Latent organisms persist in lung granulomas and/or regional lymph nodes. Reactivation occurs decades later upon T-cell depletion (HIV, transplant, anti-CD20 therapy). Explains lack of geographic restriction in HIV-associated cryptococcosis.
- Fluconazole tolerance — non-resistance survival C. neoformans shows high MICs to fluconazole (MIC 4–8 µg/mL, vs 0.5–1 for C. albicans) and is intrinsically less susceptible. Tolerance (growth below MIC) allows population survival. ERG11 mutations are less common than in C. albicans; efflux pumps (AFR1) contribute to azole tolerance. 5-fluorocytosine resistance arises through FUR1/UPP1 pyrimidine salvage mutations; thus 5-FC must never be used as monotherapy.
Host Immune Response
Innate & Adaptive Defences
Disease Spectrum
| Syndrome | Population | Severity | Key Feature |
|---|---|---|---|
| Pulmonary cryptococcosis | HIV CD4 100–200; solid organ transplant; low-dose steroids | Moderate | Asymptomatic to pneumonia; nodular/infiltrative CXR; positive serum CrAg; may self-resolve in immunocompetent |
| Cryptococcal meningitis (CM) | HIV CD4 <100; SCT; anti-CD20; iatrogenic | Critical | Sub-acute onset: headache, fever, meningismus (often absent); CSF: India ink halo, CrAg +ve, high opening pressure (>25 cmH₂O); mortality 10–40% |
| Cryptococcoma (brain mass) | C. gattii; non-HIV immunosuppressed | Severe | Ring-enhancing CNS mass; surgical resection may be required; prolonged antifungal course; C. gattii more neurotropic/virulent |
| Cryptococcus-IRIS (unmasking) | ART initiation in CM patients; CD4 recovery | Severe | Paradoxical worsening 4–8 weeks post-ART; do NOT stop ART; NO corticosteroids (increase mortality); manage ICP with LPs |
| Disseminated cryptococcosis | Profound immunosuppression | Critical | Skin lesions (umbilicated, molluscum-like), fungaemia; bone/joint; prostate is a sanctuary reservoir |
Treatment & Prophylaxis
IDSA/WHO Cryptococcal Meningitis Protocol
| Induction (2 weeks) | Amphotericin B-deoxycholate 0.7–1.0 mg/kg/day IV + flucytosine (5-FC) 25 mg/kg Q6H PO — superior fungicidal activity; 5-FC accelerates CSF sterilisation |
| Consolidation (8 weeks) | Fluconazole 400 mg/day PO after 2-week induction and CSF sterilisation confirmed |
| Maintenance / suppression | Fluconazole 200 mg/day PO — minimum 1 year or until CD4 >200 cells/µL × 6 months on ART |
| Lipid formulation AmB | L-AmB 3–4 mg/kg/day for renal toxicity prevention (transplant patients, pre-existing renal disease); equivalent efficacy to AmB-D |
| Single high-dose fluconazole | Not recommended for CM (fungistatic only); acceptable for uncomplicated pulmonary disease in immunocompetent |
| Raised ICP management | Serial lumbar punctures daily until opening pressure <20 cmH₂O; lumbar drain or VP shunt if refractory; NO acetazolamide; NO dexamethasone for ICP control (worsens outcome) |
| ART timing in HIV-CM | Defer ART 4–6 weeks after antifungal induction — earlier initiation increases IRIS risk and mortality (COAT trial); exception: very low CD4/high viral load may require earlier |
| Screening strategy | Serum CrAg lateral flow assay at CD4 <100 cells/µL — pre-emptive fluconazole if CrAg+, LP to exclude CM; WHO recommends population-level CrAg screening in high-burden settings |
| Primary prophylaxis | Fluconazole 200 mg/day where CrAg screening unavailable and CD4 <100; not routine in resource-rich settings |
| Cryptococcus-IRIS | Continue antifungals; serial LPs for ICP; NSAIDs; short-course corticosteroids (controversial, avoid in CM-IRIS); do NOT stop ART |
Connections
Lung (primary site)
CNS / meninges (neurotropism)
Prostate (sanctuary site)
Bloodstream (fungaemia)
Skin (dissemination marker)
Brain parenchyma (gelatinous pseudocysts)
CSF drainage pathways (raised ICP)
Th1/Th17 immune polarization
Macrophages (Trojan horse)
Blood-brain barrier (CD44 binding)
Ergosterol (AmB target)
Erg11 (fluconazole target)
Pyrimidine synthesis (5-FC → 5-FU)
References
- Perfect JR et al. IDSA Guidelines for Cryptococcal Disease. Clin Infect Dis 2010;50:291–322.
- WHO Guidelines for the Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-Infected Adults. WHO 2022.
- Rajasingham R et al. Global burden of disease of HIV-associated cryptococcal meningitis. Lancet Infect Dis 2017;17:873–881.
- Jarvis JN et al. Single-dose liposomal amphotericin B treatment for cryptococcal meningitis (AMBITION-cm). N Engl J Med 2022;386:1109–1120.
- Kronstad JW et al. Expanding fungal pathogenesis: Cryptococcus breaks out of the opportunistic box. Nat Rev Microbiol 2011;9:193–203.
- Jain N et al. Cryptococcus neoformans titan cell formation is regulated by G-protein signalling. Cell Microbiol 2009;11:432–442.
- Boulware DR et al. Timing of ART after cryptococcal meningitis (COAT trial). N Engl J Med 2014;370:2487–98.