Lecture 22: Fungal Toxins and Infections

• Mycetism - poisoning by mushrooms 2. Mycotoxicoses - poisoning by fungi

• Results from ingestion of mushroom that contain “performed” toxic metabolites • E.g: a. Ibotenic acid from amanita muscaria b. Amatoxins from amanita phalloides

• Produces “ibotenic acid”. a. an unstable thermolabile amino acid which can be decarboxylated to “muscimol” b. glutamate receptor agonist (activator) • Muscimol: a. agonist of gamma-aminobutyric acid (GABA) receptors b. Insecticidal properties • BOTH affect neurotransmission • Symptoms similar to alcohol: a. staggering b. delirious c. loses consciousness • death in 1% of cases from respiratory failure

• at least 9 known amatoxins • among deadliest poisons in nature • occurs in fungal genera: a. amanita (most poisonous) b. galerina c. lepiota

• potent inhibitor or RNA polymerase 2 • it causes kidney failure, liver failure, coma and death • One mushroom or less may be fatal

• at least 7 known • Occur in fungal genera: a. amanita b. galerina c. lepiota • They are structurally related to amatoxins • “Phalloidin” - binds to F-actin, preventing depolymerisation and highly toxic to liver cells • Phallotoxins are only poorly absorbed by the gut and thought to not contribute significantly to poisoning by death cap

• Needs to be quick • Evacuation of gastrointestinal tract performed by inducing vomiting, stomach lavage, or enemas • carbon may be given to absorb toxins • kidney and liver monitored

1. Intoxication through ingestion of fungi producing toxins ("mycotoxins") growing on foodstuffs 2. Associated with specific food 3. Seasonal, non-transmissible, unresponsive to drug and antibiotic treatment 4. >100 species of filamentous fungi are known to produce mycotoxins

• Ergot is a mixture of: a. alkaloids produced by species of genus Claviceps (especially C. purpurea) b. /\ grows on rye and related species • Kernels infested with fungus develop dark curved pegs called “sclerotia”

• D-lysergic acid • Ergine • Ergonovine • LSD-25 • Pibocin

• Vasoconstriction + uterus contraction (myotic abortion) • CNS: reduce activity of vasomotor centre whilst stimulating sympathetic regions of mid brain (especially hypothalamus) • Natural role: deter animal grazing • Important for starting material for drug production - many used for human treatment (migraine and Parkinson’s disease)

• Produced by Asperigillus flavus • Most dangerous mycotoxins, mainly affects animals • Responsible for killing 100,000 turkeys in a few months within a 100 mile radius of London in 1960 • from contaminated foodstuffs. E.g., a. peanuts b. cottonseed c. coconuts d. corn

• B1 • B2 • G1 • G2 Prod. by a range of fungi: a. Aspergillus flavus b. A. parasiticus c. A. ostianus d. et al

• Children more sensitive than adults - may affect development • Most characteristic effect: a. Liver damage b. Necrosis c. Cirrhosis d. Carcinoma • Aflatoxins intercalate into DNA = DNA damage (“alkylation”) + chronic exposure increases cancer risk, especially in liver and gall bladder

1. Study of fungi capable of causing disease in animals and humans 2. ~ 400 species are agents 3. Natural disease environment for most fungi is soil, when they live as saprophytes 4. Facultative parasites, become parasites when opportunity arises

• 1841 2. David Gruby

• Single cells (yeast) or mycelial form • Mycelial form outside of host • Conditions inside host cause conversion of mycelium: a. Elevated temperatures b. High CO2 and low O2 c. Levels of nutrients

1. Colonisation of superficial layers of tissue, e.g., a. hair b. skin 2. E.g., Piedraia hortae - tropical disorder causing dark nodules on hair shaft 3. Cause little damage, and minor importance

• Fungi that cause cutaneous damage are called - “dermatophytes” • Colonisation of hair, nails, skin • Inflammatory response can be intense at site of infection

• Tinea corporis (ringworm) a. red, raised lesions b. itchy • Tinea cruris (jock itch) • Tinea pedis (athletes foot) a. most common b. found in toe webbing c. Most often caused by: Trichophyton rubrum, T. mentagrophytes, and Epidermophytom floccosum

• Can access subcutaneous tissue via wounds; typically scratches from thorns • Prevalent in rural and tropical regions • Localised infections • Form abscesses called mycetomas • E.g., Sporothrix schenckii - occurs in farmers and gardeners

• Spreading of fungus from one internal organ to another • Often systemic mycosis originates in lungs via “inhalation of spores” - infection of brain quickly leads to death

1. Based on "clinical observation" and "laboratory investigation" 2. Laboratory investigation relies on: a. microscopic examination of causal agent b. Isolation of fungus by culture c. Diagnostic serological or PCR tests 3. Specimens taken from as many sites as possible. E.g., a. urine b. sputum 4. Lung biopsy may be performed for pulmonary mycotic infections

• Mostly easy to grow pathogenic fungi • Agar medium composed of a. Sabouraud’s glucose agar b. 4% malt extract agar • For more pathogenic dimorphic fungi; “brain-heart infusion agar” and “blood agar” are effective for yeast growth phase