Immunity to CandidiasisImmunity to Candidiasis

Hossein ZarrinfarHossein Zarrinfar

Medical Mycology (Ph.D.)Medical Mycology (Ph.D.)

Mashhad University of Medical SciencesMashhad University of Medical Sciences

IntroductionIntroduction

CandidiasisCandidiasis MucocutaneousMucocutaneous::

1.1. Oral: thrush, stomatitis, perlech, glossitisOral: thrush, stomatitis, perlech, glossitis

2.2. BronchocandidiasisBronchocandidiasis

3.3. Respiratory CandidiasisRespiratory Candidiasis

4.4. Vulvovaginitis and balanitis Vulvovaginitis and balanitis

5.5. Chronic MucocutaneousChronic Mucocutaneous

6.6. Alimentary: esophagitis, gastritis, peritonitisAlimentary: esophagitis, gastritis, peritonitis

Cutaneous:Cutaneous:

1.1. Intertrigo CandidialIntertrigo Candidial2.2. Paronichia and OnychomycosisParonichia and Onychomycosis3.3. Diaper Rosh(napkin Candidiasis)Diaper Rosh(napkin Candidiasis)4.4. Granuloma CandidialGranuloma Candidial

Systemic Candidiasis:Systemic Candidiasis:1.1. Urinary traetUrinary traet2.2. EndocarditisEndocarditis3.3. MeningitisMeningitis4.4. Iatrogenic Candidemia and SepticemiaIatrogenic Candidemia and Septicemia

Allergic Diseases:Allergic Diseases:1.1. CandididsCandidids2.2. Eczemas, Asthma and gastritisEczemas, Asthma and gastritis

Candidia Species Commonly (Opportunistic human Pathogens)

1)1) C.albicansC.albicans

2)2) C.glabataC.glabata

3)3) C.guilliermandiiC.guilliermandii

4)4) C.kruseiC.krusei

5)5) C.lusitaniaeC.lusitaniae

6)6) C.parapsilosisC.parapsilosis

7)7) C.tropicalisC.tropicalis

Candiia Species Uncommonly: 18 speciesCandiia Species Uncommonly: 18 species

Routs of Transmission of Candidi SpeciecRouts of Transmission of Candidi Speciec

Loss of the integrity and overgrowth of number of Loss of the integrity and overgrowth of number of yeastsyeasts

Exogenous transmissionExogenous transmission

1.1. Postsurgical endophthalmitis (Contaminated solutions)Postsurgical endophthalmitis (Contaminated solutions)

2.2. Candidemia (parenteral nutrition)Candidemia (parenteral nutrition)

3.3. Contaminated transducers Contaminated transducers

4.4. Contaminated SuppositorContaminated Suppositor

5.5. Intraneous injection in heroin abuserIntraneous injection in heroin abuser

6.6. From staff to patient and from patient to patient (burn, From staff to patient and from patient to patient (burn, geriatrics, intensive care, neonatal)geriatrics, intensive care, neonatal)

7.7. From mother to neonate in the time birthFrom mother to neonate in the time birth

Virulence FactorsVirulence Factors

1)1) Adherence to surfaces (Specific: ligand-receptor interaction Adherence to surfaces (Specific: ligand-receptor interaction and nonspecific: electerostatic charge, van der wals forces)and nonspecific: electerostatic charge, van der wals forces)

2)2) Dimor phism ( Blastoconidia are hydrophilic but germ tube Dimor phism ( Blastoconidia are hydrophilic but germ tube is hydrophobic)is hydrophobic)

3)3) Mannans (glycoproteins):Mannans (glycoproteins):

a)a) hydrophobicity adherence hydrophobicity adherence b) b) suppress the immune responsesuppress the immune response

4)4) Enzyme prodyction: proteinases (Enzyme prodyction: proteinases (aspartyl proteinases [SAP1-10])aspartyl proteinases [SAP1-10]) and phospholipasesand phospholipasesProteinases: Proteinases:

a) a) Nonspecific proteolysis of proteins involved Nonspecific proteolysis of proteins involved in defensesin defenses

b) b) Entry of yeasts from tissue Entry of yeasts from tissue barriersbarriers

5)5) Phenotypic switching (especially in invasive infections): Phenotypic switching (especially in invasive infections): adaptation to different and changing conditions in host evade adaptation to different and changing conditions in host evade from host’s defence systemfrom host’s defence system

Neutrophils and oxidants (HNeutrophils and oxidants (H22OO22 myeloperoxidase) can augment myeloperoxidase) can augment the switching process.the switching process.

6)6) Resistance to the thrombin-induced platelet microbicidal protein Resistance to the thrombin-induced platelet microbicidal protein

Secreted Aspartyl Proteases (Saps)Secreted Aspartyl Proteases (Saps)

Produced by C. albicans, C. dubliniensis, C. guilliermondii, C. parapsilosis

Sap7 appears to be the most divergent of the family Sap1 and Sap3 express within 42 h post – infection of tissue Sap6 (48 h) and Sap2 and Sap8 (60 h) Sap4 and Sap5 were never detected Tissue damage was most extensive by 48 h Extensive penetration in tissue (Sap8) Extensive hyphal growth (Sap6)

Biochemical and proteolytic properties of the Sap7 to Sap10 Enzymes are not presently known

Size of Sap1 to Sap10 proteins are 35 to 50 kDa Distinct difference in pH optima Sap1 to Sap3 having highest activity at lower pH

values but Sap4 to

Table 3. Relationship of the secreted aspartyl proteases (Saps) to candidiasis

Assay Blood/deep seated Disease Oral Skin Vagina

Virulence SAP1–4, 6 ? ? SAP2 Expression – SAP1–3, 6, 8 SAP1–3, 6, 8 – Methods Deletion mutants RT-PCR, RT-PCR, Mutants

immune immune microscopy microscopy

Adhesion molecules in cell wall of the Adhesion molecules in cell wall of the Candida Candida

1.1. Protein moiety of glycoprotein (Protein moiety of glycoprotein (ßß22- integrin family) (fibrinogen - integrin family) (fibrinogen – binding epitope in hyphae) arginine – glycine – – binding epitope in hyphae) arginine – glycine – aspartate (RGD) sequences (Caspartate (RGD) sequences (C33d and iCd and iC33b)b)

2.2. Lectinlike protein glycosides (Fucose or N-acetyl Lectinlike protein glycosides (Fucose or N-acetyl glucosamine)glucosamine)

3.3. Polysaccharide portion of a manno protein unknown Polysaccharide portion of a manno protein unknown host receptorshost receptors

Mucosal SurfacesMucosal Surfaces

. . Als1p(agglutinin – like sequence1) vein endotelial cells, HBEC (human buccal epithelial cells) .. Ala1p (Als5p)(agglutinin – adhesion1) FN (fibronectin) .. Hwp1p (outer surface mannoprotein with amino – terminal in hyphal and germ tube HBEC .. Int1p (Integrin – like protein) Epithelial .. Mnt1p (x1,2 – mannosylteransferase) HBEC

Antigenicity Antigenicity

1.1. Mannan – protein complex (Particularly the Mannan – protein complex (Particularly the polysaccharid moiety in cell wall)polysaccharid moiety in cell wall)

2.2. Enolase protein (47-48 kilodalton) (cytosol)Enolase protein (47-48 kilodalton) (cytosol)a) a) Catabolic enymatic activityCatabolic enymatic activity

b)b) Protective role in AIDS Protective role in AIDS patientspatients

3.3. Heat shock (hsp) (70-80 Heat shock (hsp) (70-80 KDaKDa) (cytosol): Immunogenic ) (cytosol): Immunogenic activityactivity

4.4. Ribosomal fractions: protective in animal models against Ribosomal fractions: protective in animal models against systemic candidiasissystemic candidiasis

Immune System Against CandidaImmune System Against Candida

Acquired Immunity Acquired Immunity Natural ImmunityNatural Immunity

Humoral ImmunityHumoral Immunity Phagocytic cellsPhagocytic cells Cell Mediated ImmunityCell Mediated Immunity ComplementComplement

T. Lymphocyte T. Lymphocyte

B. LymphocyteB. Lymphocyte

AntibodiesAntibodies

Complement Several line of activation by C. albicans :Several line of activation by C. albicans :

1.1. Treatment of yeast cells with serum and phagocytosisTreatment of yeast cells with serum and phagocytosis

2.2. Produce chemotacticpeptides by incubation of yeast Produce chemotacticpeptides by incubation of yeast cellscells

3.3. Conversion of C3 and factor B by incubation of candidaConversion of C3 and factor B by incubation of candida The classical pathway is initated by an The classical pathway is initated by an antimannan IgGantimannan IgG

(in serum of most adults)(low levels of (in serum of most adults)(low levels of antimannan IgM)antimannan IgM) MBL (mannan- binding lectin) in serum binds to MBL (mannan- binding lectin) in serum binds to

C. albicans activation of classical pathwayC. albicans activation of classical pathway C. albicans yeast cells and germ tubes also the C. albicans yeast cells and germ tubes also the

alternative pathway via antibody – dependent and alternative pathway via antibody – dependent and antibody - independentantibody - independent

References References

1.1. . . Anassie, E., Mc Ginnis, M.R., pfaller, M.A., Clinical Mycology ,2003

2. Richard A. Calderone and William A. Fonzi, Virulence factors of Candida albicans,TRENDS in Microbiology Vol.9 No.7 July 2001.

3. Ken Haynes,Virulence in Candida species, TRENDS in Microbiology Vol.9 No.12 December 2001.

4. Julian R. Naglik,1* Stephen J. Challacombe,1 and et all, Candida albicans Secreted Aspartyl Proteinases in Virulence and Pathogenesis, Mic. Mol. Bio. Revies, Sept. 2003, p. 400–428.

5. RICHARD A. CALDERONEl* AND PHYLLIS C. BRAUN2, Adherence and Receptor Relationships of Candida albicans, Microbiological Reviews, Mar. 1991, p. 1-20.