Fungi Flashcards
Identify the crucial structural feature distinguishing eukaryotic fungi from prokaryotic bacteria
o Free living = Rarely have obligate host interaction (different than viruses, parasites, some bacteria)
o Most = Saprobic (obtain nutrients from dead organic material, often in soil)
• Not photosynthetic (different from plants, some bacteria)
o Non-motile
o No diaminopimelate in cell wall (different from bacteria: DAP is in peptidoglycan)
o Eukaryotic (like some parasites, different than bacteria)
• Membrane bound nucleus and other organelles
• Genome in multiple linear chromosomes
• More related to humans, so more toxicity of antifungal agents
Identify the components of fungal cell membranes and walls that distinguish them from mammals and provide therapeutic targets.
Membrane: o Major sterol = Ergosterol o Target of antifungal drugs: • Amphotericin B • Azoles
Cell wall:
o Rigid, tough
o Contain β-glucan, chitin
o Targets of antifungal drugs (echinocandins inhibit β-glucan synthase)
Identify each fungal pathogen discussed as “yeast,” “mold,” or “dimorphic.”
Yeast
• Cryptococcus neoformans: monomorphic yeast
• Candida glabrata
• Histoplasma capsulatum: dimorphic; yeast form is invasive
Mold • Aspergillus: monomorphic mold • Dermatophytes • Zygomycetes • Candida albicans: dimorphic; mold form is invasive
Dimorphic: • Maslassezia furfur • Sporothrix schenkii • Candida albicans, most other Candida species • Histoplasma capsulatium • Blastomyces dermatitidis • Coccidioides species
Reproduction-based categories of fungi
Zygomycetes:
o Fusion of 2 compatible gametangia → zygote
Ascomycetes:
o Two compatible haploid nuclei fuse → diploid nucleus
o Meiosis = haploid progeny
o Process occurs in sac “ascus”
Basidiomycetes:
o Sexual reproduction similar to Ascomyetes
o Early part occurs in sac “basidium”
o Haploid progeny matures on outer surface of basidium
Deuteromycetes:
o No sexual stage identified
o “Imperfect” fungi
Describe the principal mechanisms by which fungi cause disease in humans.
Infection
o Requires viable fungi that adhere to or invade host tissue, survive, and proliferate
o Includes: superficial, cutaneous, subcutaneous, opportunistic, and systemic infections
Allergy
o Host Type I hypersensitivity reaction to fungal antigen
• IgE mediated
o Requires prior exposure (sensitization)
o Elicits inflammatory response
Major atmospheric fungi:
• Conidia
• Mold in Alternaria
• Cladosporium
• Aspergillus
Fungal allergens in occupations:
• Penicllium species: cheese mold → “cheese washer’s lung”
• Mucor stolonifer: moldy paprika → “paprika splitter’s lung”
Mycotoxins o Fungal products with toxic effects on humans o Most are secondary metabolites (low-molecular weight byproducts) o Mechanisms include cytotoxicity, mutagenicity, and mimicry of mammalian molecules (ex: sex hormones) Examples of fungal secondary metabolits: • Cheese flavorings • Antibiotics: o Penicillin o Cephalosporins • Other drugs o Cyclosporine A o Lovastatin Examples of mycotoxins: Aflatoxins: from Aspergillus o Raw or processed seeds or nuts o Causes hepatotoxicity, liver cancer Trichothecenes: o From Stachybotrys species on building materials o From Fusarium species in grains and breads o Causes cytotoxic and systemic effects Ergot alkaloids o From Claviceps purpurea o In grains and breads o Causes vasoconstriction, peripheral necrosis, gangrene
Host defense against fungal infections
• Innate defense
• Final clearance/containment: adaptive CMI
o CD4 T cell activation of macrophages via interferon-γ
• NOTE: complement and Ab responses generally not associated with fungal protection
o Instead: Cell-mediated responses:
• Innate immune cells = phagocytes like neutrophils, macrophages, dendritic cells
• Adaptive immune cells = T lymphocytes
Zycomycosis: describe the risk factors associated with this syndrome.
Primary risk factors
o Traumatic inoculation
o Break in skin
o Inhalation
Secondary risk factors (defects in innate immunity) o Neutropenia o Immunosuppressive therapy (steroids decrease phagocyte function) o Iron chelation therapy (Ex: deferoxamine for iron overload acts as a siderophore used for iron uptake by zygomycetes) o Acidosis (low pH causes iron release from transferrin, facilitating iron acquisition by zygomycetes; low pH may compromise phagocyte function) o Diabetes mellitus (hyperglycemia = available glucose; diminished phagocyte function) • Especially diabetic ketoacidosis
Identify the defects in host defenses and describe how these factors lead to increased susceptibility to fungal infection.
Compromise of skin barrier
o Also may disturb vascular supply → less access by host WBCs and antifungal antibiotics
Reduction or alteration of normal commensal microbiota
Inherited immunodeficiency o Most important for fungi if affects phagocytes or T cells Examples: • Chronic granulomatous disease • Severe combined immunodeficiency
Cancer
o Especially lymphohematologic malignancies (lymphoma, leukemia)
o Disturbs cytokine networks important in host defense against pathogens
Radiation therapy and cytotoxic chemotherapy (ex: cyclophosphamide)
o Kills rapidly dividing cells → neutropenia
• Increases susceptibility
Immunosuppressive chemotherapy
Includes:
• Steroids
• TNF-α antagonists (infliximab, etanercept)
• Calcineurin inhibitors (Cyclosporine A, Tacrolimus)
• Mycophenolate Mofetil:
Hospitalization
o Leads to immunosuppression due to:
• Invasive procedures, IV lines
• Antibiotic use
• Severe illness, poor nutrition, general debility
• Exposure to nosocomial agents (coagulase negative Staph, S. aureus, Enterococcus, Candida)
Extremes of age
o Very young = immature immune responses
o Elderly = waning immune response (exacerbated by poor nutrition, antibiotic use, invasive procedures, hospitalization, living in long-term care facility)
Other infections:
CMV (cytomegalovirus) and EBV (Epstein-Barr virus)
• Immuno-modulatory
• Suppress functions important for fungal defense
HIV
• Associated with increased incidence of opportunistic fungal infections: oropharygeal and esophageal candidiasis, pneumocystis pneumonia, cryptococcal meningitis
Identify the environmental ecological niches & geographic distribution for Cryptococcus neoformans.
(typed by capsule):
Cn var grubii
• Serotype A
• Causes most disease worldwide
Cn var neoformans
• Serotype D
• Common in Europe
Cn var gattii
• Serotypes B and C
• Associated with eucalyptus trees
• Previously thought restricted to tropical and sub-tropical regions but recent outbreaks in British Colombia and U.S. Pacific NW
Identify cryptococcal virulence determinants
Growth at 37°C
Capsule o Major component: carbohydrate glucuronoxylomannan (GXM) Antiphagocytic: • Large size • Conceals cell wall ligands • Negative charge o Depletes complement components Down-modulates many immune responses (especially CMI): • Activation of T cells and macrophages • Leukocyte migration • NO production • Development of CMI o Sheds extracellularly o Highly regulated expression: • Varies from 1-30 μm thick 1) In natural environment: dry, low CO2, iron available • Capsule down-regulated • Yeast readily aerosolized = can penetrate small airways of lung 2) In host environment: moist, high CO2, iron limited • Capsule is upregulated • Yeast suited to resist host defenses
Melanin
o Phenoloxidase catalyzes conversation of phenolic compounds (ex: catecholamines like NTs) to quinones
o Quinones polymerize to pigmented melanins
o Melanins = free electron scavenger = resistant to oxidative stress
• Protect from heat, pH extremes, UV or ionizing radiation, host phagocytes, antifungal antibiotics
Describe the common clinical situations in which Candida albicans can cause disease due to a localized decrease in host defenses in an otherwise immunocompetent individual.
Cutaneous Candidiasis: Risk factors: • Moisture • Abraded skin • Any condition interfering with host defenses Symptoms: • Redness, erythema • Pain • Itching, pruritis
Mucosal Candidiasis:
Risk factors:
• HIV/AIDS (most common fungal and opportunistic infection in HIV)
• Extremes of age
• Diabetes mellitus
• Cancer, chemotherapy
• Corticosteroid therapy
• Infectious mononucleosis (EBV, CMV)
• Debilitating chronic conditions
• High dose or prolonged antibacterial antibiotic therapy
• Xerostomia/ hyposalivation
• Dentures (abrasions, biofilm formation)
Symptoms:
• Adherent white plaques with underlying erythema
• Pain, poor feeding, weight loss
Describe the morphology of Pneumocystis jiroveci
Trophozoites:
• 2-5 um, relatively non-refractive
• Motile form
• Predominant form in host (10:1 to cysts)
Cysts:
• Larger, highly refractive
• Non-motile
• Thick walle
Describe the most common clinical manifestation of Pneumocystis jiroveci infection
• Pneumocystis infection → pulmonary infection
o Trophozoites attach to host pneumocytes
o Loss of host cells lining alveoli
“Foamy” esoinophilic exudate fills alveoli → honeycomb appearance
• Some contribution from fungal proliferation
• Major contributor = host inflammatory response
Result: Pneumocysits pneumonia
• Diffuse interstitial pneumonia
• Widespread or total lung involvement
• Compromised gas exchange: very low pO2 (like drowning)
o Dissemination in setting of extreme immunocompromise
Risk factors for Coccidioides
- Gender: male > female (except during pregnancy; risk increases over course of pregnancy)
- Ethnicity: Filipinos, African-Americans, Mexicans, Native Americans
- Age: 50 years
- Immunocompromised: steroids, transplant, AIDS, cancer
Azole drug interactions
Azole + P450 inducer --> decreased azole concentration ex: Carbamezepine Phenobarbital Phenytoin Isoniazid Rifabutin Rifampin Nevirapine **Acid reducing drugs reduce itraconazole and posaconazole
Azole + P450 inhibitor --> increased azole concentration ex: Erythromycin Azithromycin Clarithromycin
Azole + P450 metabolites --> increased metabolite concentration ex: Statins Cyclosporine Tacrolimus Sirolimus Protease inhibitors Ca2+ channel blockers
