Pathogenesis of Fungal Diseases (Mycoses)Most fungi are saprophytic or parasitic to plants and adapted to
SECTION 3: FUNGAL PATHOGENESIS & HOST IMMUNITY --- Pathogenesis of Fungal Diseases (Mycoses)Most fungi are saprophytic or parasitic to plants and adapted to their natural environment. Infection in humans is a chance event , occurring only when conditions are favourable. The interplay between fungal virulence factors and host defense factors determines whether infection causes disease. Key concepts: Except for dimorphic fungi (systemic mycoses) and dermatophytes, most fungi are opportunistic pathogens — they only cause disease in immunocompromised hosts Some fungi ( Candida , Malassezia ) have adapted to the human environment and exist as commensals The human body is generally a hostile environment for fungi — most fungi are mesophilic and cannot grow at 37°C Infection depends on inoculum size and host immunity Most fungal enzymatic pathways function more efficiently at the redox potential of non-living substrates than in living metabolizing tissue --- Fungal Virulence Factors- Adhesion — cell wall glycoproteins allow attachment to host cells (e.g. mannoproteins in Candida albicans act as adhesins binding to fibronectin receptors) Capsule production — resists phagocytosis (e.g. Cryptococcus neoformans ) Cytokine suppression — Candida albicans produces cytokines that suppress complement production Iron acquisition — Candida albicans can acquire iron directly from red blood cells Enzyme secretion — keratinase, elastase, collagenase, proteases damage host tissue and facilitate invasion Resistance to phagocytic killing — seen in dimorphic fungi; survive inside macrophages Mycotoxin secretion — toxic secondary metabolites that damage host tissue Thermal dimorphism — ability to switch morphology at 37°C allows survival in host tissue Blocking cell-mediated immunity — some fungi inhibit T-lymphocyte responses --- Host Defense Factors Physical/Chemical Barriers: Intact skin and mucous membranes — first line of defense Fatty acid content of skin — antifungal properties pH of skin, mucosal surfaces and body fluids — unfavourable for most fungi Epithelial cell turnover — sheds colonizing fungi Normal flora — competes with fungi, keeps them in commensal state Chemical secretions and serum factors Cellular Defenses: Polymorphonuclear leucocytes (PMNs) — natural effector cells; primary defense against fungal invasion Monocytes and macrophages — professional phagocytes; engulf and destroy fungal cells T-lymphocytes — specific cell-mediated immunity; most important adaptive defense against fungi Th-1 cells — produce gamma-interferon → activates efficient macrophage killing (important in Candida infections) --- Immunity to Fungal Infections Innate (Natural) Immunity: Non-specific physical barriers — skin, mucous membranes, secretions, normal flora pH, body temperature and serum factors Phagocytic cells (PMNs, monocytes, macrophages) Most fungi cannot grow at 37°C — body temperature itself is a defense Acquired (Adaptive) Immunity: Cell-Mediated Immunity (CMI) — MOST IMPORTANT: Mainstay of host defense against fungi because fungi survive intracellularly Provided by T-lymphocytes (specifically), PMNs and macrophages (non-specifically) Defects in CMI (e.g. HIV/AIDS) dramatically increase susceptibility to fungal infections Humoral Immunity: Both antibodies and complement are produced but their protective role is limited Antibodies help through opsonisation — important against Candida and Cryptococcus Complement acts as opsonins and can directly damage fungal cells through complement activation Complement activated via three pathways → C3 cleaved into C3b (opsonin) and C3a (anaphylatoxin promoting inflammation); C5a attracts macrophages and neutrophils Antibodies are important for serodiagnosis of fungal infections --- Factors Predisposing to Fungal Infections- Prolonged antibiotic therapy — destroys normal bacterial flora, allowing fungal overgrowth Underlying conditions — HIV/AIDS, cancer, diabetes, obesity Extremes of age — very young and very old are more susceptible Surgical procedures — compromises epithelial membrane integrity Transplants and immunosuppressive drugs — suppress CMI Irradiation therapy — damages immune cells Indwelling catheters — bypass epithelial barriers; provide entry point Drug addiction — compromised immunity and skin integrity Occupation — agricultural workers, miners, laboratory workers at higher risk --- Hypersensitivity Reactions to Fungi- Dermatophyte infection can cause "id reaction" — fungus-free skin lesions elsewhere on body due to hypersensitivity to the fungus (circulating fungal antigens) Kerion — inflamed, boggy scalp lesion resulting from a strong immune reaction to a dermatophyte Granulomas from intracellular fungi represent delayed (Type IV) hypersensitivity Fungal spores (conidia), hyphae and products are significant allergens Inhalation can cause allergic pulmonary diseases: - Allergic BronchoPulmonary Aspergillosis (ABPA) Farmer's lung Maple bark stripper's lung Bronchial asthma ---