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Fungal infections
Classification, mechanisms
| Term | Definition |
|---|---|
| What classification are fungi? | Eukaryotes |
| What is the structure of fungi? | Membrane bound nucleus w/ several chr, genomic DNA of exons/introns, PM w/ ergosterol, polysaccharide fungal cell wall, cytoplasmic organelles |
| How do fungi get their nutrition? | Absorb nutrients by feeding on dead plant/animal material in soil -> recycle nutrients, some feed on living plants -> secrete enzymes into immediate environment -> extracellular cellulose digestion -> absorption through fungal cell walls |
| What is the structure of fungal cell walls? | Glucan/mannan/galactomannan, inner chitin microfibrils (straight beta 1,4-linked NAG residues), outer glucan layer (branched beta 1,3-linked glucose residues), embedded glycoproteins (Asp N-linked, Ser/Thr O-linked), mannose glycoprotein channels |
| What are the types of fungi? | Yeasts, filamentous moulds, dimorphic fungi |
| What are the characteristics of yeasts? | Oval/round, unicellular, mitotic proliferation -> symmetrical binary fission (Pneumocystis), asymmetrical budding (Candida/Cryptococcus), form pseudohyphae (Candida -> cell elongation but no separation) |
| What are the characteristics of filamentous moulds? | Hypha (thin branching multicelluar cylinder) -> septate (Aspergillus - compartmentalised septum), aseptate (Mucor - many nuclei in common cytoplasm), apical growth by mitosis, mycelium (interwoven mass of compacted hyphae layers) |
| What are the characteristics of dimorphic fungi? | Filamentous mould in environment (24 degrees) and yeast in mammal body (37 degrees) -> difficult to spread when large filamentous mould |
| How do fungi reproduce? | Spore production, sexual reproduction, asexual reproduction |
| What are the characteristics of spore production? | Small tough light fungal cells -> adapted for dispersal to new habitats, adapted for survival in hostile environments until conditions more favourable for germination |
| What are the characteristics of asexual reproduction? | Mitotic spores produced by anamorph/mitotic state of diferentiation -> energy dense w/ low metabolic rate, dispersed by wind/water/animal contact -> germination in favourable habitat -> multiplies by mitosis |
| What are the species specific types of asexual reproduction? | Yeast -> internal endospores, moulds (Aspergillus -> conidium on external hypha, Mucor -> sporangium on internal hyphae), Deuteromycota -> imperfect fungi always in asexual state |
| What are the characteristics of sexual reproduction? | Telomorph/meiotic state of differentiation -> haploid fungus produces sexual motile gametes/hyphae -> nuclei fuse -> diploid fungus -> chr reassortment/recombination -> meiotic reduction division -> haploid sexual spores |
| How can we classify fungi? | Based on sexual spore formation -> ascomycota, basidiomycota, zygomycota, deuteromycota |
| What are the characteristics of ascomycota? | Sexual spores w/in internal ascus tubular structure, asexual spores on external conidia -> yeasts (Pneumocystis, Candida), moulds (Aspergillus, Fusarium, Microsporum), dimorphic (Histoplasma) |
| What are the characteristics of basidiomycota? | Sexual spores on external specialised basidium club-like structure -> yeasts (Cryptococcus, Malassezia) |
| What are the characteristics of zygomycota? | Sexual spores from specialised sexual hyphae fusion, asexual spores on internal sporangium -> moulds (Mucor, Rhizopus) |
| What are the characteristics of deuteromycota? | Asexual spores on external conidia -> dimorphic (Para/coccidioides, Sporothrix) |
| How do yeast get their nutrition? | Live in moist environments -> nutrient pool |
| How do filamentous moulds get their nutrition? | Hyphae penetrate into solid food material |
| How do saprotrophs get their nutrition? | Feed on dead plant/animal material -> cause food spoilage (bread mould) and rare human diseases (accidental inhalation/implantation into body after skin laceration), cause damage to property (wood rot, bathroom mould) |
| What are examples of living plant parasites? | Banana Fusarium infection, tree Dutch Elm disease (Ash dieback) |
| What metabolites do fungi produce? | CO2 (yeast raising bread dough), ethanol (alcoholic beverages), Abx (penicillin, cephalosporins, streptomycin), immunosuppressant (cyclosporin in transplant/autoimmune diseases), ergometrine/ergotamine, recombinant proteins (vaccine Ag), aflatoxin |
| What are host defences against fungal infections? | Structural barrier (skin keratinised epithelium, moist mucosal mouth surfaces) and commensal bacterial flora (mouth/genital tract) -> inhibit epithelial fungi proliferation |
| How can host defences against fungal infections be overcome? | Structural barrier damaged by physical trauma/burns/radiotherapy/anti-cancer drugs -> invade epithelium into connective tissue/blood vessels -> disseminate to other body parts, commensal flora reduced by broad-spectrum Abx -> Candida albicans overgrowth |
| How are fungi recognised by the host immune system? | Lectin PRRs -> binds to fungal cell wall polysaccharide structures, soluble in plasma (MBL C5a activates complement cascade) -> expressed by DC, macrophages, neutrophils, epithelial cells |
| What PRR recognises beta-1,3 glucan? | Dectin-1 -> Syk -> NLRP3 (inflammasome/caspase 1) or CARD9 (NF-kappaB -> pro-TNFalpha) |
| What PRR recognises mannan? | Dectin-2 |
| What PRR recognises mannose-rich structures? | DC-SIGN/Mincle |
| What PRR recognises phospholipomannan? | TLR 2 |
| What PRR recognises O-linked mannose? | TLR4 -> Myx88 -> NF-kappaB |
| What PRR recognises N-linked mannose? | Mannose receptor |
| How is a CD4+ T cell response initiated? | TGF/IL-1beta/6/23 -> Th17 cells -> IL-17/22 -> mouds IL-12/TNFalpha -> Th1 cells -> IFN-gamma -> intracellular fungal infection |
| What is the effect of IL-17? | Secreted from Th17 cells -> anti-microbial peptide production secreted onto mucosal surface |
| What is the effect of IL-22? | Secreted from Th17 cells -> activate tissue/mucosal surface neutrophils |
| What fungal recognition deficiencies are there? | Impaired fungal beta-1,3 glucan sensing (loss of function mutation) -> chronic fungal nail infection/mucosal Candida, Dectin-1 deficiency (beta-1,3 glucan), CARD9 mutation (caspase recruitment domain-containing protein 9) -> chronic yeast/ascomycota |
| What is the result of impaired IL-17? | Rare autosomal recessive inherited disorders -> IL-17 R deficiency -> susceptible to chronic superficial Candida, autoAb against IL-17/22 -> inactivated cytokines -> AIRE mutations, chronic Candida |
| What can increase susceptibility to fungal infections? | Loss of structural barrier, impaired fungal recognition, impaired IL-17, impaired neutrophil #/fuction, impaired T cells/macrophage #/function |
| What is the result of impaired neutrophil #/function? | Deep fungal infections by opportunist filamentous moulds (Aspergillus, Mucor), caused by inherited chronic granulomatous disease (mutation in neutrophil NADPH oxidase genes -> normally generate ROS to kill fungi) -> Aspergillus infections |
| What is the result of impaired T cell/macrophage #/function | Predisposed to yeast superficial/deep infections (Candida, Pneumocystis, Cryptococcus), predisposed to dimorphic fungi (Histoplasma), caused by lymphoma, AIDS, immunosuppressants (Cyclosporin/anti-TNF alpha/anti-IL-17 mAb) |
| What anti-fungal drug targets are there? | PM, microtubules, cell wall, DNA synthesis |
| What drugs are polyenes? | Amphotericin, Nystatin -> target PM ergosterol to create membrane pores and induce electrolyte leakage |
| What drugs are azoles? | Clotrimazole, fluconazole -> target 14-alpha-demethylase (CYP450) -> lower conversion of lanosterol to ergosterol for PM |
| What drugs inhibit ergosterol synthesis? | Terbinafine (inhibit squalene epoxidase -> squalene converted to squalene epoxide), azoles (inhibit 14-alpha-demethylase) |
| What drugs inhibit fungal microtubules? | Griseofulvin -> interrupt cell cytoskeleton -> can be teratogenic |
| What drugs inhibit the fungal cell wall? | Echinocandins (caspofungin) -> inhibit beta-1,3-glucan |
| What drugs inhibit fungal DNA synthesis? | Flucytosine -> converted by cytosine deaminase to 5-fluorouracil -> incorporated into RNA (inhibit RNA synthesis), inhibit thymidylate synthase (inhibit DNA synthesis) -> can cause bone marrow suppression |
| How do fungi evade phagocytosis? | Non-lytic expulsion from phagocytes, pseudohyphae kill macrophages, survive/replicate in macrophages |
| How do fungi cause infection? | Accidental ingestion of preformed fungal toxin in food -> absorbed from GI tract into circulation, inhaled fungal Ag exposure triggers hypersensitivity -> Alternaria mould airborne spores inhaled -> type I hypersensitivity, direct body invasion |
| How do fungi cause superficial infection? | Infect keratinised tissues -> dermatoophyte moulds (Microsporum, Trichophyton, Epidermophyton) hyphae drill through keratin -> spores (direct/indirect contact - athlete's foot) -> fungal Ag induce type IV hypersensitivity -> chronic Candida infection |
| How do fungi cause subQ infection? | Saprotrophs -> traumatic implantation penetrating skin (Sporotrhicosis) -> chronic nodules in subQ tissue/lymphatics -> rose filamentous moulds -> slow development (localised infection/lymphatic spread) |
| What is tinea? | Superficial fungal infection of dead keratinised tissue (ringworm) -> dermatophysis -> caused by Trichophyton |
Created by:
vykleung
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