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Lecture 2 Fungal immunity By Prof Dr. M. Refai Local defence mechanisms against mucosal infection Salivary proteins such as lactoferrin, beta-defensins, histatins, lysozyme, transferrin, lactoperoxidase, mucins, and secretory immunoglobulin A. These impair adhesion and growth of fungi in the oropharyngeal cavity. Healthy oral epithelial cells These inhibit blastoconidia and/or hyphal growth of fungi if The fungus succeeds in bridging any of the body surfaces either as a result of burns, trauma or maceration or surgical interference or application of catheter etc., The fungus will face non-specific defenses humoral defenses cellular host defenses. In general, man and animals are resistant to fungus infection The intact skin and mucous membranes are not easily invaded by fungi. None specific defence Secretory Ig A + Complement Opsonization Neutrophils, Monocytes Alveolar macrophages Phagocytosis Phagocytosis Immune cells Neutrophils Macrophages Dendritic cells, Natural killer cells T cells Epithelial and endothelial cells Specific pathogenassociated molecular patterns (PAMPs) patternrecognition receptor (PRR) immune cells. immune cells Pattern recognition of fungi Signaling pathways are activated to release Transicription factor to regulate expression of Inflammatory cytokines Strategies employed by fungal pathogens to evade host defense mechanisms 1. Shielding of stimulatory PAMPs, 2. Modulation of inflammatory signals, 3. Shedding of decoy components, 4. Persistence in intracellular environments, 5. Complement evasion. surface proinflammatory b-(1,3)-glucans or non-stimulatory a-(1,3)-glucan cell wall Shielding of stimulatory PAMPs detection of the invading pathogen C. albicans & dectin-1 dectin-1 recognizes the ß-glucans at the level of budding scars in the C. albicans, but it cannot recognize the ß-glucans in the hyphae, where they are shielded by a layer of mannans Histoplasma capsulatum the α -(1,3)-glucan present in its outer layer cell wall contributes to pathogenesis by shielding its immunostimulatory β -glucans. Paracoccidioides brasiliensis Paracoccidioides brasiliensis transforms into its pathogenic yeast form, a change in its cell wall glucan polymer linkage occurs from β (1,3) to α -(1,3)-glucan. Cryptococcus neoformans Cryptococcus neoformans masks its surface PAMPs through the production of an extracellular capsule of glucuronoxylomannan (GXM) Coccidioides immitis Coccidioides is recognized by the host by its immunodominant spherule outer wall glycoprotein (SOWgp). During endospore differentiation, the fungus secretes a metalloproteinase (Mep1) which digests SOWgp This enables the fungus to evade phagocytosis and killing at its vulnerable endospore stage of development Strategies employed by fungal pathogens to evade host defense mechanisms 1. Shielding of stimulatory PAMPs, 2. Modulation of inflammatory signals, 3. Shedding of decoy components, 4. Persistence in intracellular environments, 5. Complement evasion. Modulation of inflammatory signals cytokine production humoral response Preferential activation of TLR2 over TLR4 by certain fungal morphotypic PAMP stimulates a Th2 humoral response over a Th1dependent antifungal proinflammatory cytokine production. C. albicans C. albicans induce immunosuppression through TLR2-mediated IL-10 release, this leads to generation of CD4+CD25+ T-regulatory cells with immunosuppressive potential Aspergillus fumigatus A. fumigatus evades immune recognition by germination into hyphae with subsequent loss of TLR-4 recognition, The TLR2-mediated IL-10 pathways remain intact, thus shifting the balance towards a permissive Th2-type profile Strategies employed by fungal pathogens to evade host defense mechanisms 1. Shielding of stimulatory PAMPs, 2. Modulation of inflammatory signals, 3. Shedding of decoy components, 4. Persistence in intracellular environments, 5. Complement evasion. Shedding of decoy components Shedding of surface protein gpA by the fungus as decoy to competitively inhibit mannose receptor (MR). Strategies employed by fungal pathogens to evade host defense mechanisms 1. Shielding of stimulatory PAMPs, 2. Modulation of inflammatory signals, 3. Shedding of decoy components, 4. Persistence in intracellular environments, 5. Complement evasion. Persistence in intracellular environments Upon internalization by immune or non-phagocytic cells, Candida or Aspergillus can resist intracellular killing, germinate and eventually escape Aspergillus fumigatus Alveolar macrophages The first defensive cells that inhaled conidia The conidia are internalized by the macrophages and prevented from growth for several hours until the macrophage begins to destroy them. At 24 h after internalization, 90% of the conidia are killed. The conidia then germinate to hyphae The hyphae are too large to be engulfed Aspergillus fumigatus neutrophils Resting conidia are relatively resistant to killing by either reactive oxygen intermediates or neutrophil cationic peptides and their ingestion triggers neutrophil degranulation and the respiratory burst only weakly. Resting conidia activate the alternative pathway induce neutrophil chemotaxis Aspergillus fumigatus Polymorphonuclear neutrophils bind the surface without the need for complement or immunoglobulin This binding triggers secretion of reactive oxidative intermediary agents that rapidly damage the hyphae; 50% of hyphae are destroyed in 2 h Histoplasma capsulatum Macrophages represent the first line of defense during infection with H. capsulatum, they rapidly phagocytose the inhaled conidia and transforming yeast cells, the infected macrophage subsequently activate effector T cells and enhance the release of Th1-associated proinflammatory cytokines (IL-12, IFN-γ ,and TNF-α( Histoplasma capsulatum the main cytokines involved in Histoplasma clearance from the host are IL-12, IFN-γ, and TNF-α IL-12 through its ability to regulate IFN-γ production is critical in inducing a protective immune response in primary infection with the pathogen. IFN-γ is pivotal for the host's innate resistance to systemic infection with H. capsulatum. Strategies employed by fungal pathogens to evade host defense mechanisms 1. Shielding of stimulatory PAMPs, 2. Modulation of inflammatory signals, 3. Shedding of decoy components, 4. Persistence in intracellular environments, 5. Complement evasion. Complement evasion Binding of complement-inhibitory C4 binding protein (C4BP)and Factor H on fungal surface. Immune response to fungi: HI The main recognized functions of antibodies in fungal infections include prevention of adherence, toxin neutralization, antibody opsonization and antibody-dependent cellular cytotoxicity CMI The type of CMI induced is critical in determining resistance or susceptibility to fungal infection. In general, Th1-type CMI is required for clearance of a fungal infection, Th2 immunity usually results in susceptibility to infection or allergic responses CMI Th1 cells produce predominantly cytokines such as IFN-g, and promote cell-mediated immunity and phagocyte activation. Th2 cells produce predominantly cytokines such as interleukins 3 and 4 (IL-3 and IL-4) and tend to promote antibody production Cell mediated immunity Resistance to several mycoses is associated however with cell mediated immunity, particularly phagocytosis and killing of invading fungi by peripheral blood monocytes, alveolar and peritoneal macrophages polymorphonuclear leukocytes. i. Alveolar macrophage defense The first phagocytic cells to encounter the inhaled or aspirated fungal particles have the capacity to kill Aspergillus conidia by both oxidative and non-oxidative mechanisms. have relatively weak oxidative candidicidal activity fungi characterized by hyphal forms, are too large to be ingested completely by phagocytic cells. the alveolar macrophages Histoplasma capsulatum: Macrophages are the primary host cells The yeast form survive within macrophages and multiplies intracellularly. Thus the macrophage, which usually eliminates organisms from the primary site of infection, becomes a site of continued fungal growth and aids in dissemination of the yeast to other tissues. ii. Peritoneal macrophages can phagocytize, inhibit intracellular growth or inhibit germination of conidia of Aspergillus or Candida. Activated macrophages appear to play a role in resistance against disseminated candidosis. iii. Normal peripheral blood monocytes Monocytes can damage and apparently kill Aspergillus hyphae, even though hyphae are too large to be ingested completely. Monocytes and macrophages have been shown to be important cells in host defense against dimorphic fungi. When activated they have increased phagocytosis and decrease growth of intracellular yeasts. iv. Polymorphnuclear leukocytes (PMN) PMN play a major role in host defense against fungi. PMN can kill Candida blastoconidia, Coccidioides immitis arthroconidia and Blastomyces conidia. can also damage the hyphal forms of Aspergillus and Candida. The important role of the PMN in the host defense against fungus infection becomes obvious after the fungus escapes control by macrophage and monocyte cell lines and start mycelial growth, where an impressive ability of PMN to damage these organism is evident Application of immune response Vaccination Serodiagnosis Important points to consider in antifungal immunity and its relevance to vaccination usually fungi display only moderate virulence antifungal immune responses are usually redundant. almost all pathogenic fungi have mechanisms to evade or intoxicate immune responses Most fungal diseases pose obstacles to the concept and practice of vaccination coccidiomycosis, histoplasmosis, blastomycosis, and paracoccidioidomycosis are geographically limited, and low-incidence deep-seated diseases widespread illnesses e.g. aspergillosis, cryptococcosis, and candidiasis typically occur in the immunocompromised theoretically—ineligible for active immunisation Antibodies used for passive immunity Fungal vaccines Fungal vaccines Dermatphyte vaccines The inactivated vaccines stimulate the CMI, as demonstrated by skin tests and leukocyte migration inhibition tests. Vaccines containing T. verrucosum conidia inactivated with formalin have been described for use in cattle inactivated vaccine plus adjuvant An inactivated vaccine plus adjuvant containing conidia and mycelium of two T. equinum strains has been used in the immunization of horses The vaccine does not prevent the disease, but the lesions are less severe in vaccinated animals in compared to non-vaccinated animals. Insol Dermatophyton inactivated vaccine effective in horse, dog and cat, can be used as treatment of the disease, improving the clinical outcome. It contains strains of T. verrucosum, T. mentagrophytes, T. sarkisovii, T. equinum,M. canis,M. canis var. distortum, M. canis var. obesum, and M. gypseum. The inactivated vaccine Dermatovac-IV It contains an adjuvant and an optically standardized inactivated suspension of conidia and mycelium of the fungi M. canis, T. equimun, M. gypseum and T. mentagrophytes The Ringvac bovis LTF1301 live vaccine The most effective and widely used LTF-130 strain of T. verrucosum, has a characteristic high level of immunogenicity, low virulence and great stability has been used effectively in Russia and Norway Vaccine-induced protection against 3 systemic mycoses(Coccidioides posadasii , Histoplasma capsulatum , and Blastomyces dermatitidi endemic to North America Wüthrich et al. J Clin Invest 568–554:)2(121;2011 Serological diagnosis Serological tests are important in the diagnosis of systemic mycoses The standard methods of serology are commonly used, i.e. agglutination, precipitation, Complement fixation, immunoflourescence and ELISA. Serological diagnosis the results often permit differentiation between colonization by fungi and a true mycotic infection. In all serological methods only the titre dynamics are meaningful A single serological result is of no diagnostic value. Serological diagnosis The choice of the test Candida infection Antibody developed against the polysaccharide component of surface glycoprotein Antigen: extracted polysaccharides from C. albicans serotype A Antibody type: -IgM in early infection. the indirect haemagglutination test -IgG in late infection indirect immunoflourescence. Antibodies developed against protein antigens of the cell content are detected by precipiation tests. Serological diagnosis The choice of the test Candida infection Because of the ubiquitous nature of Candida species , these serologic tests are limited in discriminating between normal and disease levels of antibodies. More specific tests are used for detection of circulating C. albicans surface antigens and cytoplasmic proteins. Serological tests commonly used are latex agglutination, immunoflourescence Serological diagnosis The choice of the test Cryptococcus infections Antibodies to Cr. neoformans are usually not detected at early infection, but later or on recovery Antibodies can be detected using. indirect immunoflourescent technique, haemagglutination inhibition test or ELISA. If an infection of the CNS is suspected, cerebrospinal fluid must be submitted for serological testing. Serological diagnosis The choice of the test Cryptococcus infections During infection, capsular material is solubilized in the body, and being an antigen, it can be titrated with a specific rabbit anti-Cr. neoformans antiserum using latex agglutination test. A positive agglutination is diagnostic for cryptococcosis. This test is very useful in the early infection. Serological diagnosis The choice of the test Aspergillosis Complement fixation test with conidia suspension, Indirect immunoflourescence with intact fungal elements, Agglutination tests with extracted polysaccharides on latex particles or erythrocytes. Precipitation test (Double immunodiffusion and immunoelectrophoresis ) Serological diagnosis The choice of the test Aspergillosis Detection of Aspergillus antigenaemia in patients with invasive aspergillosis is more sensitive and specific. ELISA using monoclonal antibodies is increasingly used in diagnosis nowadays. Serological diagnosis The choice of the test Blastomycosis Serological tests are not useful in the diagnosis or prognosis. Cross-reactions are common with other diseases like histoplasmosis and coccidioidomycosis. Paracoccidioidomycosis Immunoduffusion test is extremely useful. The CF test is quantitative and useful in assessing prognosis, but cross reactions occur Serological diagnosis The choice of the test Histoplasmosis 1. Latex agglutination, 2. Complement Fixation, 3. Immunodiffusion, 4. ELISA Cross-reactions with blastomycosis and other fungus infections are seen. Serology for histoplasmosis is a little more complicated than for other mycoses, but it provides more information than blastomycosis Coccidioidomycosis Complement fixation, immunodiffusion and latex agglutination tests Serological diagnosis The choice of the test Skin tests Histoplasmin. Histfarcin Coccidioidin intradermal injection of 0.1 ml evoke in infected individual a positive delayed hypersensitivity reaction larger than 5 mm in diameter after 24-96 hours Thank you