Fungal infections Flashcards
Opportunistic fungi
Live in GI tract/on skin of host. Suppression of immune system > dissemination.
Nosocomial infections.
Eg Candida.
Dangers of fungal pathogens?
Some obligate pathogens, but infections are rare in temperate climate zones. Predisposing factors: breaking of physical barriers, immunosuppresion.
Immune response to fungi
Mainly mediated through Th17, IL17 response.
Some TLRs involved in innate mucosal immunity.
Fungi characterists
Discrete eukaryotic phylum.
Non-motile, unicellular or multicellular, aerobic. Heterotroph, first digestion then uptake (exoenzymes).
Fungi structure
Large vacuole. Cell wall consisting of chitin, glucan and mannan polymers. Storage of glycogen (like animals) not starch (like plants). Membranes contain ergosterol (not cholesterol, like animals).
Fungi reproduction
Reproduction by spores (often dispersed by wind).
Sexual (meiotic) and asexual (mitotic) spores.
Basidiomycota
fungus lives undergorund and forms mycelium. over ground: mushroom (reproductive organ)
cells have limited life span
Cryptococcus neoformans
Can cross BBB and cause brain infections.
Often in immunocompromised patients
Ascomycota
Filamentous fungi. Ascus for sexual reproduction
Yeast
S. cerevisae>
sexual reproduction: alpha cell, a cell
Clinical manifestations (4 examples)
Tenia versicolor (Malasseizia furfur) Skin lesions (Cryptococcus neoformans) Oral thrush (Candida labicans) Lung infection (Aspergillus fumigatus)
How can fungi cause disease in humans (3 ways)?
Disease in humans due to allergies, poisoning, infection.
Infection can be severe but very rare.
Why are fungal infections rare?
Most fungi are not able to grow in humans as host. Usually grow on dead matter under environmental conditions. Rare: feed on live matter such as humans with full immune system under non-environmental conditions.
Parasitic lifestyles within hosts (plants/animals)
Plants: biotrophic (long time) or necrotrophic (actively kill)
Animals: commensalism (long-term), few obligate pathogens
opportunism: commensals infect host bc of defense system failure
Defense mechanisms against fungi
- Physical barriers (skin/mucosal surfaces, temperature)
2. Immune systems (fungal PAMPs recognized by TLRs, IL-17/Th17 response: dectin-1/2 recognize fungal glucan)
Predisposing factors for fungal infections
Immunodeficiency,
Breaking of physical barriers
(mainly Candida, Aspergillus)
Candida risk groups
- systemic candidosis dangerous for early born infants
- women: vaginal candidosis
- HIV patients: oral Candida
Classes of antifungal drugs
Polyenes,
azoles/morpholines.
echinocandins
Candida infections (sequence)
Mainly C. albicans.
Colonization(adhesions) > superficial infection (tissue destriction, invasive growth) > invasive infection (immune escape) > systemic infection (hyphae > yeast transition, spread through blood stream)
C. albicans
Polymorphic yeast: yeast form and hyphal (mycelial) form.
Lives as commensal in GI-tract. Reproduces mainly clonal.
Porduces: SAPs, secretory lipases, phospholipases, peptide importers.
Tissue destruction by Candida
Hyphae allow tissue penetration.
Contact sensing (thigmotropism).
Growing hyphae secrete molecules that destroy host cell (stage-specific enzymes).
Fungal cell wall - functions
Prevents lysis. Provides matrix for protein attachment. Additional compartment for nutrient acquisistion/digestions.
Site of host-pathogen interaction!
Fungal cell wall - defense (components)
- carbohydrate layer (prevents lysis, manual damage)
- dual composition: glucan/chitin (compensation if either is defective)
- mannoprotein coat (protection, masking)
- enzymes that negate host defense
Fungal cell wall adhesion components
- neg mannan (adherence to pos. plastic)
- specific adhesion molecules
- biofilm formation
(> dissemination into blood stream > fungal sepsis)
Histoplasma capsulatum infection
Environmental form (mold/conidia) and disease causing form (yeast). Histoplasmosis: mostly asymptomatic, unless immunocompromised. (Healthy: encapsulation/calcification of fungal cells.)
Iron-aquisition: surface receptor captures hemin, secretion of siderophores (chelate iron), ferric reduction
Aspergillus fumigatus infection
Grows on compost > inhalation of conidia > germination in immunocompromised > localised infection.
Response: Phagocytosis (but: fungi produce ROS-scavenging melanin pigments).
MICx
MICx: minimal inhibitory concentration (conc at which growth is inhibited by at least x%)
Measuring antimicrobial drug susceptibility
Epsilometer-test (test strip with gradient), broth microdilution (ELISA)
Approaches to fight fungal infections
1) improve host immune status
2) inhibit pathogen growth (fungistatic)
3) kill pathogen (fungicidal)
(immunization not possible)
Polyenes (Amphotericin B)
Bipolar. Forms pores in membrane by complexing ergosterol > proton gradient disturbed > cell death/growth-stop
Azoles
Target ergosterole biosysnthesis:
Ergosterol depletion >membrane becomes stiff, protein compounds cannot interact.
Enzme inhibition by toxic byproduct:
inhibit ERG11/CYP51 > membrane alteration, formation of growth-inhibiting byproduct
Echinocandinds
Target glucan synthesis. Enzyme inhibition.
Reasons for fungal therapy failure
Species shift due to intrinsic resistance: new drug > depletion of susceptible species > rise of resistance species
Resistance transmission
No resistance plasmids. No horizontal gene transfer. No spread of resistant strains between patients.
Transient resistance.
Generated via upregulation of compensatory mechanisms.
Eg cell wall strengthening, increased drug efflux etc
Resistance mutations
Amphotericin B resistance: ERG3 mutation > loss of ergosterol, no toxic byproduct
Azole resistance: ER11/CYP51 mutation > > reduced durg affinity, increased efflux
Echinocardins : (glucan synthase)
Phylogenetic classification of fungi
By 18S sequencing of ribosomal RNA.
On basis of sexual reproduction
Why is it difficult to find drug targets in fungi?
Are eukaryotes > similar to us, selectivity problematic
