2. Introduction:
Fungi are Eukaryotic, spore-bearing, heterotrophic
organisms that produce extracellular enzymes and
absorb their nutrients.
Fungi – Kingdom Mycota
Divisions - Phyla – Chytridiomycotina, Glomeromycota,
Zygomycota, Basidiomycota, Ascomycota
Microsporidia, Neocallimastigomycota
Fungi:
Of the 50-250,000 fungal species less than 200
cause human disease and only a dozen or so on a
regular basis
Yeasts: unicellular fungi reproduce by budding
Moulds (filamentous): produce hyphae and
mycelium
Dimorphic: grow as moulds (environment) or
yeasts (in human host)
Cell wall:
The fungal cell wall is essential for growth and
viability
Pathogen associated molecular patterns (PAMPS) –
the immune systems of most organisms recognise
3. fungal cell wall components such as ß-d-glucan
and mannans
Melanin – is an important component of fungal cells
walls especially in spores. It protects against UV
radiation and Reactive Oxygen Species
Composition can affect action of antimicrobial
agents – Candida mutants lacking
mannosylphosphate in their cell wall displayed
enhanced resistance to cationic antimicrobial
peptides via reduced peptide binding (Harris et al.
2009)
Mycotoxins:
Mycotoxins are low-molecular-weight secondary
metabolites of fungi
Often produced by food spoilage organisms or in
basidiocarps (Mushrooms)
mycotoxins are an important chronic dietary risk
factor
Aflatoxins - Aspergillus spp.; Citrinin – Penicillium
spp.; Ergot Alkaloids – Claviceps spp. – Ergotism;
Fuminosins – Fusarium spp.
4. Humans and Fungi:
Humans present a series of diverse
microenvironments and barriers to nutrient
acquisition, including:
pH – human body has wide pH range – fungi prefer
acidic conditions
Temperature – 37 °C is inhospitable to many fungi
Nutritional immunity – sequestration of essential
micronutrients such as iron
Physical barriers – skin is composed of polymers
that many fungi cannot degrade
Gaseous tension – the ration of O2 to CO2 varies
between the surface and within tissue
Host immune system
Innate immune system
Pamps, prr
Tlr dectin (segal)
5. Primary Route of Infection
Fungi That Cause Human Infection:
• Yeast: Candida albicans, Cryptococcus neoformans
• Mould: Aspergillus, Penicillium, Fusarium,
Scedosporium
• Dimorphic: Histoplasma capsulatum
Classification of human fungal infections:
• Superficial: ringworm (dermatophytes), thrush
(Candida species), dandruff (Pityrosporum)
• Subcutaneous: involve the dermis of the skin, deep
tissues or bone. Usually found in tropics/sub-tropics
where caught walking barefoot eg, mycetoma
6. • Systemic: due to pathogenic (Histoplasma) or
opportunistic (Aspergillus) fungi
Dermatophytosis:
Tinea – describes an infection caused by a
dermatophyte (ringworm fungi)
Specialised pathogenic fungi
Caused by – Trichophyton, Microsporum,
Epidermophyton
Worldwide distribution
Key feature is keratin degradation
Don’t tend to grow at 37 °C
Invasive Fungal Disease:
Invasive fungal infections are major causes for
morbidity and mortality in severely ill or
immunocompromised patients
Main causative agents are Candida spp, Aspergillus
spp.
Emerging infectious fungi – Fusarium spp.
Scedosporium spp, Zygomycetes, e.g. Mucor spp
Invasive aspergillosis (IA) occurs in 10% of patients
undergoing haematopoietic stem cell
transplantation (HSCT) and 25% in autopsy of
leukaemic patients
IA has reported mortality rates of 86% and 66% for
pulmonary and sinus IA
7. Candida spp:
Is usually a harmless commensal organism
It causes both superficial and invasive infections where
the host is immunocompromised or epithelial barriers
have been damaged
Candida albicans – primary cause of candidiasis
Aspects of virulence
Dimorphism
Phenotypic and mating type switching
Biofilms – higher resistance to antifungals
Aspergillus fumigatus (Neosartorya
fumigata):
Ubiquitous soil microbe
Decay of organic matter in compost heaps
Dispersed by spores, conidia.
Opportunistic pathogen of mammals and birds
Most important cause of Invasive Fungal Disease in
Immunocompromised individuals
8. Mycetoma:
Is most common in Africa and South America
Is a chronic destructive disease affecting skin,
underlying tissue and sometimes adjacent bone
Caused by various fungi including Madurella spp.,
Scedosporium spp., Leptosphaeria spp.
Infection results from traumatic implantation of
spores into the skin, e.g. thorns, splinters
Histoplasmosis:
The most common endemic mycosis in North
America, also found in Central and South America
A thermally dimorphic fungus, found as a mould in
the environment but as budding yeast in tissue
Inhalation of spores is the primary route of
infection
Prolonged exposure to aerosolised spores is a
major risk factor
Fewer than 5% of individuals exposed to the fungus
develop symptomatic disease
9. Diagnosisof Fungal Infection:
Microscopy – direct staining of fungi in sections
can distinguish between yeasts and molds
Culture – can lead to diagnosis of the exact
species. Candida can be grown in blood cultures
but Aspergillus cannot
Serology – direct detection of fungal antigens in
serum samples. ELISA to detect galactomannan
(Platelia – BioRad) or detection of ß-d-glucan, does
not detect Cryptococcus spp or zygomycetes
Radiography – direct observation of patients to
spot characteristic signs of infection, e.g. halo
signs, cavities
PCR – assays target fungal ribosomal operon,
nucleic acid extraction from blood or BAL.
Potentially very sensitive but still no standardised
tests
Antifungals
Azole Fungicides:
Itraconazole
Voriconzaole
Posaconazole
Fluconazole
Inhibit ergosterol
biosynthesis – affect
cell membranes
10. Echinocandins:
Caspofungin
Micafungin
• Inhibit 1,3-beta-
glucan synthase,
affects cell wall
• Broad spectrum,
low toxicity
Fluorinated Pyrimidines:
Flucytosine (5FTC)
• Inhibit nucleic
acid synthesis
Polyenes:
Amphotericin B
Nystatin
• Forms Pores in
membranes by
interacting with
ergosterol
• Toxic
Antifungal Drug Resistance:
Efflux pumps in fungi of the ABC and MFS
superfamilies and variation in target genes (e.g.
cyp51A) are involved in resistance to azoles
Resistance to polyenes is uncommon. Resistant
isolates of rare Candida spp show altered levels of
membrane sterols
11. Resistance to FTC is associated with reduce uptake
and reduced activity of genes responsible for
conversion of FTC to FUMP; FUMP disrupts RNA
synthesis
Mutations in the FKS gene (target) can lead to
resistance to echinocandins or resistance may be
induced by cell wall salvage mechanisms….
12. Reference:
General Mycology Books
Introduction to Modern Mycology by J.W. Deacon
The Fungi by M.J. Carlile, S.C. Watkinson and G.W.
Gooday
Review Articles
Cooney, N. M. & Klein, B. S. (2008). Fungal
adaptation to the mammalian host: it is a new
world, after all. Curr Opin Microbiol 11, 511-516.
Hope, W. W., Walsh, T. J. & Denning, D. W. (2005).
Laboratory diagnosis of invasive aspergillosis.
Lancet Infect Dis 5, 609-622.
Segal, B. H. (2009). Aspergillosis. N Engl J Med 360,
1870-1884.
Websites
http://www.doctorfungus.org/
http://www.aspergillus.org.uk/
