Fungal Pathogens

Three categories of medical importance related to fungi

mycotoxicoses, hypersensitivity diseases and host colonisation and resulting disease state.

Mycotoxicosis

often the result of accidental or recreational ingestion

Why is identification of an ingested substance often difficult in mycotoxicosis cases?

Patient isn’t always able to provide a good clinical history or describe the ingested substance

St Anthony’s Fire epidemic, middle ages

Due to contamination of rye with Claviceps purpurea which produces ergot alkaloids → convulsions and gangrene due to vasoconstriction.

Mycotoxicosis treatment

Induced emesis is often the first line of treatment followed by supportive therapies like assisted breathing or fluids.

Lysergic acid diethylamide

semi-synthetic derivative of psychotropic agents psilocybin and psilocin

Turkey X disease

poultry contaminated with Aspergillus flavus → gross haemorrhage and necrosis. Has carcinogenic properties

hypersensitivity

host dependent, results from immunoglobulin production and lymphocyte stimulation against spore proteins. Doesn’t require fungal growth.

hypersensitivity pneumonitis →

rhinitis, asthma and alveolitis

How many fungal species cause significant human disease?

Approx 50. Number will likely increase as more new species emerge. Most mainly affect immunocompromised people

pathogenic fungi as dimorphic

exist as either yeasts or filamentous forms

What’s observed for fungal identification and diagnosis?

spore morphology alongside molecular and immunological tools

superficial mycosis

fungus only infects the surface layer of skin, hair or nails. Usually treatable with topical antifungal creams or liquid aerosols eg miconazole nitrate/griseofulvin

Trichophyton species

cause fungal infections of feet and other moist surfaces. Transmission through spores on flaking/itching skin

subcutaneous mycosis

infects deeper layers of the skin. Mainly treated topically although oral drugs are taken in severe cases

saphrophyte Sporothrix schenckii

causes sporotrichosis. Occupational hazard for people working in close contact with soil. Spores enter via cut skin

What species cause chromoblastomycosis?

Fonsecaea pedrosoi, Phialophora verrucose and Cladosporium carrionii

Chromoblastomycosis growth and symptoms

fungal growth subcutaneous and cutaneous. Crusty wart-like lesions form on hands and legs

Conditions for chromoblastomycosis infection

tropical/subtropical, enters via puncture wounds

Systemic mycosis

Internal organs infected. Usually caused by inhalation of airborne spores from soil.

primary mycosis

healthy individual infected with fungus

secondary mycosis

predisposing conditions make individual more susceptible to infections

Histoplasmosis

Widespread primary fungal infection caused by dimorphic Histoplasma capsulatum. Inhaled spores germinating in the lungs.

Coccidiomycosis

Caused by dimorphic Coccidioides immitis. Soil saprophyte airborne when it rains. Respiratory symptoms → pneumonia

Where does Blastomyces dermatitidis live?

rotten wood and soil near water

Blastomyces dermatitidis (dimorphic) infection - blastomycosis

Very slow growing in lungs. Subcutaneous dermal lesions form if left untreated.

Paracoccidioidomycosis (caused by Paracoccidioides brasiliensis)

primarily subtropical, may also be aquatic. Initially pulmonary, leads to lesions on face and other extremities

Echinocandins

Inhibit glucan synthesis by targeting 1,3-beta glucan synthase, disrupting fungal cell wall integrity.

Cryptococcosis - caused by yeast form of Cryptococcus neoformans.

Occurs in almost any organs, originally infecting lungs or a wound. 2nd most common opportunistic pathogen in HIV/AIDS patients

Candida albicans genome

Highly dynamic genome - they undergo chromosomal rearrangements to generate genetic diversity

Pneumocystis pneumonia (often caused by Pnemocytosis jirovecii)

opportunistic infection

hyper IgM syndrome

X linked or autosomal recessive trait

C. albicans in medical settings

forms biofilms which are difficult to treat with antifungal agents

polyenes

bind ergosterol and disrupt fungal membrane integrity, however they also target cytosterol.

azoles and allylamines

inhibit ergosterol synthesis

griseofulvin

disrupts microtubule aggregation in mitosis

polyoxins

inhibit chain synthesis

5-flurocytosine

nucleotide analog which inhibits nucleic acid synthesis, targeting Candida and Cryptococcus neoforman infections

issues with 5-flurocytosine

relatively weak antifungal effects and resistance develops quickly

How do polyenes and azoles work?

bind ergosterol, deplete in the membrane and cause toxic intermediates to accumulate, destabilising the fungal membranes so they leak cations and die.