SECTION 3: FUNGAL PATHOGENESIS & HOST IMMUNITY --- Pathogenesis of Fungal Diseases (Mycoses)Most fungi are saprophytic or parasitic to plants and adapted to the
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 --- Sources of Transmission of Mycoses Endogenous: - From the patient's own normal flora - Main source in nosocomial (hospital-acquired) infections because hospitalized patients are immunocompromised - Exogenous: - Main source of fungal infection — primarily from the environment (soil, decaying matter, animal droppings) - Few fungal infections are communicable between humans or between animals - ---