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Fungus Flashcards

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Biology 101 flashcards
0
Q

Fungal cell wall

A

Membrane - ergosterol instead of cholesterol
(target of amphotericin)
Cell wall - unrelated to bacteria
- lots of cell mass, 90% polysaccharides
- inner - glucan and chitin - glycosilidic cross-link -> stability
- glucan also allows expansion and contraction (middle layer)
- glucan is key antigen for immune response
- outer - glycoproteins

Capsule - Cryptococcus only
- glucuronoxylomannan (GXM) polysacc -> shed during infection

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1
Q

Overview of fungi

A

Kingdom within eukaryotes (have nuclear membrane)

  • > 3 Phyla -> 3 medical genera (by sexual structure)
  • Ascomycota (asci contain ascospores)
  • largest, most diverse -> Aspergillus, Candida, (Saccharomyces, Neurospora)
  • Basidiomycota (basidium) - Cryptococcus neoformans
  • Zygomycota (zygosporangium) - Mucos sp.

Non-motile (medically-important)
Digest food externally -> absorb
Both sexual and asexual reproduction
Limited anti-fungal rx dt similarities with mammalian cells

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2
Q

Antifungal overview

A

Fewer targets due to similarities with mammalian cells

Azoles -> p450 enzymes - ergosterol synthesis
Polyenes -> ergosterol
Echinocandins -> beta glucan synthesis

Resistance - usually genomic vs acquired elements

  • increased expression
  • alteration of targets
  • can have high mutation rates (-> use multiple agents)
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3
Q

Polyene antifungals

A

Bind to sterols -> disrupt membrane permeability
- greater affinity for ergosterol (fungi) vs cholesterol (host)
Poorly absorbed from GI
High toxicity

Amphotericin B - used systemically but toxic, fungicidal
Nystatin - only used topically or oral (not absorbed)
- only fungistatic at attainable concentrations

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4
Q

Azoles antifungals

A

Target p450 enzyme for ergosterol synthesis

  • > weird steroids in cell membrane
  • > inhibit membrane/hyphae growth (static)
  • also more susceptible to phagocytosis

Oral, systemic but hepatotoxicity in 0.01%
Thrush, systemic, chronic (ex AIDS)
Fluconazole, ketoconazole

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5
Q

Echinocandins

A

Inhibit synthesis of cell wall
- beta glucan synthase
- cidal
Caspofungin

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6
Q

Antimetabolite antifungals

A

Flucytosine
Uracil -> 5F-uracil -> inhibits protein synthesis
Thymidine -> 5F-deoxyuracil -> inhibits DNA synthesis

Can be cidal or static depending on organism

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7
Q

Overview of fungal growth

A

Exogenous (free-living) vs
Endogenous (must be in human or animal)
- ex Candida in GI

Absorptive heterotrophs - secrete enzymes, absorb smaller compounds

Acid tolerant (grow optimally at pH s agar

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8
Q

Secondary metabolites

A

Synthesized by non-ribosomal polypeptide or polyketide synthase
NOT necessary for fungal growth

Beneficial:
- lovastatin from Aspergillus
- equisetin (anti-viral) from Fusarium
- penicillin from Penicillium
Aflatoxins - produced by Aspergillus, Fusarium
- grain or peanuts contaminated
- mycotoxicoses, carcinogens (low amounts needed)

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9
Q

Yeast

A

One of two main forms (vs hyphae - different organisms)

Oval cell
Division = budding/fission
apical -> pinches off cell and nuclear membranes
Smooth pasty colonies

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10
Q

Hyphae

A

Elongated filament

Septa -> mononuclear segments
 - vs aseptate/coenocytic (division and growth without fission)
Growth - exclusively apical
 - Spitzenkorper = special vesicles near tip
 - can extend into new substrate
  - penetrating due to turgor pressure
  - release polymer degrading enzymes
 - can be rapid (40 microns/s)
 - can also grow aerial -> spores
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11
Q

Spores

A

Reproductive propagule
- conidia = asexual - either micro (airborne) or macro (-> ID)
- arthrospore - fragmentation of hyphae
Usually form from aerial hyphae
- hyphae + spores = mycelium
Can be small (1 micron) -> lower respiratory

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12
Q

Overview of yeast growth

A

Often dimorphic - both yeast and hyphal depending on env’t
- elongated yeast = pseudohyphae = intermediate form
- beginning of hyphae from yeast = germ tube
Classical thermal
- soil (low temp) -> filamentous hyphae -> conidia
- body temp -> yeast
- unnatural, “dead-end” env’t (no spore production)
Candida albicans
- soil -> yeast; body -> hyphae
- find yeast, hyphae and pseudohyphae in infected tissue

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13
Q

Cutaneous mycoses pathogenesis

A

Dermatophytes - keratinase -> nutrient source
- filamentous septate hyphae
- invade hair from inside (endothrix) or outside (ectothrix)
-> produce micro and macroconidia
Epidermophyton
Trichophyton - anthrophilic - human-> human via skin fragments
Microsporum - zoophilic - pets
- fluoresces in UV light

Non-dermatophytes - some dimorphic
Cladosporium - geophilic - soil (dimorphic!)

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14
Q

Cutaneous mycoses clinical

A

Most common fungal infections (25% prevalence)

Dermatophytes -> tinea (ex capitus, pedis, cruris)
Tinea versicolor
- Malassezia furfur (normal flora) -> dandruff, hypopigmented
- dimorphic yeast and hyphae
- lipophilic, can be in blood if IV lipids
Tinea nigra - Cladosporium werneckii -> produces melanin

Dx: skin scrape -> KOH mount with Calcofluor
- can do culture (Sabourad’s) -> microscopy
Tx: topical antifungal (azole)
- oral azole, terbinafine, griseofulvin
- ciclopirox/Penlac for nails
- limit moisture, may need ID

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15
Q

Subcutaneous mycoses

A

Rare!
Puncture or abrasion -> contamination with soil fungus

Sporotrichosis:
- Sporothrix shenkii - classical dimorphism (“cigar” yeast at 37C)
- puncture -> nodules (-> disseminated if immune compromise)
Chromoblastomycoses
- dematiaceous (multiple soil species) - produce melanin
- puncture -> wart-like crusty lesion with brown cells
- mycetoma - abcess with pus -> requires surgery

Dx: KOH mount, biopsy
Tx: oral azole or flucytosine
Prevention - protective clothing

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16
Q

Overview of fungal infections

A

Cutaneous -> keratinized skin, nails, hair
- direct contact -> inflammatory rx
Subcutaneous - trauma -> dermis, fascia, etc
Systemic - blood or organs, from GI, resp
Opportunistic - invasive in immune compromised

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17
Q

Candida epidemiology

A

Normal colonizer of oral, vagina, GI (from birth)
- DTH skin test (+) in all immunocompetent

Infections - common invasive life-threatening
- most common fungal BSI, 4th most common nosocomial BSI
- immunocompromised (liver transplant)
- invasive procedures (GI surgery, catheters)
- ICU (trauma, NICU)
Almost all are Candida albicans
400K/yr worldwide, most in developed

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18
Q

Candida pathogenesis

A

Source: normal endogenous (or nosocomial in ICU)

Non-classical dimorphism (polymorphic) - all forms found in tissue
Yeast - normal room temp
- overgrow if immunocompromised (esp cellular), antibiotics
-> germ tubes -> vegetative/invasive hyphae
-> also pseudohyphae
Hyphae
- vegetative - form on or below agar (NOT aerial)
- adhesins vs keratinocytes ->
- invasion -> white punctate lesions -> thrush/pseudomembrane
(usually limited to upper epithelial layers)
-> yeast spread to new sites (also stress resistant)
Bloodstream if heavy skin colonization, immune compromise
- or biofilm on catheter -> yeast

19
Q

Candida clinical syndromes

A

Normal hosts:
- vaginitis common
- diaper rash (moist areas)
- oral erythema
Immunocompromised
- oral thrush - infants, HIV, chemo (poor cellular immunity), dry mouth
(one of earliest, most common after HIV)
-> pain, dysphagia, susceptibility to other infections
- esophageal - leukemia, lymphoma, suppressed - serious

20
Q

Candida species

A

C albicans - most common (50-60%)
- positive rapid germ tube test (1 hour in 37C)
C glabrata - second most common
- normal commensal, also only in mammal hosts (not env’t)
- more resistant to azoles, amphotericin
- no germ tubes or pseudohyphae
- 15% of infections worldwide
C tropicalis, parapsilosis
- negative rapid germ tube, positive pseudohyphae
- similar presentation to albicans

21
Q

Candida diagnosis

A

Mucous, skin
-> tissue - KOH mount, PAS, GMS
-> culture (blood, Sabourad’s) -> smooth white colonies
Deep/blood infections - difficult
- blood cultures (Wright’s) may be negative
- new molecular methods -> higher sensitivity?

Identification

  • rapid germ tube - (+) for albicans
  • chlamydospores on special media - not normally performed
  • definitive = fermentation, assimilation of carbon sources
22
Q

Candida treatment

A

Oral - prevent with nystatin, azole rinses etc
- tx with fluconazole, caspofungin (inc esophageal)
Vaginitis - topical azoles, fluconazole
Disseminated - use scoring system/algorithm
- usually fluconazole
- echinocandins, azoles, amphotericin

23
Q

Immunity to fungi

A

Innate = essential!
- non-inducible (skin, microbiome)
- recognition via PAMP, lectin receptors
(cell wall beta glucan vs dectin-1 receptor)
- neutrophils
- macrophages
Adaptive
- mostly CD4 -> Th1 -> IFN-g -> macrophage -> granulomatous response -> can have reactivation
- some Th17 -> recruit neutrophils, induce epithelial protection at mucosal surfaces
- antibodies present but unclear fx

24
Q

Overview of fungal dx

A

Histology
- KOH or NaOH - disolves tissue, leaves fungi intact (dt carbs)
- PAS, methanamine silver
- india ink -> Cryptococcus capsule
Culture - may be dangerous due to spores!
- yeast -> 48 hours -> differential media
- molds - slower, may be negative
-> wet mount with lactophenol cotton blue to ID spores
- pathogens can grow at 37C!!
DNA probes
Serology

25
Q

Immune susceptibility to fungal

A

Helps determine likely/posible pathogens

Breach of non-inducible - microbiome (antibx), catheters
Can be receptor, signalling, recruitment, effector
Receptor - ex dectin-1 polymorphism -> Aspergillus
Effector - esp neutrophils, macrophages
- CD4 -> Th1 -> IL12, IFNg, TNFa = essential
- also CD8, Th2, Th17, Treg -> length/severity

Ex: Immune reconstitution inflammatory syndrome (IRIS)
-> increase in CD4 vs established pathogens (Cryptococcus, Pneumocystis jirovecii)

26
Q

Fungal pre-dispositions

A

Neutropenia -> Candida, Aspergillus, Mucormycoses, Trichosporon, Scedosporium, Fusarium

T-cell (HIV) -> Cryptococcus, Histoplasma, Blastomyces, Coccidioides, Paracoccidioides, P marneffi, dermatophytes, Candida

Skin/mucosal trauma - Candida, Aspergillus, Fusarium
Chronic granulomatous - Aspergillus, Candida (disseminated)
TNFa inhibitors - Aspergillus, Histoplasma
Graft vs host - Aspergillus

Ketoacidosis, Deferoxamide - Mucormycoses

27
Q

Overview of endemic fungal pathogens

A

Inherent/primary pathogens! (do not need immune compromise)
Geography - restricted region!
- 3-24,000 deaths/yr in US, mortality 1-75%
Exposure - inhalation of spores, rarely human-human
-> dimorphism (yeast at 37C)
- lab cultures can be dangerous
Immune = cell-mediated -> macrophage -> granuloma
- latency within granuloma
- disseminates in immune compromise
- much more severe in HIV+
- skin DTH to determine exposure
- highly varialble - can be short assymptomatic -> latent, lethal

Coccidiodes
Histoplasma
Blastomyces
Paracoccidiodes
Penicillium marneffei
28
Q

Coccidiodes mycology

A

C immitis, posadasii
Barrel arthroconidia (2-6 micron) -> fragment -> airborne
- within alveoli -> large spherules (12-100 micron)
-> rupture -> release endospores -> new spherules

150K cases annually in US
southern CA, Arizona -> central Texas (dry, hot, alkaline)
- reportable, 2/3 cases in AZ

29
Q

Coccidiodes presentation

A

Macrophages -> neutrophils (resistant to neutro) ->
Cell mediated immunity = protective
- 2-4 weeks, DTH (+)

Often asymptomatic - more sx in dark-skinned men (ex Filipino)
Pulmonary - 40% lower resp (sputum, CP, fever, anorexia)
- 2-6 weeks
- “Valley Fever”
Erythema nodosum (EN) - 10%
- non-septic nodules in lung
- indicate protective immunity (not disseminated)
Rare - disseminated (usu defective cellular immunity)
-> granulomatous skin lesions, osteolytic, meningitis
- more common in third trimester

30
Q

Coccidiodes dx and tx

A

tissue -> KOH or stains -> spherules
Sabourad’s culture -> dimorphism, tissue form
- hazardous!!
Serology - IgM (2-4 weeks) -> IgG
- proportional to current burden (increase if disseminated)

Primary - no tx needed
Disseminated - azoles, amphotericin

31
Q

Histoplasma mycology and pathogenesis

A

Branching septate hyphae ->

  • tuberculate macroconidia (ID)
  • microconidia -> inhaled -2-3d> ovoid yeast
  • > intracellular growth within macrophages
  • > migrate widely to nodes, spleen, liver
  • 9-15d> cell-mediated immune response

Virulence = growth within macrophages
- produces bicarb, ammonia -> raises pH of phagosome
Can have extracellular yeast, infect epithelial cells

32
Q

Histoplasmosis presentation (and geo)

A

Widely distributed
Ohio and Mississippi River Valleys (up to 90% DTH +)

Most assymptomatic
Acute pulmonary - self-limited, flu-like
- anatomic abnormalities -> colonize pulmonary recesses
Opportunistic -> chronic - similar to TB

33
Q

Histoplasma dx

A

Disseminated - blood (Wright’s) + for intracellular yeast
Tissue stain
Culture on special media -> dimorphic with tubercular macroconidia
Antigen in urine
Serology - decreases when inactive
- cross-reacts with Blastomyces

Skin test only used for epi (disrupts serology)

34
Q

Blastomyces mycology and geography

A

Mold -> pear conidia ->
Characteristic yeast (= diagnosis via KOH, stain)
- thick-walled, large with broad based single bud

Geography - similar to Histo? skin test cross-reacts…
- Ohio and Mississippi rivers, Carolinas
- recreation along wooded waterways
Clinical disease is more common
Dogs susceptible in endemic zones - frequently severe/lethal

35
Q

Blastomyces pathogenesis

A

Conidia -> inhalation -> yeast -> multiply
-> disseminate via macrophages, blood, lymph
Bad1 = virulence - promotes uptake by macrophages
-> replicate and travel until activated by T cells
- homology with invasin of Gram (-)
Immunity - several weeks -> T cells, Ig, DTH+ -> protective

Presentation:
Asymptomatic or flu-like
Disseminates -> organs (not uncommon) - can have 60% mortality
Trophic for skin, bone -> ulcerative lesions

36
Q

Paracoccidioidis

A

South America - forested, tropical, armadillo nests
Most common men (coffee plantation)

Large yeast with multiple blastoconidia -> “pilot wheel”

Often chronic, subclinical with latent periods
primary pulmonary -> mucosal lesions (50%) -> cutaneous (25%)

37
Q

Penicillium marneffei

A

Only thermally dimorphic (pathogenic) Penicillium

SE Asia - 3rd most common infection with HIV regionally

Pulmonary -> disseminated -> often fatal

38
Q

Overview of opportunistic fungi

A

Geographically widespread
Almost always affect immunocompromised
- 100% lethal if untreated (still high if treated)
Grow well at 37C

90% of disease from 4 genera:
Cryptococcus
Aspergillus
Mucor
Pneumocystis
39
Q

Cryptococcus epidemiology

A

Almost all cases associated with AIDS or other compromise
Most life threatening infections of any fungus
- most meningo-encephalitis
Est 1 million worldwide - 620K deaths/yr in sub-Saharan
- mortality rate 15-20% US treated, 55-70% South America, Africa

C neoformans - widespread in soil, pigeon shit -> compromised
- 2 different serotypes
C gatti - trees, Canada -> Pacific NW
- both compromised and healthy

40
Q

Cryptococcus pathogenesis

A

Basidiomycetes - grows as yeast in agar and tissue
- urease (+), grows well at 37C
-> inhalation of spores or dessicated yeast
Capsule - glucuronoxylomannan (GXM)
- essential for virulence
- extracellular - protects within phagolysosome
-> ID via India Ink stain
Phenol oxidases - DA -> melanin - protects from oxidative damage

Lungs -> systemic -> preferential to CNS -> meningo-enceph
- either microcapillaries -> BBB or via macrophages

41
Q

Cryptococcus clinical

A

Meningo-encephalitis most common
- insidious onset -> h/a, stiff neck after high fungal burden
Pulmonary -> cough, SOB, encapsulated nodules
Subclinical urinary, resp

Dx:
Capsule antigen in urine, plasma, CSF = definitive
- latex agglutination assay
Can visualize capsule - India ink, mucicarmine, PAS, methanamine
- less sensitive and specific than antigen
Culture - CGB agar: gatti turns yellow -> blue vs neoformans
- bird seed culture, L-dopa

42
Q

Aspergillosis mycology and pathogenesis

A

A flavus, fumigatus (most common), terreus (resistant)
- only hyphae, not dimorphic
Hyphae - septate, aerial -> conidiophore -> brush conidiospore -> Airborne -> germ tubes -> colonize cavities -> septate, branched

Often fills cavities from trauma, TB, etc
Penetrating -> disseminated

Requires immediate and aggressive antifungal therapy
Ubiquitous -> 200K infections/yr

43
Q

Aspergillosis clinical presentations

A

Immune compromise -> invasive (acute) or chronic
- neutrophils, organ transplant, steroids, COPD
-> fever, cough, CP, etc
- aspergilloma - “fungus ball” - fills cavity from TB, trauma
- dx via hyphal morphology
- serum test for galactomannan - only sensitive if neutropenic without antifungal therapy
Allergic bronchopulm Asp - ABPA -
- A fumigatus -> Th2 mediated disease
- prevalence 20% CF, 5-15% asthma
- dx via eosinophilia, IgE

44
Q

Mucormyces

A

Zygomycetes - Mucor, Rhizopus - many similarities to Aspergillus

  • hyphae/mycelium only, not dimorphic
  • BUT not septate -> coenocytic with sporangiophores
  • right angle branching, “folded”
  • faster, more virulent than Asp -> increasing

Rhinocerebral (50%): DKA -> rhino -> sinus -> cerebral
Pulmonary: most in hematologic, neutropenic
Deferoxamine therapy predisposes
Other sx: cutaneous, pulmonary, disseminated

Difficult to isolate/ID organism - half are Rhizopus
Growing resistance dt azole prophylaxis therapy

10K infections/yr

45
Q

Pneumocystis mycology

A

Specific species for each mammal host - co-evolution
C jiroveci = human - CANNOT BE CULTURED
- ubiquitous (70% Ig +) -> 400K cases/yr

Cyst -> rupture -> sporozoites -> pleiomorphic trophozoite

? Is it a parasite?
- morphology similar to Apicomplexa
- susceptible to pentamidine, not amphotericin
- cholesterol vs ergosterol in membrane
Evidence for fungus:
- DNA, elongation factors
- thymidylate synthase, dihydrofolate reductase (diploid)
- cell wall = chitin, glucan, mannoproteins

46
Q

Pneumocystis clinical

A

Susceptibility

  • low CD4 (AIDS, inflammation -> plasma cells -> Ig -> frothy exudate
  • diffuse interstitial pneumonia -> impaired O2 exchange
  • sudden onset, high mortality

Dx: methanamine silver or fluorescent specific antibodies
- PCR may be useful
Tx: does not respond to classic antifungals

Microbiology (23 decks)

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