mycology review. fungal cell wall: multilayered produces fungal cell shape polysaccharides – most...
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Mycology review
Fungal cell wall: multilayeredproduces fungal cell shape
• Polysaccharides – Most medically important fungi have chitin and fibrillar
glucan– Fibrils : strength
• Chitin (N-acetyl-D-glucosamine) and glucan– Glue-like compounds
• glucans• galactans, mannans and mixed polymers • Glycoproteins
– Enzymes for nutrient digestion and invasion• Glycolipids
Chitin fibrils(1-4)-linked N-acetyl-D-
glucosamine
(NAG polymer)
Synthesis:
UDP-N-acetyl-D-glucosamine
+ NAGn chain)
chitin synthetase
NAGn+1 chain
Synthesis and properties similarto that of cellulose
(1-4)-linked D-glucose
Protoplasts (spheroplasts)
• Lack cell wall
• Burst in hypotonic solution
glycosidases (snail enzyme)
Protoplast
H2O
0.15N NaCl
1.0M sorbitol
Fungal sterols
Ergosterol: C28 sterols (Humans cells have C27 sterols i.e.; cholesterol)
Target for polyene antifungals (nystatin, amphotericin B)
• The basic units of growing fungi are yeasts and hyphae– Yeasts
• Single cells dividing usually by budding– Hyphae (sing. Hypha): mold
• Long filaments growing at apex branching
YEAST and MOLD
silver stain
Mold growthApical growth +Hyphae branchto form mycelium
BranchingStaining of
Spitzenkörper: Structure found in fungal hyphae which is the organizing center for hyphal growth and morphogenesis
Hickey, P.C. & Read, N.D. (2003). The biology of the living fungi. British Mycological Society: Wokingham, UK. Available from http://www.fungalcell.org/cdrom/ Sponsored and published by The British Mycological Society http://www.britmycolsoc.org.uk
Septum formation behind tip
Hickey, P.C. & Read, N.D. (2003). The biology of the living fungi. British Mycological Society: Wokingham, UK. Available from http://www.fungalcell.org/cdrom/ Sponsored and published by The British Mycological Society http://www.britmycolsoc.org.uk
Growth direction
Hyphal features• Older walls may become
remodeled and elastic to enable branch growth.
• Wall changes needed in other situations.
• Rigidity of cell wall gives forward pressure into solids
• Mycelium (plural mycelia)
http://homepages.inf.ed.ac.uk/rbf/HIPR2/libmed.htm
www.rhodes.edu/biology/hill/hill/ResearchBackground.html
MYCELIUM
DIMORPHIC FUNGI
• Growing both in the form of a yeast and a mold• The environment determines their morphology.
– This conversion is associated with a change in cell wall composition.
– Complete reversal of a morphological change follows return of the fungus to the initial environment:
37°C 25°C
Summary Basic Growth Forms
Molds Yeast
Cell wallenzymes
Extra-cellularenzymes
Forwardpressure
Distribution
+
+
Yes No
Spores Fluid films
+
+
Naming fungi• Hyphae and Septa
– Little variation
• Sporulation structures and spores – Variable and are basis of most identifications
• Increasingly rRNA gene sequencing is being applied
Sexual and asexual sporulation structures give names
• Asexual forms (anamorphs)– These are the whole structure – the spores and any
specialized spore producing structures – Conidiospores (conidia) with conidiophores
• Blastic conidiogenesis• Thallic conidiogenesis
– Sporangiospores and sporangium with sporangiophore• Sexual forms (teleomorph)
– Ascospores (in an ascus) in a fruiting body– Basidiospores (on a basidium) in a fruiting body – Zygospores (made by zygomycetes)
Naming yeasts• Often little morphologic differences
• Yeasts grouped by morphology and pigment and how they divide, then put into distinct species on basis of a metabolic profile.
• Most features of metabolic profile associated with different patterns of sugars and forms of nitrogen (nitrate, nitrite, ammonium etc) used
• DNA sequencing coming on fast
Infections
• Skin pathogens– tinea versicolor– dermatophytes
• Subcutaneous• Deep seated pathogens• Opportunists
– Those controlled mainly via T cell-mediated immunity– Those controlled mainly via neutrophils– Candidiasis (a mixture)
tinea versicolor• Areas of depigmentation, occasionally
hyperpigmentation, on skin. No inflammation
• Overgrowth of Malassezia spp. that are part of the normal flora of skin (yeasts that require lipid for growth)
• Yeasts not grow on regular Sabouraud agar
• Identified by KOH mount of scraping (clusters of round yeasts with filaments)
• Lesions fluoresce greenish yellow in Wood’s light
dermatophytosis
• Molds that infected keratinized tissues (hair, skin, nails)
• Many species (Trichophyton, Microsporum) + Epidermophyton floccosum but the 3 genera are closely related
• Grow on Sabouraud agar and produce spores that allow their identification. These spore types are not found in human tissues where septate hyphae, with or without arthrospores, are the only features produced
KOH mount - Dermatophyte in skin showing hypha breaking into arthrospores
Scrape at growing edge where mycelium is causing inflammation
Stained KOH MOUNT
tinea cruris
Cultivation on selective medium containing cycloheximide(dermatophytes less susceptible) and antibacterials
Spores developing in culture allow species identification
Sources for infection
Anthropophilic species: humansZoophilic species: animalsGeophilic species: soil
Anthropophilic species tend to cause less inflammation.
tinea pedis (athelete’s foot) typically anthropophilic
tinea capitis (hair)both zoophilic and anthropophilic (most commonly anthropophilic in USA at present)infection may be ectothrix (arthrospores in outer layer around air shaft) or endothrix (arthrospores massed within hair shaft)
tinea capitis
Ectothrix species Microsporum canis and M. audouinii
Usually fluoresce in Woods lightNot usual after puberty
tinea capitis Endothrix species
Doesn’t fluoresce in Woods light. Continues after puberty
Trichophyton tonsuransmost common world wide
Id reactions to fungal infection under foot. (No fungus seen or cultivatable from id)
Treatment of dermatophytes
Limited area of skin: topical agents
tinea capitis and large areas of involved skin or nails oral therapy (azoles, griseofulvin, allylamines)
When possible, confirm there is a dermatophyte via microscopy
Mycotic keratitisInfection of the eye
• Infection of the eye caused by many different fungi. • 2006 outbreak associated with Fusarium - a mold
growing in contact lens solution held for long periodsAnamorph shows sporulation Characteristic of Fusarium
Anamorphs produced in culture identify mold species causing keratitis
Subcutaneous infections
• Fungi grow in the environment and penetrate into the body through skin via trauma (thorns, splinters etc)
• Mycetoma
• Chromomycosis
• Sporotrichosis
Mycetoma and Chromomycosis• Both often chronic diseases developing slowly over several
years. Many different species form these diseases and actinomycetes also can cause mycetoma
• Mycetoma diagnosis - large granules of mycelium• Chromomycosis - pigmented fungal cells• Different species identified from anamorph in culture
Sporotrichosis
• Usually lymphocutaneous. Infection follows trauma injecting fungus (splinters, etc).
• Single etiologic agent, Sporothrix schenckii• Temperate regions• Dimorphic
– Cigar shaped yeast at 37 C (and in disease)– Mold at room 25 C
• Dissemination rare, seen in AIDS and severely immunosuppressed
Sporothrix dimorphism Room temperature vs 37 C
Lymphocutaneous sportrichosis• Non healing initial lesion that doesn’t respond to
antibacterials• New painful lesions appear along draining lymphatics• Diagnosis - Culture most successful, often too few
yeasts to be seen in tissue • Clinical signs (most often Sporothrix) but could be
Mycobacterium marinum or some other microbes
Lymphocutaneous diseaseSaturated potassium iodide KI works (large amount over several weeks)Azoles (e.g.; itraconazole)
Systemic diseaseamphotericin B, azoles. KI does not work
Treatment of sporotrichosis
Deep-seated true pathogens• Infect and can cause disease in immunocompetent persons
as well as immunosuppressed• Geographic limitation – predominate in specific regions.• Infect via lung: then can disseminate to many sites
including skin• Dimorphic - environmental form differs from parasitic• Originally considered rare, deadly diseases but, in most
cases, now recognized as common infection.• Severe clinical disease is quite rare: most infected recover
without significant illness. Evidence for infection without clinical disease comes from positive skin test reaction to Histoplasma and Coccidiodes antigens
Main pathogensMain foci in N. America
Histoplasma capsulatum Ohio River - Mississippi River Valley dominant (sporadic worldwide)
Coccidioides immitis (C. posadasii)Desert regions of the South West (Sonoran Life Zone also similar regions in Mexico and parts of S. and Central America)
Blastomyces dermatitidisSimilar to Histoplasma but reaching further north into Ontario. Some regions of Africa and India. Rare compared to others and more common in dogs than in humans
Note: distributions incorrectly labeled in Murray text p.768
• Histo = Histoplasma/histoplasmosis• Cocci = Coccidioides/coccidioidomycosis• Blasto = Blastomyces/blastomycosis
Resistance• Dominated by T cell-mediated immunity for Histo &
Cocci (but ? Blasto) so people with HIV or immunosuppression get worse infections
• Men more susceptible than women in Blasto and Cocci • BUT if pregnant & non-immune, susceptibility is far
greater for Cocci for which growth is stimulated by estradiol
• Sign of resistance– DTH skin test developing (Th1 response)
• Sign of continuing and expanding infection, – rising CF antibodies (Th2 response)
Typical Pathogenesis• Infection via lung by spores of environmental
form• Fungi converts to pathogenic form and
establishes local infection then disseminates to many sites often including skin/mucosa
• Diagnosis made by detecting the fungus in lesions using histology and culture. Serology can be helpful
Histoplasmosis• Ohio River-Mississippi River geographic region• Fungus thrives in bird guano enriched soils (especially
under starling roosts) and in bat guano• In environment, mold produces macroconidia and
microconidia (microcroconidia are spores that are small enough to reach alveoli)
• Inhalation establishes infection and germinating microconidia convert to yeast form
• In disease, histoplasma yeasts remain intracellular within macrophages (included fixed macrophages) except when the cell breaks open. Then rapidly picked up by other macrophages
• Found in liver, bone marrow, etc. Can be seen in blood monocytes when severe immunosuppression present
Histoplasma capsulatum environmental and parasitic forms
Mycelium bearing Yeast within macrophages
infectious microconidia (arrows) and macroconidia
Symptoms differ in non-immune and immune persons
Primary infection• Immunologically naïve• ~ 10-14 days before
immune response controls fungal growth
• Symptoms associated with inflammation (fever, pain, etc.) but not seen for ~ 2 weeks
Secondary infection• Rapid immune response. • Usually controls fungus
quickly with minimal/no symptoms
• Heavy exposure to spores can cause massive symptomatic inflammation peaking around 4 days but then fairly rapid resolution
Lab tests for diagnosis/Treatment of histoplasmosis
• Antibody detection can be very helpful in chronic infections
• Urine antigen in severe disseminated infection• Biopsy for histopathology and culture
• Treatment– Newer azoles (fluconazole, itraconazole, voriconazole,
posaconazole) replacing Amphotericin B– Definitely needed if immunodeficient (incl. AIDS) or
progressive disease not coming under control
CoccidioidomycosisPulmonary infection with dissemination to many sites including skin and CNS
1% infected healthy persons are symptomatic and can need medical care.
Coccidioides is the most virulent fungal pathogen. Found in desert soils and produces infectious arthrospores
Increased severity in AIDS
Coccidioides
Growth on Sabouraud agarin vitro at room temp and 37 C
Form found in desertsoils
Mycelium Arthrospores
Converts to parasitic form during infection(
• Post puberty females more resistant than males– Stronger response associated with erythema nodosum and
erythema multiforme. Lesions are hypersensitivity reactions do not contain fungi
• Pregnant very susceptible if not already immune– increasing risk of dissemination with infection at later stages of
pregnancy
Coccidioidomycosis - Dissemination
Treatment and Resistance
• Amphotericin B • Newer azoles
• CNS infections– lifelong if immunosuppressed, e.g. in AIDS
DTH skin test positive – Good prognosisRising CF antibodies (IgG) - poor prognosis
Th1 based resistance aimed at endospores
Blastomycosis• Rare. Pulmonary infection with dissemination• Environmental source not known. i• In Great Lakes region(USA and Canada), Atlantic region
USA, occasional overseas• Disease more common in dogs than humans• Central role of T cell-mediated immunity not clear.
Seems PMNs may be quite important too• 95% cases in males• No epidemiologic skin test survey available but
antibody production is a good marker of infection
Blastomyces dermatitidisYeast with broad base bud at 37 C and in infection
conidiophores at room temp
Pulmonary and systemicblastomycosis affecting bone
Infection is via the lung, pulmonary disease may be severe or very mild. Severe skin lesions and lesions in the skin, bones, and prostate are the dominant presentation in many patients.
Blastomycosis treatment
• Amphotericin B has largely been replaced by newer azoles
Opportunists
• Unusual cause of infection unless patient has a predisposing condition such as an immunodeficiency
• T cell deficiencies– Cryptococcosis, pneumocystosis, microsporidiosis– Mucosal =/- cutaneous candidiasis
• Neutropenia– Aspergillosis, invasive candidiasis, systemic zygomycosis
58
CryptococcosisEtiologic agent: • Cryptococcus neoformans
var. neoformans (pigeon manure) throughout worldvar. gattii (Eucalyptus trees) more restricted to regions
where winter freezing is not found. But a recent hybrid is causing outbreak in British Columbia, Canada where it is assocaited with Douglas fir
Grows as an encapsulated, budding yeast in vitro and in vivo
59
Virulence determinants
• Acidic capsular polysaccharide– Antiphagocytic and T-independent antigen– Readily observable in India Ink
• Phenoloxidase– oxidizes phenolics to form a deep pigment similar to
melanin. Appears to be valuable in invasion of CNS
60
Bird seed agar: phenoloxidase production by Cr. neoformans but not by Candida albicans turns colony dark
61
Infection
• Pulmonary initially, ± dissemination May cause severe lung disease on occasion but often disseminates without much sign of lung disease. Clinically, CNS meningitis and/or skin lesions often first sites that show an infection s present
• Susceptible groups include those where T cells are compromised– AIDS– High dose steroids– Sarcoid treatments– Persons with chemotherapy
63
Rapid Diagnosis via Detection of AntigenLatex agglutination test for cryptococcal capsular
polysaccharide. (Latex coated with antibody)Particularly valuable for CSF from meningitis
where test is more sensitive than direct India Ink
No agglutination Agglutination
64
Cryptococcosis
• Treatment– Amphotericin B + 5-FC combined– Azoles (used for long term therapy or following
initial treatment)
65
Pneumocystis
• Major cause of pneumonia in AIDS. Much more common until prophylaxis was given routinely but still often the primary AIDS-defining infection.
• A fungus (from genes such as for rRNA) that causes respiratory infection
• Human species differs from animal pneumocystis species. • It does not show significant growth in vitro • Does not respond to typical antifungals and used to be
thought to be a protozoan. • Main treatment TMP-SMZ (pentamidine a back-up)
66
Pneumocystis• Genetic analysis suggests multiple reinfections. Little
evidence for chronic carriage (previously believed) • Immunocompetent people totally resistant to disease• AIDS, SCID associated with severe pneumonia
Massive interference with oxygen diffusion from alveoli
68
Prophylaxis
• Instituted when CD4 count <200 l
• trimethoprim-sulfamethoxazole**** • if not tolerated
– dapsone – aerosolized pentamidine– others
Microsporidiosis
69
Agents closely related to fungi that grow intracellularly
Microsporidiosis
Unusual opportunist. Found in AIDS. Related to fungi. May cause Severe GI disease similar to cryptosporidiosis in AIDSAlso can sometimes cause disease at other sites (can be rubbed in eye and infect conjuctiva
Very tiny “spores” within cells detectable with special stains including calcofluor white and the modified acid fast stain used for Cryptosporidium
Treatments are limited
A modified Gram stain used to show microsporidia in diarrhea occurring in AIDS
70
71
Opportunists associated with neutrophil deficiencies
72
Neutrophils (and macrophages) kill spores by phagocytosis
Extracellular killing by neutrophils E.g. invasive candidiasis and invasive aspergillosis
Successful attack on large structures
74
• In USA, most commonly caused by Aspergillus fumigatus
• Other species occasional including voriconazole-resistant A. lentulus which looks like A. fumigatus
Aspergillosis
75
Aspergillus fumigatus
• Grows very well at 45 C• Mold producing abundant blastoconidia on
composts and rotting plant materials• Generally infects via lung (unless injected
somehow: e.g. contaminated bandages on wounds, contaminated i.v. drugs)
77
Pulmonary phagocytes fail to kill sporesin presence of high dose steroid treatment
conidia
78
Hyphae branch (usually 45º) as mycelium expands and penetrates blood vessel walls
Septate branching hyphaethat are
angiotropic
Infarcts follow blood vessel wall penetration
80
CT scan:Characteristic “air” cresent sign can indicate invasive aspergillosis in lung
81
Treatment of Aspergillosis• Newer azoles (Voriconazole and Posaconazole) tend to be
replacing amphotericin B and liposomal Amphotericin B
• Disease progresses rapidly – treatment urgency: i.e. need to treat on suspicion.
• Diagnosis often via histology on biopsy (later confirmed by culture).
• Tests for fungal products in blood are available in some research hospitals but not clear as to value.
82
Aspergillus diseases (not associated with neutropenia)
• Allergic bronchopulmonary aspergillosis– Spores germinate in bronchioles and begin to grow– Allergic mucus response leads to plugging of bronchioles.
Much antibody produced– Significantly reduced lung capacity
83
Aspergilloma
• Fungal mycelium grows as a ball in pre-existing scarred cavity (T.B, sarcoid)
• Corrodes edge: danger eventually of hemoptysis
• Fungus is growing largely saprophytically in area outside reach of immune system
• Treatment usually needs surgery
Cavity with aspergilloma
85
Zygomycosis
• Caused by Zygomycetes • Anamorphs have sporangia and
sporangiospores • Spores germinate to form hyphae and
mycelium. Generally hyphae are wide, often irregular, lack regular septa.
• Hyphae are angiotropic
86
87
Zygomycosis (Mucormycosis)• Systemic disseminated zygomycosis
– Neutropenia is main predisposing factor.– Hyphae are angiotropic and usually irregular
compared to Aspergillus
88
Rhinocerebral zygomycosis
Infection via nasal turbinates and sinuses into CNS
This type of zygomycosis is largely restricted to persons with uncontrolled diabetes where ketoacidosis is present
Damage around orbit can be seen
Candida and Candidiasis
89
90
Candidiasis
Skin and mucosal infection with local invasion of mucosa - (T cell-mediated immunity is important for skin and mucosal resistance)
• Diabetes• T cell deficiency – severe thrush and esophagitis
often in AIDS• Various conditions (often temporary) such as
disruption of normal microbiota (vaginitis common)
91
Skin and Mucosal resistance• Predominantly T cells
important for resistance
• Candida– AIDS defining in
HIV-positive
Release of cytokines fromTh1 cells stimulatesepidermal growth
92
Severe esophageal candidiasis in AIDSulcerative erosions and barium leak
93
In areas where skin remains wet
94
Vaginitis: satellite lesions and cottage cheese-like discharge
95
Routes for invasion of blood
• Normal flora of GI tract may penetrate through wall
• Indwelling catheters left for long term– Candida invades from skin and follows the outside
of the line to the catheter tip. Colonizes tip • Dissemination including occasional endocarditis
Candidiasis
Deep-seated infections• Neutrophils an essential defense.
Neutropenia is a major predisposing factor
97
Routes for invasion of blood
• Normal flora of GI tract may penetrate through wall
• Indwelling catheters left for long term– Candida invades from skin and follows the outside
of the line to the catheter tip. Colonizes tip • Dissemination including occasional endocarditis
98
Disseminated candidiasis in neutropenic patients
Often see skin lesions
99
Dissemination not uncommonly includes eye and vitreous fluid
100
Diagnosis of Candida infected tissues Both yeasts and filaments present = Candida
101
102
Direct smear from urine with pseudohyphae and yeasts
103
Chronic mucocutaneous candidiasis
• Rare• Candida on dry skin
and nails. Masses of antibodies
• Susceptibility is multifactorialT cell (anergy may be
restricted to Candida)EndocrinopathiesZinc deficiency
104
Candida• Main species is C. albicans (normal flora of mucosal
surfaces in humans and majority of vertebrate animals)
• Other species identified by different pattern of sugar assimilations. Species identification can be important for treatment choices, especially when serious disease present.
• Some species resistant to fluconazole or other azoles• Increasing variety of species being seen
105Yeast colonies Yeast cells
Candida species and basic growth form on Sabouraud agar (a high glucose medium)
106
Special test for C. albicans
107
Candida albicans
• Highly flexible morphology with filamentous forms binding different human proteins than do yeast forms. Filaments appear more invasive
• Phenotypic switching enhances capacity to change with environment
• Serious skin and mucosal infections do not cause disseminated disease unless PMNs become dysfunctional
Antifungal agents:
best target is only in fungi not in humans.
Fungitoxic drugs cause fungal death
Fungistatic drugs prevent further growth (gives immune system time to catch up)
5-fluorocytosine (5-FC) fungicidal
enters via cytosine permease
deaminated to 5-fluorouracil (5-FU)(cytosine deaminase absent in human cells)
permease
5-FC 5-FCInside fungal cell
5-FU
deaminase
RNA translation
DNAsynthesisinhibition
Fungal sterols as a target
• Fungal sterols are generally C28 sterols; especially ergosterol.
• (Humans cells have C27 sterols i.e.; cholesterol
Allylamines
(terbinafine = Lamisil®, naftidine)
Inhibit squalene epoxidase .fungistatic
Fungistatic/toxic
Accumulate in stratum corneum. High activity for ringworm infections
Acetyl CoA
Squalene
Squalene epoxide
Lanosterol
Ergosterol
Azoles
Inhibit lanosterol demethylase
Fungistatic
MiconazoleKetoconazoleFluconazoleItraconazoleVoriconazolePosaconazole
Acetyl CoA
Squalene
Squalene epoxide
Lanosterol
Ergosterol
Azole resistance in Candida albicans
Several different types of resistance
• Mutation in target (lanosterol demethylase)• Upregulation of pumps exporting drug
Different drugs affected differently by pumps.
• Different yeast species that are inherently resistant to azoles are appearing as pathogens
Polyenes
First fungitoxic drugs
Amphotericin B (AmB)
Nystatin (oral, not absorbed)
Bind to ergosterol and form ion channels in fungal membrane
Reduced nephrotoxicity of AmB if given as lipid complex or in liposomes
Resistance uncommon (often sterols changed)
Acetyl CoA
Squalene
Squalene epoxide
Lanosterol
Ergosterol
Echinocandins (caspofungin, 2001: micafungin, 2005)
Inhibit (1-3) glucan synthetase involved in forming carbohydrate polymers in hyphal walls.
Approved for invasive aspergillosis and invasive and serious mucosal candidiasis
Resistance when occurs has been linked to mutations in -glucan synthetase
Metabolism is cytochrome P450-independent
Griseofulvin:
Accumulates in stratum corneum
First effective oral therapy for dermatophytes (only fungi responding)
Interferes with microtubules and spindle formation during mitosis
Numerous other drugs are topical agents. May be caustic and impossible to use as systemic therapy
E.g. Whitfield ointment
salicylic acid, benzoic acid (weak acids, not ionized at lower pH)
HA
HA H+A-
acidification
Main types of disease• Allergy • Hypersensitivity pneumonitis
– Occupational in many cases due to chronic exposure to antigens (fungi, actinomycetes, others)
– smallest spores get furthest into lungs– <5 m reach alveoli
• Toxicity– Mushrooms– Ergot – Mycotoxins
• Infections
Mushroom Toxins
• Main lethal toxins act more slowly than rapid non-lethal toxins
• In most cases of potentially lethal toxins, e.g. -amanitin , the main signs of disease in deep organs appear ~one day after ingestion
• Rapidly acting toxins, psilocybin, muscarine usually act with 2 hours typically.
-amanitin• Inhibits RNA polymerase II (mRNA synthesis)• Liver main target but also affects other sites• Toxin excreted in bile (enterohepatic circulation)
and in urine• Fulminant hepatitis can develop.• Depending on extent of liver damage,
transplantation may be needed• Typical disease is associated with feeling a little
unwell a few hours after ingestion, recovering, then becoming really sick the following day
Muscarine• Rarely serious• Cholinergic poisoning (muscarine receptor
binding)• Acts rapidly within an hour typically• Causes PSL (perspiration, lacrimation, salivation)• Atropine is antidote but only needed when very
serious poisoning occurs• Simple test to rule out fear is to check pupil
enlargement in a dark room. Poisoning is associated with retention of pin-point pupils
Ergot• Mainly associated with poisoning via bread
since gets into grain• Contains many toxins. Outbreaks associated
with blood vessel constriction in extremities caused tingling – St Anthony’s fire. Can lead to extremity loss. Other outbreaks associated with bizarre behavior
• Recent outbreaks occur in areas where not good control on food quality
Mycotoxins• Toxins, mainly formed in poorly stored, especially
not fully dried, food but also can form when grain is damaged in field conditions and molds get going before harvest
• Most toxins destroyed by heating (not aflatoxin B1)• In most cases, toxicity at low concentration inhibits
immune response and ,makes livestock less able to fight infection - failure to grow
• Trichothecenes are cytotoxic, have been explored as chemical warfare agents and as potential therapies for cancer
• Aflatoxin B1 is both clearly toxic, killing animals when eaten at high concn. Survivors or ones receiving small amounts develop cancer (especially liver)
Aflatoxin B1• Formed by Aspergillus flavus (and sibling species
Aspergillus oryzae) ONLY• I.e. NOT formed by A. fumigatus• Requires activation by liver enzymes to AFB2a• AFB2a forms adducts with DNA which are
associated with oncogenic activity• In persons infected with hepatitis B or hepatitis C
viruses, the ingestion of elevated aflatoxins in foods is linked to increased liver cancer
• Allowable levels in foods (grains, corn, nuts especially) strictly controlled