The innate immune system consists of constitutive and inducible mechanisms that are involved in combating fungal pathogens. The constitutive mechanisms include several barriers like body surfaces, mucosal epithelial surfaces of the respiratory, gastrointestinal and genito-urinary tracts. Also microbial antagonism (normal flora of the body prevent colonization of pathogens e.g. lactobacilli and bifidobacteria are effective against candidiasis), collectins (inhibit fungal growth by increasing permeability of the cell wall) and defensins (antimicrobial peptides) are a part of the specific constitutive innate mechanisms. Besides these most of the host defence mechanisms are inducible after infection and are activated when specific molecular structures present on the pathogen (pathogen associated molecular patterns PAMPs) are recognized by pattern recognition receptors (PRRs). The innate antifungal defences are made up of host cell-surface receptors, effector cells and humoral factors. The following flowchart depicts the two main purposes served by innate immune responses to fungi.
HOST CELL SURFACE RECEPTORS
The innate system recognizes conserved fungal patterns PAMPs by means of germ-line encoded receptors- PRRs. These PRRs include several TLRs and non-TLRs (dectin-1, lectin-type receptors, Fc, complement receptors, mannose receptors, integrins) receptors.
a. Toll like Receptors (TLRS)
TLRs are a family of conserved mammalian cellular receptors, 11 human TLRs have been described so far. They are expressed on the surface of cells (macrophages, dendritic cells (DCs), neutrophils, B and T-cells, endothelial cells) of the immune system. All the TLRs are involved in activation of stereotyped responses like inflammatory response by recognizing PAMPs and other ligands on fungal pathogens. Besides this individual TLRs are also able to induce specific programs in a (Myeloid differentiation primary response gene 88) MyD88-dependent or independent manner in innate immune system cells that are specific for a particular pathogen. TLRs bear structural homology with IL-1R intracellular domains thus, similarities are observed in TLR and IL-1R signalling. Once TLRs and IL-1R are activated on interaction with their specific ligands, they recruit adapter molecules like MyD88 which initiate downstream signalling events leading to activation and nuclear translocation of nuclear factor ultimately activating several cytokine and chemokine genes. It was observed that MyD88-/- mice were prone to higher levels of fungal infection as compared to control mice. This reflects the important function of MyD88 as an adapter molecule for TLR-dependent responses.
b. Protease-Activated Receptors (PARs)
During inflammation, host- or fungal-derived proteases are released into the extracellular environment. Some of the proteases can specifically cleave and trigger PARs; it is a family of four G-protein-coupled receptors. Recent study reveals novel interactions between TLRs and PARs that contribute to signal diversity in inflammation and host responses to fungal infections. It has been observed that PAR1 and PAR2 have opposing roles in governing the inflammatory response and pathology to Aspergillus or Candida. These findings identify a previously unknown cross talk between PARs and TLRs in fungal infections.
c. Soluble Receptors
• Pentraxin-3 (PTX3) belongs to the collectin family and is a soluble opsonic receptor. It binds to conidia but not to hyphae by galactomannan-sensitive interaction. PTX3 is necessary for response to Aspergillus species, as PTX3-/- mice show impaired conidial internalization and killing. Also PTX3 recognizes distinct fungal morphotypes.
• Mannose binding lectin-A (MBL) is another soluble opsonic receptor in serum, which binds to carbohydrate patterns displayed by fungi.
d. C-type Lectin Receptors
These include dectin-1 and 2, DC-SIGN, mannose receptor and the galectin family of receptors.
e. Complement Receptors (cr)
The CR3 (CD11b/CD18) is one of the most important complement receptors, which binds to complement-associated products. The ligation of CR3 is an efficient means of engulfing opsonised fungi. CR3 can recognize a broad range of fungal ligands. It has been observed that internalization of Histoplasma capsulatum through CR3 establishes its intracellular growth inside Macrophages but the associated ligation along with Fc gamma IIIR results in phagocytosis and triggers a respiratory burst facilitating clearance of fungal pathogens.
The major cellular effectors of innate immunity against fungi include professional phagocytic cells like neutrophils, macrophages, DCs. The following flowchart states the antifungal functions of these effector cells;
Neutrophils are important effector cells which express TLRs and dectin-1. They are the first cell to be recruited at the site of infection; and they in turn recruit other effector cells. They limit the fungal growth through a combination of oxidative and non-oxidative mechanisms which are stimulated in response to fungal PAMPs.
• In oxygen-dependent mechanisms enzymes like nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and inducible nitric oxide synthase initiate the oxidative pathways known as respiratory burst. This leads to the production of toxic substances- nitric oxide, reactive oxygen intermediates (ROIs), reactive nitrogen intermediates (RNIs) and peroxynitrite. ROIs damage fungi by producing protein modifications, nucleic-acid breaks and lipid peroxidations. Fungi have developed evasion mechanisms to inhibit the respiratory burst through the production of specific scavengers of oxidative killing by phagocytes- catalase, mannitol and melanin.
• The oxygen-independent mechanisms consist of degranulation and release of neutrophil cationic peptides, lysozyme, antimicrobial peptides- defensins, arachidonic acid and iron sequestration. They also secrete cytokines and chemokines which are involved in the protective immune response.
Neutrophils are essential for host defence against Candida, Fusarium and Aspergillus species, and absence or defects in neutrophils are important predisposing factors to certain disseminated fungal infections. Certain therapies associated with neutropenia (cancer therapy) or chronic granulomatous disease (CGD) resulting in impaired neutrophil function lead to increased susceptibility to invasive apergillosis, candidiasis.
They can also impair the host response; it has been shown that CD-80 expressing neutrophils inhibit the expression of the TH1 response in an experimental model of candidiasis.
The main contribution of Macrophages to antifungal defence is by phagocytosis and destruction of fungi. They can ingest organisms that have been opsonized with antibody, complement or collectins, and can also phagocytose unopsonized fungal elements through recognition receptors like integrins. The fate of opsonized fungi is different from unopsonized fungi because they follow a different pathway in phagocytes.
• Macrophages like neutrophils posesses oxygen-dependent and independent fungistatic and fungicidal activities.
• Besides this they also produce cytokines and chemokines (protective immune response), and also function as antigen presenting cells (APCs) presenting fungal peptide antigens to CD8+ T cells and CD4+ T cells.
• Macrophages lining the aveoli are the first line of defence against inhaled fungal pathogens, alveolar Macrophages ingest A. fumigatus conidia into phagolysosomes, killing them.
• Macrophages are also involved in process of granuloma formation which is neccessary for containment and elimination of fungal infection.
Fungi have evolved certain mechanisms and virulence factors to evade phagocytosis and survive inside Macrophages Histoplasma capsulatum and Cryptococcus neoformans, are some of the intracellular pathogens which thrive within Macrophages.
c. Dendritic Cells (DCs)
Langerhan's cells and immature dermal DCs are the first cells to encounter fungi; they play an important role in induction of acquired immune response and restriction of fungal growth. Immature DCs interact with antigens in peripheral tissues; ingestion of these fungal antigens leads to DC maturation, also fungal infection provides danger signals leading to the production of pro-inflammatory cytokines which induce DC maturation and increase the efficiency of fungal antigen presentation. Hence, these mature DCs can now migrate to the paracortical T-cell zones of the lymph nodes, and interact with T cells.
DCs recognize and internalize several fungi like C. neoformans, H. capsulatum and Malassezia furfur. DCs are able to distinguish between different fungal morphotypes and they internalize these morphotypes. They ingest both the yeast and hyphal forms of C. albicans and the conidial and hyphal forms of Aspergillus species. DCs internalize fungi by means of different receptors; they also exhibit different forms of phagocytosis.
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