Fungal Infections: Host Defense Mechanisms

• Fungal infections (mycoses) happen because of interactions between the host's immune system and the fungal pathogen.
• Host factors and the mechanisms of host-pathogen interactions are important for effective treatments and prevention.

Host Factors Influencing Susceptibility to Fungal Infections

• Innate immunity
• Adaptive immunity
• Genetic factors
• Immunosuppressive conditions
• Metabolic and environmental factors

Innate Immunity

• The body's initial defense against fungal pathogens
• Includes physical barriers, immune cells, soluble factors, and signaling pathways
• These work together to detect and eliminate fungal infections

Physical and Chemical Barriers

• Skin acts as a mechanical barrier with keratinized cells against fungal invasion
• Mucus traps fungi and prevents adhesion
• Ciliary movement clears fungal spores in the respiratory tract
• Antimicrobial peptides disrupt fungal membranes
• Commensal microbiota competes with fungi for nutrients and space
• This prevents overgrowth of opportunistic fungi

Phagocytic Cells

• Neutrophils engulf and destroy fungi, and produce reactive oxygen species that damage fungal cells
• Neutrophil extracellular traps release antimicrobial proteins
• Macrophages engulf fungi and can kill them intracellularly; secrete cytokines to recruit other immune cells
• Dendritic cells recognize fungi, present antigens to T cells, and drive Th1 and Th17 responses

Cytokines

• Small proteins that regulate immune responses and communication between cells
• Interleukin-17 enhances neutrophil recruitment and antifungal defense
• Interferon-gamma helps macrophages kill intracellular fungi

Complement System

• Plasma proteins induce inflammatory responses to fight infection
• Opsonization marks fungi for phagocytosis
• Membrane attack complex lyses fungal cells
• Candida albicans evades complement attack by producing complement inhibitors

Adaptive Immunity

• A specialized, long-lasting immune response that develops after exposure to a pathogen or vaccination
• Adaptive immunity is highly specific and improves with repeated exposure
• Includes T cells, B cells, and antibodies
• Chronic or systemic mycoses are examples of conditions where adaptive immunity works best

T-Cell Responses

• Primary mediators of adaptive immunity against fungal pathogens
• Orchestrate cytokine production, regulate inflammation, and recruit other immune cells
• Th1 activates macrophages to destroy intracellular fungi, for example, Histoplasma capsulatum
• Th17 is important for mucosal immunity, which is important for Candida infections

B-Cells and Antibodies

• B cells recognize fungal antigens and produce antibodies (immunoglobulins)
• B cells help activate other immune cells such as macrophages and neutrophils
• Opsonization involves antibodies coating fungal cells, making them easier for phagocytes to consume
• Neutralization blocks fungal adherence to host tissues
• Complement activation helps destroy fungal cell walls
• IgG and IgA aid in fungal opsonization
• IgM can neutralize fungal components
• IgE is involved in allergic reactions to fungi

Genetic Factors

• Genetic factors play a crucial role in an individual's susceptibility to fungal infections
• Some people are naturally predisposed due to mutations in genes that regulate immune responses
• These predispositions often involve defects in innate and adaptive immunity

Deficiencies in PRRs

• Pattern Recognition Receptors (PRRs) detect Pathogen-Associated Molecular Patterns (PAMPs)
• Dectin-1 recognizes β-glucans

Primary Immunodeficiencies

• Chronic Granulomatous Disease (CGD) is caused by mutations in genes responsible for producing NADPH oxidase
• NADPH oxidase is needed for immune cells like neutrophils and macrophages to kill pathogens

Metabolic and Environmental Factors

• Diabetes mellitus: High glucose levels favor fungal growth, impair immune function and phagocytosis
• Iron overload: Some fungi thrive in iron-rich environments
• Prolonged antibiotic use: Disrupts normal microbiota, leading to fungal overgrowth
• Malnutrition: Weakens immune responses against fungal pathogens

Immunosuppressive Conditions

• HIV/AIDS: Reduced CD4+ T cells lead to severe fungal infections like Cryptococcosis
• Cancer and Chemotherapy: Lower neutrophil counts increase risk of invasive mycoses
• Organ Transplant & Immunosuppressants: there is Higher risk for opportunistic fungi

Host-Pathogen Interactions

• Mycoses (fungal infections) result from interactions between a fungal pathogen and the host immune system
• The outcome depends on fungal virulence factors, the host's immune response, and environmental factors

Fungal Adherence and Colonization

• For infection to occur, fungi must first attach to host tissues and establish a niche for growth
• Candida albicans: Als3 binds to epithelial and endothelial cells
• Aspergillus fumigatus: RodA protein helps spores adhere to lung surfaces
• Cryptococcus neoformans: Cps1 protein aids in brain endothelial adhesion
• Candida biofilms on catheters and implants protect the fungus from immune attack and antifungal drugs
• Spores of Aspergillus have a hydrophobic coat, helping them resist clearance by mucus and fluids

Host Recognition and Immune Activation

• The host innate immune system recognizes fungal Pathogen-Associated Molecular Patterns (PAMPs) using Pattern Recognition Receptors (PRRs)
• PAMPs are small molecular structures found in microbes but not in host cells; serve as red flags for the immune system
• PRRs are proteins in the innate immune system that detect PAMPs; the body's early warning system
• Dectin-1 recognizes β-glucans in fungal cell walls
• Dectin-2 bind to mannans present in Candida species

What Happens After PRRs Detect a Threat?

• PRRs bind to PAMPs which activates signaling pathways
• Cytokines are released to recruit immune cells
• Neutrophils and macrophages engulf fungi through phagocytosis
• Inflammation is activated to fight infection
• Adaptive immunity (T cells, B cells) is stimulated

Fungal Invasion and Evasion of Host Defenses

• Hyphal Growth & Tissue Penetration: breaking through epithelial barriers
• Protease & Lipase Secretion: extracellular enzymes that degrade host tissue
• Iron Acquisition Systems: siderophores to scavenge iron from host proteins
• Capsule Formation blocks PRR recognition; Melanin Production neutralizes ROS
• Biofilm Formation protects against immune attack
• Candida induces IL-10 secretion, reducing inflammation and leads to immune suppression
• Intracellular Survival avoids lysosomal degradation inside macrophages

Host Immune Response and Tissue Damage

• If the host immune response fails, the fungus can invade tissues and spread
• Host immune responses can lead to tissue damage while fighting the infection
• The balance between eliminating fungi and preventing host damage determines the disease outcome

Resolution or Chronic Infection

• Fungal Clearance: Successful immune response eliminates the infection
• Latent Infection: Fungi persist in a dormant state (Histoplasma in granulomas)
• Chronic Disease: Persistent infection due to incomplete clearance (Aspergillosis, Candida biofilms)
• Disseminated Mycosis: Severe infections in immunocompromised hosts (Cryptococcal meningitis in AIDS patients)