Lecture 22: Fungal Toxins and Infections Flashcards
1
Q
What are different types of fungal poisoning?
A
- Mycetism - poisoning by mushrooms
2. Mycotoxicoses - poisoning by fungi
2
Q
What is mycetism?
A
- Results from ingestion of mushroom that
contain “performed” toxic metabolites - E.g:
a. Ibotenic acid from amanita muscaria
b. Amatoxins from amanita phalloides
3
Q
What are the toxins of amanita muscaria?
A
- 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
4
Q
What are amatoxins?
A
- at least 9 known amatoxins
- among deadliest poisons in nature
- occurs in fungal genera:
a. amanita (most poisonous)
b. galerina
c. lepiota
5
Q
What is alpha-amanitin?
A
- potent inhibitor or RNA polymerase 2
- it causes kidney failure, liver failure,
coma and death - One mushroom or less may be fatal
6
Q
What are phallotoxins?
A
- 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
7
Q
How is mushroom poisoning treated?
A
- 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
8
Q
What is mycotoxicoses?
A
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
9
Q
What are Ergot alkaloids?
A
- 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”
10
Q
What are different ergot alkaloids?
A
- D-lysergic acid
- Ergine
- Ergonovine
- LSD-25
- Pibocin
11
Q
What are the effects of alkaloids?
A
- 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)
12
Q
What are Aflatoxins?
A
- 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
13
Q
What are the four principle aflatoxins and what are they produced by?
A
- B1
- B2
- G1
- G2
Prod. by a range of fungi:
a. Aspergillus flavus
b. A. parasiticus
c. A. ostianus
d. et al
14
Q
What are the effects of aflatoxins?
A
- 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
15
Q
What is medical mycology?
A
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
16
Q
When and by who isolated the fungus from ringworm
A
- 1841
2. David Gruby
17
Q
What is meant by dimorphism in fungi?
A
- 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
18
Q
How does fungal superficial infection take place?
A
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
19
Q
What is meant by cutaneous infection?
A
- Fungi that cause cutaneous damage are
called - “dermatophytes” - Colonisation of hair, nails, skin
- Inflammatory response can be intense at
site of infection
20
Q
What are examples of tinea infections (types of cutaneous infections)
A
- 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
21
Q
What are subcutaneous infections?
A
- 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
22
Q
What is systemic infection?
A
- 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
23
Q
How are systemic infections diagnosed?
A
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
24
Q
Explain the in vitro culturing of fungi
A
- 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
25
What is meant by serology diagnosis
```
1. Serology tests for detection of fungal
antigens or specific antibodies to
pathogenic fungi
2. types of test include:
a. Immunodiffusion
b. Whole cell agglutination
c. Enzyme-linked immunosorbent
assay (ELISA)
3. Effectiveness of each technique
depends on disease
```
26
What are molecular methods for diagnosis?
1. PCR currently being developed for diagnosis
| 2. Sensitivity of PCR opens door to false positives
27
What are 4 important fungal diseases?
1. Aspergillus fumigatus - causes aspergillosis
2. Aspergilloma - causes aspergilloma
3. Candidiasis
4. Cryptococcus
28
What is aspergillosis?
1. Causes aspergillosis
2. Type: Aspergillus fumigatus
3. Sometimes occurs in farmers and people
handling decaying organic matter
4. Leukaemia and immunosuppressive
disorder patients at risk
5. Spores inhaled germinate, hyphae
penetrate tissue and invade blood
vessels = thrombosis occurring
6. A. fumigatus can also cause myotic
abortion and eye ulcers when
introduced via wound
29
What is aspergilloma?
1. Referred to as "fungus ball"
2. Commonly caused by A. fumigatus
3. Occupies previous existing cavities in
lung, particularly old tuberculosis
lesion, forming compact ball of mycelia
4. Resulting aspergilloma becomes
surrounded by dense fibrous wall.
5. Balls are solitary and vary in size
(generally less than 8cm)
6. Few symptoms, just moderate cough
7. However, haemorrhage may occur if
infection reaches blood vessel -
Requires "surgical removal"
30
What is candidiasis?
1. "Candida albicans" -predominantly form
of yeast like cells, capable of dimorphism
2. Opportunistic, living as saprotroph in
healthy host
3. Primarily disease of mucous membrane,
where soft, grey/white lesions form
4. Lesions contain mycelium of fungus,
lying over red oozing mucosa
5. Systemic infection is rate, if it does
reach the blood stream though, can
spread to kidneys, spleen, bone,
brain, and lungs
6. Death is very rare
7. Can occur in other mammals and birds
31
What is Cryptococcus?
1. "Cryptococcus neoformans"
2. A basidiomycete, having a yeast
growth form
3. Found in pigeon roots and nests.
4. Outbreaks have occurred among
workers demolishing old buildings
5. Fundus disseminates the lungs and
affects the "meninges" - "Crytococcal
meningitis"
6. Meningitis occurs most frequently in immuno-compromised patients:
a. Hodgkin's disease
b. AIDS
32
How are fungal infections treated?
1. Often difficult, since both host and
parasite is eukaryotic
2. Administration of antifungal antibiotic -
however there is very few antimycotic
compounds which can be used in human
treatment
33
What is "polyene macrolide"
```
1. Antibiotics produced by Streptomyces
spp and include:
a. amphotericin B
b. nystatin
c. pimaricin
2. Common large ring structure
3. Bind specifically to sterol in fungal
membrane (ergosterol)
a. increase permeability
b. leakage of cellular constituents
c. lysis
d. death
```
34
What is amphotericin B?
```
1. Administered intravenously in a bile
salt suspension
2. active agonist of most fungi
3. Treats systemic infection and sever
superficial mycosis
4. At low concentrations, antibiotic can
also boost immune function
5. Toxic to kidneys at higher
concentrations
```
35
What is nystatin?
1. Too toxic for administration intravenously
2. cannot be absorbed by digestive tract
3. therefore used (alongside with pimericin)
to treat superficial infections such as
thrush
36
What are the newer antifungal drugs?
```
1. Imidazole's and triazole's are most
effective
a. broad spectrum, and effect
ergosterol in plasma membrane
2. E.g., Ketoconazole can be absorbed
through gastrointestinal tract,
inhibiting synthesis of ergosterol.
NON-TOXIC TO HUMAN CELLS
```
