An integrated model of the recognition of Candida albicans by the innate immune system Nature Reviews / Microbiology Volume 6 / January 2008 Lab of Biochemistry, Korea University Division of Influenza Virus, National Institute of Health, KCDC Shin Kyeongcheol /

1. Candida albicans (C. albicans)? Non-pathogen vs Pathogen – Often colonization w/o causing disease – Host defence ↓ ⇒ Become a pathogen Different forms of Candida albicans World J Biol Chem. Feb 26 (2010). SAP : Secreted aspartyl proteases (Saps) encoding gene Nat Rev Immunol. Jan 4 (2004).

2. Innate immunity and host defence Major player : Neutrophil, Macrophage Innate immunity had been performed only simple ‘ingest and destroy’ tasks. –How recognize? –Why different responses? Recently, it becomes clear. –PRRs recognize PAMPs. –PRRs initiate and modulate subsequent adaptive immunity.

3. Pattern recognition recepters (PRRs) PRRs sense conserved chemical signatures callded pathogen-assosiated molecular patterns (PAMPs). 4 major classes of PRRs – Toll-like receptors (TLRs) Cell membrane associated and intracellular receptors Recognition of fungal components –C-type lectin receptors (CLRs) Membrane-bound receptors Recognition of polysaccharide structures from Candida albicans – NLRs and RIG1 receptors Intracellular receptors Recognition of Bacterial peptidoglycans and viral nucleic acids, not fungi – PRRs = Extracellular pathogen-recognition domain + Intracellular signaling domain

3. Pattern recognition recepters (PRRs) ClassReceptorsRecognition TLRs TLR 2Phospholipomannan TLR 4O-linked mannans TLR 6Zymosan TLR 9Fungal DNA CLRs Dectin 1β-glucans Mannose receptor (MR), DC-SIGNN-linked mannans NLRs RIG 1 receptor Nucleotide-binding oligomerization (NOD)- like receptors (NLRs). Retinoic-acid inducible gene 1 (RIG 1). Bacterial peptidoglycans, Viral nucleic acid, Not Fungi ◎ The recognition of components by pattern recognition receptors (PRRs) ◎ The PRRs structure representing by two domains DomainExamples Extracellular pathogen - recognition domain Leu-rich repeat (LRR) domain in TLRs C-type lectin domain (CLD) in CLRs Intracellular signalling domain TLR-interleukin 1 receptor (TIR) domain in TLRs Immunoreceptor Tyr-based activation-like motif (ITAM) in CLRs

4. The C. albicans cell wall Figure 1. The structure of the Candida albicans cell wall.

5. Immune cells for C. albicans recognition Figure 2. Cell populations and pattern-recognition receptors involved in Candida albicans recognition. ◎ Monocytes : TLRs > LRs (Lectin receptors) ◎ Macrophages : TLRs ≤ LRs ◎ Dendritic cells : Most of the PRRs ◎ Neutrphils : TLRs ≤ PRs (Phagocytic receptors) ◎ T cells : TLRs

6. Recognition of C. albicans components Mannans and mannoproteins –Localization in the outermost part of the cell wall. –Immunostimulatory activities. –Recognition mainly by MR, DC-SIGN and TLR4. β-glucans –60% of cell wall components. –Recognize restriction region, such as bud scars. –Recognition mainly by CR3 and Dectin 1. –Phagocytosis by neutrophils mediated β-(1,6)-glucans. Other C. albicans components –Chitin : Induces recruitment of immune cells. –Fungal DNA : Recognition of non-self DNA by TLR9.

7. Activation of host defence by PRRs C. albicans uptake –Dectin 1, MR and DC-SIGN mediate directly to uptake of fungal particles. –TLRs : Subsequent maturation of the phagosome, presentation of Ag. C. albicans killing –Dectin 1 induces the respiratory burst. –Respiratory burst : production of toxic oxydants, activation of granule protease. Cytokine production

7. Activation of host defence by PRRs Figure 3. Recognition of Candida albicans at the membrane level.

8. Escape mechanisms based on PRRs Figure 4. Candida albicans mechanisms to escape the innate response using pattern-recognition receptors.

9. Conclusions There are several principles that characterize recognition of Candida albicans. 1. Recognition depend on several PAMPs in the fungal cell wall. 2. Specific intracellular signalling pathways, and distinct consequences for the host immune response. 3. Cell-type-specific response of the various PRRs. 4. The fully integrated response to a specific pathogen depends on the mosaic of PRRs and receptor complexes.

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