Skin Diseases Caused by Fungal Organisms

Introduction

1. Superficial mycoses - confined to the stratum corneum, hair, and nails
2. Subcutaneous mycoses - involving dermis and subcutaneous tissue
3. Deep/systemic mycoses - hematogenous spread, often in immunocompromised patients

Classification of Causative Organisms

I. Dermatophytes (Most Common)

• Anthropophilic (humans) - e.g. T. rubrum, T. tonsurans, E. floccosum
• Zoophilic (animals) - e.g. M. canis (cats/dogs), T. verrucosum (cattle)
• Geophilic (soil) - e.g. M. gypseum

II. Non-Dermatophyte Yeasts

• Malassezia furfur - causes Pityriasis/Tinea versicolor
• Candida albicans - cutaneous candidiasis

Major Clinical Entities

1. Tinea Capitis

• Dermatophytosis of the scalp; mainly in children
• Patchy lesions with erythema, scaling, crust formation, and hair loss
• Causative agents: T. tonsurans (US), M. canis
• Types of hair invasion: ectothrix (Microsporum) vs endothrix (Trichophyton)
• Treatment requires oral antifungals (griseofulvin, terbinafine)

2. Tinea Corporis (Ringworm of the body)

• Most common superficial fungal infection of glabrous skin
• Affects all ages, especially children
• Predisposing factors: excessive heat, humidity, exposure to infected animals
• Clinical: Expanding round plaque with elevated, scaling, erythematous border and central clearing ("ringworm" appearance)
• Histopathology: Mild spongiotic (eczematous) dermatitis with intraepidermal neutrophils and neutrophilic microabscesses in the stratum corneum

3. Tinea Pedis (Athlete's foot)

• Most prevalent form; affects 30-40% of the population at some point
• Diffuse erythema and scaling, initially in toe web spaces
• Predisposing factors: occlusive footwear, communal bathing areas

4. Tinea Cruris (Jock Itch)

• Inguinal areas; predominantly obese males in warm weather
• Moist red patches with raised, scaly, well-defined borders
• Predisposed by heat, friction, and maceration

5. Tinea Unguium / Onychomycosis

• Dermatophytosis of the nails
• Nail thickening, discoloration, onycholysis (separation of nail plate)
• Requires prolonged oral antifungal therapy

6. Tinea Barbae

• Dermatophyte infection of the beard area in adult males
• Relatively uncommon

7. Tinea Versicolor (Pityriasis Versicolor)

• Caused by Malassezia furfur (a yeast, NOT a dermatophyte)
• Located on the upper trunk; highly distinctive
• Lesions: groups of macules of varied color (hypo- or hyperpigmented) with fine peripheral scale
• "Spaghetti and meatballs" pattern on KOH mount - short curved hyphae + round spores
• Hypopigmentation due to azelaic acid produced by Malassezia, which inhibits tyrosinase

8. Cutaneous Candidiasis

• Caused by Candida albicans
• Sites: intertriginous regions (axillary, inguinal, inframammary folds), oral mucosa, genitalia, nail folds
• Characteristic: Erythematous plaques with satellite lesions (small peripheral pustules/papules)
• Predisposed by diabetes, immunosuppression, antibiotic use, obesity, corticosteroid therapy

Histopathology of Dermatophyte Infections

• Properties of the organism
• Host immune response
• Degree of secondary bacterial superinfection

1. Mild spongiotic (eczematous) dermatitis in the epidermis
2. Intraepidermal neutrophils and neutrophilic microabscesses - especially in the stratum corneum
3. Superficial perivascular lymphocytic infiltrate in the dermis
4. Fungi located in the anucleate cornified layer (stratum corneum) of lesional skin, hair, or nails

Fig: (A) Tinea corporis - erythematous plaque. (B) Histology showing spongiotic dermatitis with neutrophilic abscesses. Inset (PAS stain): deep red/pink hyphae within stratum corneum. [Robbins & Cotran Pathologic Basis of Disease]

Special Stains for Diagnosis

Culture & Laboratory Diagnosis

• Sabouraud Dextrose Agar (SDA) with cycloheximide + chloramphenicol: standard isolation medium; incubated at 20-25°C for up to 4 weeks
• Dermatophyte Test Medium (DTM): Contains phenol red indicator; turns red with dermatophyte growth (proteolytic activity raises pH)
• Wood's Lamp: Microsporum species fluoresce green (except M. audouinii/M. canis)
• KOH Preparation: Demonstration of septate hyphae confirms dermatophytosis

Pathogenesis

1. Attach to and invade keratinized tissues (skin, hair, nails)
2. Use keratin as a nutrient source
3. Evoke innate immune response (neutrophil recruitment, epidermal spongiosis)

Treatment Summary

Summary Table

• Robbins & Cotran Pathologic Basis of Disease, Superficial Fungal Infections, Ch. 25
• Fitzpatrick's Dermatology, 9th Ed., Ch. 160 - Dermatophytes & Superficial Mycoses
• Sherris & Ryan's Medical Microbiology, 8th Ed., Ch. 6

Chaperone Proteins

Definition

Classification of Chaperone Proteins

1. Heat Shock Proteins (HSPs) - Major Family

2. Non-HSP Chaperones (ER-specific)

• Calnexin / Calreticulin - Ca²⁺-dependent lectins; retain glycoproteins in ER until properly folded
• Protein Disulfide Isomerase (PDI) - Catalyzes disulfide bond formation/rearrangement
• GRP78 (BiP) - Master regulator of the Unfolded Protein Response (UPR) in ER

Mechanism of Action

Step-by-Step Chaperone Cycle (HSP70 example):

1. Recognition - HSP70 (with co-chaperone HSP40/DNAJ) binds exposed hydrophobic segments of unfolded/nascent polypeptide
2. ATP binding - ATP binding promotes low-affinity open state of substrate-binding domain
3. ATP hydrolysis - Converts to ADP; causes high-affinity clamped state; polypeptide held in folding environment
4. Release - Nucleotide exchange factor (GrpE/BAG) promotes ADP-ATP exchange; polypeptide released
5. Iteration - Cycle repeats until native state achieved, or polypeptide is transferred to HSP60 chaperonin barrel

Chaperonin Mechanism (HSP60/GroEL-GroES):

• Forms a double-ring barrel structure
• Substrate polypeptide is encapsulated inside the barrel
• ATP hydrolysis drives conformational change, providing an isolated environment for folding ("Anfinsen cage")
• Prevents aggregation with other proteins during folding

The Proteostasis Network (PN)

Fig: The Proteostasis Network. Molecular chaperones guide nascent polypeptides to native state. When quality control fails, misfolded proteins cause improper trafficking (emphysema), toxic folds (amyloidoses/neurodegeneration), or premature degradation (cystic fibrosis). [Harrison's Principles of Internal Medicine, 22nd Ed.]

1. Chaperones - promote correct folding / refolding
2. Ubiquitin-Proteasome System (UPS) - E1-E2-E3 enzyme cascade tags misfolded proteins with ubiquitin chains for proteasomal degradation
3. Autophagy-Lysosomal Pathway (ALP) - handles large aggregates and damaged organelles

Heat Shock Response (HSR)

• Trigger: Heat, hypoxia, UV, oxidative stress, chemicals - cause protein misfolding
• Sensor: HSF-1 (Heat Shock Factor 1) - transcription factor
• Normally: HSF-1 exists as an inactive monomer in cytoplasm, bound and repressed by HSP70 and HSP90
• Upon stress:
  1. HSP70/90 are titrated away to bind misfolded proteins
  2. Free HSF-1 trimerizes and translocates to nucleus
  3. Binds Heat Shock Elements (HSE) in promoters of HSP genes
  4. Massive upregulation of HSPs
• Attenuation: When stress resolves, HSP70 re-binds HSF-1, causing dissociation from trimer back to inactive monomer

Unfolded Protein Response (UPR) - ER Chaperones

• Sensor: GRP78/BiP - master ER chaperone; normally bound to and silencing three ER stress sensors
• Activation: BiP is titrated away to misfolded proteins, releasing three stress sensors:
  1. IRE1 (→ splices XBP1 mRNA → transcription of ER chaperones)
  2. ATF6 (→ translocates to Golgi → cleaved → activates chaperone genes)
  3. PERK (→ phosphorylates eIF2α → global reduction in protein translation)
• Outcomes:
  • Upregulation of ER chaperones (calnexin, BiP, PDI)
  • ERAD (ER-Associated Degradation) - misfolded proteins retrotranslocated to cytoplasm and degraded by UPS
  • If stress is irreversible → apoptosis via CHOP

Pathological Significance of Chaperone Dysfunction

Fig: Organ-specific diseases of protein folding caused by chaperone/proteostasis failure. [Harrison's Principles of Internal Medicine, 22nd Ed.]

1. Neurodegenerative Diseases (Toxic Folds / Amyloidoses)

2. Improper Protein Trafficking

• α1-Antitrypsin Deficiency: Mutant α1-AT is misfolded, retained by ER chaperones (BiP), not secreted to lungs → emphysema; accumulation in hepatocytes causes liver cirrhosis

3. Premature Protein Degradation

• Cystic Fibrosis: ΔF508 CFTR mutation causes misfolding; BiP recognizes and retains it in ER; CFTR is degraded before reaching the cell surface → absent Cl⁻ transport

4. Cancer

• HSF-1 is constitutively activated in cancer cells
• HSP90 stabilizes oncoproteins (HER2/ERBB2, BCR-ABL, mutant p53)
• Overexpression of HSP70 suppresses apoptosis by blocking cytochrome c-mediated caspase activation
• HSP27 inhibits apoptosis by sequestering cytochrome c and blocking Bax oligomerization
• Clinical significance: HSP90 inhibitors (geldanamycin, 17-AAG) are in clinical trials as anticancer agents

5. Aging

• Chaperone activity declines with age
• Mutant mice deficient in HSP family chaperones age rapidly
• Mice overexpressing such chaperones are long-lived
• Loss of proteostasis in aging underlies age-related neurodegeneration

Chaperones and Immunity

• HSP60, HSP70, HSP90 are immunogenic - act as "danger signals"
• Released from stressed/dying cells; activate dendritic cells and macrophages via TLR2/TLR4
• HSPs act as natural adjuvants - carry antigenic peptides from tumor cells and present them to the immune system
• Basis for HSP-peptide vaccine development in cancer immunotherapy

Summary Table

• Harrison's Principles of Internal Medicine, 22nd Ed., Ch. 504 - Protein Folding Diseases
• Robbins & Cotran Pathologic Basis of Disease, Ch. 1 & Ch. 2