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Receptors of the innate immune system
06.04.2009
Nadine Sündermann
Receptors of innate immunity
- are germline encoded- consist of a ‘‘recognition’’ domain and a protein-protein-
interacting region for downstream signaling - act as a molecular switch to trigger innate immune activation - tightly regulate the subsequent adaptive immune responses to
microbial infections - recognize specific components of microbes - are widely distributed in or on a variety of cell types - can detect a wide range of ligands derived from either
pathogenic or nonpathogenic microbial infections
Receptors of innate immunity
Mainly 4 types of PRRs are involved:
TLRs: Toll – like Receptors
NLRs: nucleotide-binding and oligomerization domain (NOD) – like receptors
RLRs: retinoic acid-inducible gene I (RIG-I) – like receptors
CLRs: C-type lectin receptors
The 4 types of PRRs
Change in gene expression in response to invasive microbes
Toll – like receptors
- type 1 integral membrane
glycoproteins
- key components of the host’s first
line of defence
- recognizing a variety of microbial
products and initiating a complex
immune response
- designed to eliminate the invading
pathogen
- extracellular domain is made up
of multiple LRRs (leucinerich
repeats) providing a platform for
pathogen binding, giving a
specific pattern-recognition site
NOD – like receptors
- are exclusivly intracellularly and are part of a family of 23 members:
Nod1 (CARD4) and Nod2 (CARD15) detect distinct substructures from bacterial peptidoglycans synergizes with extracellular recognition with TLRs, helping to clear the pathogen by up-regulating synthesis of proinflammatory factors
NALPs (NACHT/LRR/PYD-containing proteins), which include Nalp2, Nalp3 and Ipaf, are important components of caspase-1-containing inflammasomes
NOD – like receptors
RIG-I – like receptors
- are cytosolic- family of cytoplasmic RNA
helicases - are exclusively viral
sensors- complement the TLR viral
sensor system of DCs made up by TLR3, TLR7, TLR8 and TLR9
- RIG-I = retinoic-acid-inducible protein 1
- MDA-5 = melanoma-differentiation-associated gene 5
C-type lectin receptors
- bind to carbohydrates in a calcium-dependent manner
- lectin activity is mediated by conserved carbohydrate-recognition domains (CRDs)
- involved in fungal recognition and the modulation of the innate immune response
- expressed by most cell types including macrophages and DCs
- Dectin-1 is a specific receptor for β-glucans
• infectious diseases and their secondary effects have always been one of the biggest threats to humans and are still the second major cause of death
• economic and environmental changes in human lifestyles
more than 30 emerging pathogens during the past 30 years• large number of studies in immunology and microbiology have
revealed pivotal roles of host innate immune system in sensing microbial infections via specific innate immune receptors
Bacterial recognition of host innate immune receptors
- TLRs and NLRs:
have distinct intracellular localizations and independent signaling pathways
but share their ligands, such as bacterial cell wall components and flagellin but
maintaining concurrent signaling pathways
can interact at the level of their intracellular signaling cascades (e.g. by CARD) but only
cell type specific,
NOD1 and NOD2 ligands and TLR ligands can induce self-tolerance, but not
crosstolerance, to each other in vivo (Kim et al., 2008)
+MD-2
Virus recognition of host innate immune receptors
- host immune system has evolved to detect and interfere with viral infections at the levels
of cell entry, replication, packaging and exit
- their contributions to either protective or pathological immune responses largely depend
on the type of virus, route of infection, and other host factors (Finberg et al., 2007)
- viral nucleic acids recognized by these innate immune receptors can be divided into 4
groups: ssRNA, double-stranded (ds) RNA, ssDNA, and dsDNA (Ishii and Akira, 2005)
Virus recognition of host innate immune receptors
- Viral RNA: sensed by TLR3 (TLR3 recognizes dsRNA generated during viral replication),
TLR7 or TLR8 (recognize genomic ssRNA, all being in the endosome of specialized
immune cells (DCs) and are thought to detect viral RNA delivered from outside of cells
- 3 homologous DExD/H box RNA helicases designated RLRs sense cytosolic viral RNA
within both immune and nonimmune cells
TLR9 recognize viral DNA as well as a TLR9-independent, but uncharacterized recognition
machineries in the cytoplasm DAI (ZBP1 or DLM1) containing 2 Z-DNA binding domains
might be a potential cytoplasmic DNA sensor (Takaoka et al., 2007)
Parasite recognition of host innate immune receptors
- Symbiotic relationships between hosts and eukaryotic microbes are often silent and
chronic, in part by their sophisticated machineries that can manipulate the host
immune system
- Glycosylphosphatidylinositols (GPIs) are found in all eukaryotes, but some parasites
such as Leishmania and Plasmodium species express 10 – 100x more GPIs,
structurally distinct from those of the host cells (Gowda, 2007) – recognized by
TLR2 and/or TLR4
Fungi recognition of host innate immune receptors
- TLR2, TLR4, and TLR9 are involved in sensing fungal components, such as zymosan,
phospholipomannan,mannan, and fungal DNA
- But: although MyD88 -/- mice are highly susceptible in vivo to infections with various
fungi, the physiological roles of the in individual TLRs in fungal infection are still
controversial
- dectin-1 is the major receptor for soluble and particulate β-1,3- and/or β-1,6-linked
glucans – induces phagocytosis, production of reactive oxygen species in macrophages,
and cooperation with TLR2, resulting in optimal immune activations such as the
production of proinflammatory cytokines
Molecular basis of TLR – Ligand interaction
Structure:
- Ectodomain containing horseshoe-like solenoid
shapes (LRR motifs spaced by hydrophobic amino
acid residues)
- transmembrane region
- cytoplasmic signaling domain homologous to IL-1R
termed the Toll/IL-1R homology (TIR) domain
Functionality:
- dimerisation through the C-terminal region of the
extracellular domain
- LRR motifs responsible for TLR ligand binding (only
agonist, not antagonist induces conformational
changes of extracellular domain) subsequent
activation through intracellular TIR domain
Factors that influence Microbial Signature of TLR
ligands- TLRs can distinguish microbes as nonself and
host cells as safe self
- infections change microenvironments of infected
sites which can modify the characteristic of TLR
ligands:
- E. g. TLR9 activation by host-derived DNA can
be enhanced by the presence of cofactors such
as HMGB1, a nuclear DNA-binding protein
released from necrotic cells during tissue
damage, or the antimicrobial peptide cathelicidin
(LL37), or in the presence of anti-DNA or anti-
nuclear (chromatin) antibodies (Ab).
HMGB1’s receptor RAGE and the FcgR receptor
(CD32) for IgG
Intracellular Trafficking of TLRs and their ligands
- Recognition of viral ssRNA
by TLR7 from pDCs
by RIG-I from most other cell types
- Viral RNA was delivered to a TLR7-expressing
vesicle via endosomal uptake, but pDCs have
constitutive autophagy induction (capture viral RNA
replicated in the cytosol via an ATG5-dependent
manner and deliver the RNA into a TLR7- expressing
late endolysosome)
- ATG5 acts as a negative regulator of RIG-I-mediated
viral RNA recognition, and type I IFN is subsequently
produced through IPS-1
- UNC93B is a necessary molecule for recruiting TLR7
(TLR3 and TLR9) from ER to the endosome
- Once ssRNA is recognized by TLR7, NF-kB and
IRF7
VSV
Conclusion
- Immune system is complex mechanism – still many interactions are not known
- it is impossible to cover all the new findings that demonstrate novel mechanisms or the critical importance of innate immune receptors for host defense against microbial infections
- distinct mechanisms of sensing ‘‘microbial signatures’’ create unique molecular switches to trigger the immune system
- continued mapping of the complex networks of host-microbe interactions may improve the understanding of self/non-self discrimination in immunity and its intervention
Thank you for your attention!
NOD – like receptors
Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are key initiators of inflammation during host defence. Acting as dimers, the ten different TLRs display differential recognition of microbial products. TLR4 detects lipopolysaccharide (LPS), which is specific to Gram-negative species. TLR1/2 and TLR2/6 recognize triacylated and diacylated lipoproteins, respectively, from mycobacteria. TLR5 responds to flagellin from the flagella of multiple bacteria, TLR7 and TLR8 detect single-stranded RNA (ssRNA) from viruses or synthetic compounds such as imiquimod, and TLR9 detects CpG motifs that are common in bacterial and viral pathogens. Each of these receptors signal via MyD88, leading to transforming growth factor--activated kinase 1 (TAK1) activation, which, in turn, induces the nuclear factor-B (NF-B) and p38/c-Jun N-terminal kinase (JNK) pathways. TLR3 recognizes double-stranded RNA (dsRNA) and can also activate these pathways, but does so via the adaptor protein TRIF (Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon-). TLR3 also activates the transcription factor interferon-regulated factor 3 (IRF3), leading to induction of genes such as that encoding interferon-. Two other adaptor proteins, MyD88 adaptor-like (MAL) and TRIF-related adaptor molecule (TRAM), also participate in TLR signalling but are more restricted than MyD88. MAL is used by both TLR2 and TLR4, whereas TRAM is used only by TLR4 to activate IRF3 via TRIF. Drugs have yet to be approved that interfere with these pathways, although the peptide RDP-58 has been reported to interfere with TRAF6 (tumour-necrosis factor receptor-associated factor 2) and is in Phase II clinical trials for Crohn's disease. A peptide based on the viral protein A52R also interferes with TRAF6. Similarly, NLRs sense microbial products, with NOD1 and NOD2 recognizing the peptidoglycan products muramyl dipeptide (MDP) and the dipeptide iE-DAP, respectively. These NLRs then signal via the protein kinase RIP2 to NF-B. Another NLR, termed NALP3, is a crucial regulator of caspase 1, leading to the maturation of the pro-inflammatory cytokine interleukin-1 (IL-1). NALP3 forms a complex with two proteins, ASC and Cardinal, via distinct domains termed PYD and FIIND, respectively, and is activated by the pathogenic Listeria spp. and Staphylococcus spp., and also by uric acid. The caspase 1 inhibitor pralnacasan is in clinical development for rheumatoid arthritis. FIIND, domain with function to find; IB, inhibitor of NF-B; IKK, IB kinase; IRAK, IL-1 receptor-associated kinase; LRR, leucine-rich repeats; MALP2, mycobacterial associated lipopeptide 2; MKK, mitogen-activated protein kinase kinase; PYD, Pyrin domain;TBK1, transforming growth factor--activated kinase 1.
FIGURE 1 | Schematic representation of the structure and main signalling pathways of the PRR families.From the following article:Cooperation of Toll-like receptor signals in innate immune defenceGiorgio Trinchieri and Alan SherNature Reviews Immunology 7, 179-190 (March 2007)doi:10.1038/nri2038
Intracellular Trafficking of TLRs and their ligands
Controlled by cell surface sorting adaptor
TIRAP, TLR4 can be engaged with LPS-
MD-2 complex on the cell surface, then
signal through the MyD88 complex with the
kinase IRAK4 and signal transducer TRAF6
to activate NF-kB early through IKK-a,b,g
kinase. TRAM, another adaptor protein,
acts as sorting adaptor for TLR4 into the
early endosome and subsequent
recruitment of TRIF and the activation of
‘‘late’’ NF-kB via TRAF6 and RIP1, and that
of IRF3 via the signal transducer TRAF3.