Fungal Dimorphism
Thermal dimorphism is the capacity of a fungus to exist as a mould in the environment at 25 to 30 degrees Celsius and as a yeast (or, in Coccidioides, a spherule) in tissue at 37 degrees Celsius. The switch is driven mainly by temperature and is reversible.
The thermally dimorphic fungi of medical importance are:
- Histoplasma capsulatum (including the African variant Histoplasma duboisii)
- Blastomyces species
- Coccidioides immitis and Coccidioides posadasii
- Paracoccidioides brasiliensis complex and Paracoccidioides lutzii
- Sporothrix schenckii complex
- Talaromyces marneffei
- Emergomyces species
Paracoccidioides loboi is not cultivable, so its dimorphic behaviour is unknown.
Thermal dimorphism must be distinguished from morphological switching that occurs in other fungi under non thermal triggers.
| Organism | Mould phase (25 to 30 degrees Celsius) | Tissue phase (37 degrees Celsius) | Infectious propagule |
|---|---|---|---|
| Histoplasma capsulatum | Septate hyphae with small microconidia (2 to 4 micrometres) and tuberculate macroconidia (8 to 14 micrometres) | Small yeasts inside macrophages with narrow based budding | Microconidia and hyphal fragments |
| Blastomyces | Hyphae with round to oval conidia on short conidiophores (lollipop appearance) | Large thick walled yeasts with a single broad based bud | Conidia |
| Coccidioides | Hyphae that fragment into alternating barrel shaped arthroconidia and empty disjunctor cells | Spherules filled with endospores | Arthroconidia |
| Paracoccidioides | Slow growing, nonspecific hyphae with small conidia and chlamydoconidia | Large yeast with multiple buds (pilot wheel) | Conidia |
| Sporothrix | Delicate septate hyphae with oval to pyriform conidia in a rosette (daisy) arrangement at the conidiophore tip, and along the hyphae | Cigar shaped or oval yeasts, often sparse in tissue | Conidia introduced by inoculation |
| Talaromyces marneffei | Green grey colony with red diffusible pigment; biverticillate penicilli | Small yeasts that divide by fission with a central septum | Conidia |
| Emergomyces | Septate hyphae with conidia | Small yeasts with narrow based budding | Conidia |
The infectious particle in nature is the mould phase conidium or arthroconidium. Inhalation delivers it to the alveolus, where the temperature shift triggers conversion. The environmental form and the tissue form are therefore different organisms to the eye. A mould in the culture dish corresponds to a yeast or spherule in the biopsy.
Geographical and environmental associations:
| Organism | Principal regions | Environmental association |
|---|---|---|
| Histoplasma capsulatum | Ohio and Mississippi river valleys, Latin America, Africa, Asia | Soil enriched with bird and bat guano |
| Histoplasma duboisii | Sub-Saharan Africa | Soil |
| Blastomyces dermatitidis | North American Great Lakes, Ohio and Mississippi river valleys; Blastomyces percursus in Africa and the Middle East | Moist soil near waterways, decaying wood |
| Coccidioides immitis | California | Arid alkaline soil |
| Coccidioides posadasii | Arizona, Texas, Mexico, Central and South America | Arid alkaline soil |
| Paracoccidioides | Latin America, notably Brazil, Colombia, Venezuela, Argentina | Moist soil in rural regions |
| Sporothrix | Worldwide; Sporothrix brasiliensis in Brazil | Soil, plants, infected cats |
| Talaromyces marneffei | Southeast Asia, southern China, northeast India | Soil in the rainy season; bamboo rats |
| Emergomyces africanus | South Africa | Soil; disease predominantly in advanced HIV |
Temperature is the principal signal, sensed through heat shock responses and signalling kinases. Additional signals act in some species:
- Histoplasma requires sulphydryl compounds (cysteine or cystine) for yeast phase growth in vitro. A transcription factor network including Ryp1, Ryp2, Ryp3 and Ryp4 is required to establish and maintain the yeast phase, and mutants locked in the mould phase are avirulent.
- Blastomyces uses the hybrid histidine kinase DRK1 as a master regulator of the phase transition. The yeast phase adhesin BAD1 (formerly WI-1) mediates binding to macrophage receptors and is a major immunodominant antigen.
- Coccidioides conversion to the spherule in vitro needs 37 degrees Celsius and elevated carbon dioxide.
- Paracoccidioides mycelium to yeast transition is inhibited by oestrogen. This helps explain why adult chronic paracoccidioidomycosis occurs predominantly in men, with a male to female ratio above 10 to 1, whereas women of reproductive age are relatively protected.
- Sporothrix strains that grow poorly at 37 degrees Celsius tend towards fixed cutaneous disease on cooler body sites.
Yeast phase cell wall composition also changes. Histoplasma and Blastomyces yeasts increase alpha 1,3 glucan in the outer wall, which masks immunostimulatory beta glucan from Dectin 1 and so limits innate recognition.
The yeast or spherule is the form the immune system must handle.
- Histoplasma: the yeast lacks a capsule despite its species name, which refers to the halo seen around yeasts in tissue sections. It is taken up by macrophages, survives within the phagosome, which does not become strongly acidic, and obtains iron through siderophores and reductive uptake. Spread follows lymphatic and reticuloendothelial routes to the hilar nodes, liver, spleen and bone marrow.
- Blastomyces: yeasts are large and resist phagocytosis, and BAD1 aids adhesion and immune modulation.
- Coccidioides: the spherule grows to 20 to 80 micrometres and divides internally into hundreds of endospores. Rupture releases endospores, each of which can form a new spherule, so replication proceeds in cycles over several days. Spherules are too large to be phagocytosed.
- Paracoccidioides: multiply budding yeasts disseminate from the lung to mucosa, skin, lymph nodes and adrenals.
- Talaromyces marneffei: yeast like cells replicate by fission inside macrophages of the reticuloendothelial system.
- Sporothrix: after traumatic inoculation, the yeast phase appears in the dermis with granulomatous and suppurative inflammation.
| Process | Organism | Trigger | Significance |
|---|---|---|---|
| Thermal dimorphism | Systemic dimorphic fungi | Temperature | Mould to yeast or spherule at body temperature |
| Yeast to hypha switch | Candida albicans | Serum, 37 degrees Celsius, neutral or alkaline pH, carbon dioxide, N acetylglucosamine, nutrient limitation | Hyphae mediate tissue invasion and secrete candidalysin; yeasts favour dissemination; this is polymorphism and not thermal dimorphism |
| White to opaque switching | Candida albicans | Genetic and environmental signals | Opaque cells are mating competent and favoured on skin |
| Capsule and titan cell formation | Cryptococcus | Carbon dioxide, low iron, serum, lung environment | Evasion of phagocytosis |
| Yeast to hyphal conversion | Malassezia | Heat, humidity, sebum | Pityriasis versicolor |
| Adventitious sporulation | Aspergillus terreus, Fusarium, Scedosporium, Lomentospora | Growth in tissue and blood | Yeast like or conidia like forms in tissue and positive blood cultures from moulds; Aspergillus fumigatus almost never yields positive blood cultures |
- Culture and tissue look different. Identification of the mould phase rests on microscopic morphology, DNA probes where available, MALDI TOF and sequencing. In vitro conversion to the yeast phase is slow and rarely used.
- Direct microscopy and histopathology identify the tissue form directly. Because dimorphic cultures take weeks, early diagnosis depends on microscopy, histopathology and antigen detection.
- Antigen cross reactivity is common. Urinary or serum Histoplasma antigen cross reacts with Blastomyces, Paracoccidioides and Talaromyces marneffei, and the galactomannan assay is frequently positive in histoplasmosis, blastomycosis and talaromycosis.
- Biosafety. Mould phase cultures produce airborne conidia that are infectious. Laboratories must be told when a dimorphic fungus is suspected, and the plates are handled in a biological safety cabinet with high containment practices. Coccidioides is the most hazardous.
- No person to person transmission occurs in ordinary clinical contact, because patients carry the tissue phase and not the infectious mould phase.
