Subversion of Cell Signaling by Pathogens Evading the Immune response
Ryan Rego Antibiotic resistance: World on cusp of 'post-antibiotic era'
The world is on the cusp of a "post-antibiotic era", scientists have warned after finding bacteria resistant to drugs used when all other treatments have failed. There has not been a new class of antibiotics discovered since the 1980s. Most primitive of immune systems?? Primitive Immune Systems
a | Antiviral defence mediated by restrictionmodification systems. Restriction endonuclease enzymes (REases; shown in red) cleave invading viral DNA at short sequence motifs known as recognition sites (pink boxes). Methyltransferase enzymes (MTases; shown in blue) can modify DNA at the same recognition sites (appended with blue boxes) to prevent cleavage by their cognate REase. The sequence specificity of a REase is hardwired for a particular recognition site and thereby offers innate immunity to unmodified viruses that harbour these sites in their DNA. Whereas unmodified invading DNA of mobile genetic elements is rarely methylated fast enough to receive protection from restriction, modification is generally effective in preventing cleavage of the host chromosome and thus allows for a rudimentary form of self and non-self discrimination. b | Antiviral defence mediated by CRISPRCas (clustered, regularly interspaced palindromic repeatCRISPR-associated proteins) systems. CRISPR arrays are composed of alternating units of repeat sequences (black squares) interrupted by unique spacer sequences (coloured diamonds). Newly encountered phage sequences (shown in red) can be incorporated as spacer DNA within the host CRISPR array through the process of CRISPR adaptation, providing a genetic memory of past infection. Transcription of the CRISPR array provides primary transcripts (known as pre-CRISPR RNAs (pre-crRNAs)) that are processed into short, mature species that each include a single spacer sequence. During CRISPRCas targeting, Cas protein complexes are guided by individual mature crRNAs to mediate the destruction of invading nucleic acids that harbour a matching target sequence. By virtue of sequences in their flanking repeat elements, spacer DNA of the CRISPR array is intrinsically spared from CRISPRCas targeting to prevent autoimmunity COMPONENTS ACTIVITY RESPONSE AND POTENCY SPECIFICITY COURSE MEMORY
Innate Immunity Adaptive Immunity COMPONENTS ACTIVITY RESPONSE AND POTENCY SPECIFICITY COURSE MEMORY An example of infection by a pathogen and the start of the innate immune response
followed by activation of the adaptive response, clearing of the infection and the presence ofmemory cells ready to produce antibodies for future responses to infection by the same pathogen. PAMP Pathogen Associated Molecular Pattern
Bacterial carbohydrates (LPS, mannose) Flagellin lipoteichoic acid peptidoglycan double stranded RNA unmethylated CpG DAMP Damage-Associated Molecular Pattern Purine metabolites (ATP, adenosine, uric acid) DNA and RNA PRR Pathogen Recognition Receptor Innate Immune Response based on PAMP or DAMP recognition
Infections of pathogenic bacteria or viruses cause release of PAMPs that bind to PRR, such as TLRs, on immune cells and stimulate an innate immune response that is accompanied by inflammation, activation of adaptive immunity, and eventually processes to resolve the infection and allow for tissue repair. (B) The dangers model recognizes that similar events occur when cells are stressed or injured and that necrotic cells release molecules that are normally hidden within the cell. In the extracellular space, these DAMPS can bind to TLRs or to specialized DAMP receptors to elicit an immune response by promoting the release of proinflammatory mediators and recruiting immune cells to infiltrate the tissue. The immune cells that participate in these processes include APC, such as dendritic cells and macrophages, as well as T-cells and PMN. Innate Immune Response based on PAMP or DAMP recognition Valles et al., 2014 Pattern recognition by TLRs, NLRs, CLRs and RLRs
Toll-like receptors (TLRs) are type I transmembrane proteins of the interleukin-1 receptor family that possess an amino-terminal leucine-rich repeat (LRR) domain for ligand binding, a single transmembrane domain and a carboxy-terminal intracellular signalling domain. TLRs are widely expressed by many cell types, although most cells express only a specific subset of these receptors. NOD-like receptors (NLRs) are cytosolic receptors that contain N-terminal caspase-recruitment domains (CARDs), a central nucleotide oligomerization domain (NOD) and a C-terminal LRR domain. NLRs recognize a wide variety of microbial PAMPs and endogenous damage-associated molecular patterns (DAMPs), and several notable examples of this family are NOD1, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and absent in melanoma 2 (AIM2). C-type lectin receptors (CLRs) comprise a large family of soluble and transmembrane proteins that possess one or more C-type lectin domain, which was initially characterized as a calcium-dependent carbohydrate-binding domain in mannose-binding lectin (MBL). CLRs recognize a wide range of carbohydrate structures on pathogens, although many CLRs also recognize self molecules and are therefore suggested to participate in both innate immune responses and cell and tissue homeostasis. Notable examples of this family include the soluble CLR MBL and the transmembrane proteins dectin 1 (also known as CLEC7A) and DC-specific ICAM3-grabbing non-integrin (DC-SIGN). Immune cells involved in the immune response Cellular location of TLRs and the identity of their ligands/agonists
The stimulation of surface TLRs (TLR-2, TLR-4, and TLR-5) with appropriate ligands results in the activation of NFB. The ensuing increase in levels of pro-inflammatory cytokines and the influx of inflammatory cells then provides an environment, which protects against both virus and bacterial challenge. Activation of intracellular TLRs (TLR-3, TLR-7, TLR-8, and TLR-9) leads to IRF activation and the production of Type 1 IFNs and pro-inflammatory cytokines, again providing an environment not conducive for pathogens. With the exception of TLR-3, stimulation of a TLR by its ligand results in the activation of a signal transduction cascade that leads to the production of cytokines via the activation of the adapter molecule myeloid differentiation primary response differentiation gene 88 (MyD88) and nuclear factor-B (NF-B) (14,16). TLR-3 utilizes MyD88-independent signaling pathways that employ the adapter molecule Toll/IL-1R (TIR) domain-containing adapter producing interferon- (IFN-) (TRIF). Activation of TLR-3 leads to the production of both Type 1 IFN as well as pro-inflammatory cytokines. Refer to Figure2for a more detailed description of TLR-signaling pathways. Mifsud et al., 2014 TLRs interact with MyD88 and NF-kappaB to produce various adaptive response molecules Mechanisms of defense against viruses
Mechanisms of innate immunity inhibition of infection and induction of antiviral state type I interferons (IFN- and ) - killing of infected cells (NK cells) Antiviral action of type I interferons
Uninfected cells Infected cells Expression of class I MHC molecules Expression of enzymes that inhibit viral replication Protection from infection Killing of infected cells by CTLs Destruction of infected cells by NK cells Destruction of infected cells by NK cells Destruction of infected cells by NK cells Mechanisms of defense against viruses
Mechanisms of adaptive immunity Humoral immunity B cells and antibodies - neutralization (IgG and IgA), ADCC (IgG) and opsonization (IgG) Cell-mediated immunity Neutralization of viruses Protective mechanisms of antibodies Mechanisms of defense against viruses
Mechanisms of adaptive immunity Humoral immunity B cells and antibodies - neutralization (IgG and IgA), ADCC (IgG) and opsonization (IgG) Cell-mediated immunity CD8+ and CD4+ T cells - killing of infected cells (CD8+ T cells) - activation of CD8+ T cells and and B cells (CD4+ helper T cells) Mechanism of killing by CTLs Mechanism of killing by CTLs Mechanism of killing by CTLs Mechanism of killing by CTLs Mechanism of killing by CTLs Mechanisms of defense against viruses
Mechanisms of immune evasion - inhibition of antigen processing and presentation (many viruses) - inhibition of immune response (many viruses) - infection of immune cells (HIV...) - establishment of latency (HSV, HIV...) - inhibition of apoptosis (Herpes and Pox viruses...) Mechanisms of defense against parasites Mechanisms of innate immunity
Protozoa and helminths mostly resistant - complement and phagocytosis (protozoa) - eosinophils and macrophages (helminths) Mechanisms of defense against parasites
Mechanisms of adaptive immunity Protozoa B-cells, CD4+ TH1 and CD8+ T cells - antibodies (B-cells) Entamoeba sp., Plasmodium sp. IFN- production and macrophage stimulation (CD4+TH1 cells) - Leishmania sp. - cytotoxicity (CD8+ T cells) Plasmodium sp. Helminths B-cells and CD4+ TH2 cells - stimulation of B-cells to produce IgE(IL-4) - stimulation of eosinophils (IL-5 and IgE) - degranulation of mast cells (IgE) Strategies for Evasion
Overwhelm the host Disarm host defenses Offense versus Defense Evasion Disarm innate immunity Regulate MHC molecules responsible for antigen presentation Interfere with CTL and Natural Killer cells Alter antigen presentation Go and hide(NOT FOR TODAY) Signaling pathways downstream of PRRs in mammals, insects, nematodes and plants.
In insects and mammals, a family of TLRs mediates the recognition of highly conserved microbe-associated molecules, and there is considerable correspondence between the downstream signaling components. The C. elegans genome encodes a single Toll-like protein that does not seem to function in immune signaling and does not encode Rel-like transcription factors such as mammalian NF-B or drosophila Dif and Relish. However, C. elegans, drosophila and mammals share a conserved p38 MAPK signaling module. Moreover, C. elegans has a TIR domaincontaining protein, TIR-1, that functions in innate immune signaling upstream of p38 (refs. 61,64), controls the expression of antimicrobial peptides (D. Kim and F.M.A., unpublished data; N. Pujol and J. Ewbank, personal communication) and is homologous to the mammalian SARM protein. Plants have a family of receptor-like kinases such as the flagellin receptor FLS2. Although the overall structure of the FLS2 signaling pathway seems similar to that of the PRR signaling pathways in animals, there is no conservation of any individual components and the similarity most likely reflects the ubiquity of eukaryotic MAPK stress-response cassettes that respond to environmental signals. Mechanism of the innate Immune response in plants being colonized by different pathogens
Pathogens of all lifestyle classes (color coded and labeled) express PAMPs and MAMPs as they colonize plants (shapes are color coded to the pathogens). Plants perceive these via extracellular PRRs and initiate PRR-mediated immunity (PTI; step 1). Pathogens deliver virulence effectors to both the plant cell apoplast to block PAMP/MAMP perception (not shown) and to the plant cell interior (step 2). These effectors are addressed to specific subcellular locations where they can suppress PTI and facilitate virulence (step 3). Intracellular NLR receptors can sense effectors in three principal ways: first, by direct receptor ligand interaction (step 4a); second, by sensing effector-mediated alteration in a decoy protein that structurally mimics an effector target, but has no other function in the plant cell (step 4b); and third, by sensing effector-mediated alteration of a host virulence target, like the cytosolic domain of a PRR (step 4c). It is not yet clear whether each of these activation modes proceeds by the same molecular mechanism, nor is it clear how, or where, each results in NLR-dependent effector-triggered immunity (ETI). Dang et al., 2013 Science Pathogen infection in plant cells induce mobile immune signals important for the innate
immune response Local pathogen infection results in the production of the mobile immune signals methylsalicylic acid (MeSA), azelaic acid and glycerol-3-phosphate (G3P), and the lipid-transfer proteins DEFECTIVE IN INDUCED RESISTANCE 1 (DIR1) and AZELAIC ACID INDUCED 1 (AZI1). These mobile signals are transported through the vasculature to systemic, uninfected parts of the plant, where through an unknown mechanism they induce the accumulation of salicylic acid, which is a signal molecule for systemic acquired resistance. Accumulation of salicylic acid induces: the secretion of pathogenesis-related (PR) proteins with antimicrobial activities; histone methylation and other chromatin modifications that prime immune-related genes for increased expression and establish immune memory; and somatic homologous recombination through the actions of BREAST CANCER SUSCEPTIBILITY 2 (BRCA2) and RAD51 to potentially establish a transgenerational memory of immunity. epithelial renewal Pseudomonas entomophilia infection in plants
Infection-induced host-translational blockageinhibits immune responses and epithelial renewal Pseudomonas entomophilia infection in plants We find thatP.entomophilaingestion induces a global translational blockage that impairs both immune and repair programs in the fly gut.P.entomophila-induced translational inhibition is dependent on bacterial pore forming toxins and reactive oxygen species produced by the host in response to infection. Translational arrest is mediated through activation of the GCN2 kinase and inhibition of the TOR pathway as a consequence of host damage. Together, our study draws a model of pathogenesis in which bacterial inhibition of translation by excessive activation of stress responsive pathways inhibits both immune and regenerative epithelial responses. Chakrabarti et al., 2012 Decoy strategies elaborated by pathogens and pests to interfere with plant hormone biosynthesis/signaling pathways. Phytopathogenic bacteria, phytoplasmas, fungi, and oomycetes secrete various effectors inside plant cells during infectious process. Once in the host cells, some effectors specifically bind to (underlined), induce and/or decrease (arrows/crossed lines) target gene expression or protein activity. Consequently, ABA-, SA-, or Auxin-mediated defense mechanisms are activated/repressed. Like animals, plants possess a surveillance system detecting conserved microbial molecular signatures, termed pathogen- or microbe-associated molecular patterns (PAMPs), to trigger immunity (Boller and Felix, 2009). In addition, host-derived signals generated during pathogen infection or mechanical damage, called damage-associated molecular patterns (DAMPs), serve as another means by which the host senses pathogen infection (DOvidio etal., 2004; Huffaker etal., 2006). Receptors perceiving PAMPs and DAMPs are collectively called pattern recognition receptors (PRRs). Unlike animal PRRs, which consist of both plasma membrane-localized Toll-like receptors (TLRs) and cytoplasmic NOD-like receptors (NLR), plant PRRs are exclusively plasma membrane-localized receptor-like kinases or receptor-like proteins (Monaghan and Zipfel, 2012). Plants do carry a large number of NLR proteins, but they do not appear to recognize PAMPs or DAMPs. Instead, plant NLRs exclusively detect intracellular pathogen effector proteins and trigger immune responses in a highly specific manner. In this review, plant immunity triggered by PAMPs and DAMPs through PRRs is referred to as pattern-triggered immunity (PTI; Tsuda and Katagiri, 2010), whereas intracellular effector-triggered immunity through NLRs is referred to as effector-triggered immunity (ETI; Jones and Dangl, 2006). Together PTI and ETI limit microbial entry, restrict pathogen propagation, or kill pathogens inside plant tissues. Denance et al., 2013 Suppression of Plant PRR-Mediated Surveillance System by Pathogen Effectors
Bacterial and filamentous pathogen-derived PAMPs, e.g., flg22 and chitin fragments (Chi), induce host defense responses mediated by plant PRRs, e.g., FLS2, CEBiP, and CERK1. Intracellular effectors from P.syringae (AvrPto, AvrPtoB, AvrPphB, HopF2, HopAI1, and HopU1), X.campestris campestris (AvrAC), P.sojae (Avr3b and Avr1b), and H.arabidopsidis (ATR1 and ATR13) target the indicated PTI signaling events inside the plant cell. Precise targets for H.arabidopsidis ATR1 and ATR13 remain unknown. Apoplastic effectors including C.fulvum Ecp6 and M.oryzae Slp1 compete with chitin receptors CEBiP and CERK1 for chitin binding. The C.fulvum apoplastic effector Avr4 protects fungal hyphae from degradation by plant-derived chtinases (CHN). While it remains to be seen if any filamentous pathogen effectors directly attack PRR complex components, some fungal pathogens have evolved alternative strategies to counter PRR surveillance system in the host plant. LysM domain proteins are widely distributed in fungal pathogens and have emerged as important effectors (Bolton etal., 2008). The C.fulvum apoplastic effector Avr4 binds chitin through its LysMs and protects the fungal cell wall from plant chitinases ( van den Burg etal., 2006). This may prevent the release of chitin and subsequent detection of this PAMP by host chitin receptors ( Figure2). Importantly, the C.fulvum apoplastic effector ECP6 and the M.oryzae apoplastic effector Slp1 have been shown to interfere with PRR function ( de Jonge etal., 2010; Mentlak etal., 2012). These effectors possess three LysMs and compete with chitin receptors for chitin binding, preventing fungal recognition in plants. Both ECP6 and Slp1 are required for full virulence of the fungi, indicating that avoiding host surveillance is important for the establishment of parasitism. Thus bacterial and fungal pathogens have evolved different tactics to evade or block PRR-mediated surveillance. In addition to PRR complexes, pathogen effectors can target downstream components to suppress PTI (Figure2). The P.syringae type III effectors, including HopAI1 and HopF2, directly attack components of MAPK cascades to inhibit PTI signaling ( Wang etal., 2010; Zhang etal., 2007, 2010). HopAI1 is a phosphothreonine lyase that dephosphorylates MAP kinases, whereas HopF2 uses ADP-ribosyltransferase activity to inhibit MAP kinase kinases. In addition, P.syringae type III effector HopU1 is a potent ADP ribosyl-transferase that specifically modifies RNA binding proteins GRP7 and GRP8, thereby impeding their RNA-binding function and inhibiting plant immunity ( Fu etal., 2007; Jeong etal., 2011). Dou and Zhou, 2012 Examples of how pathogens evade the immune response Moraxella catarrhalis and Neisseria meningitidis use specific virulence proteins to activate carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which co-associates with and inhibits Toll-like receptor 2 (TLR2) signalling. The underlying crosstalk involves phosphorylation of the CEACAM1 immunoreceptor tyrosine-based inhibitory motif (ITIM), which recruits SH2 domain-containing protein tyrosine phosphatase 1 (SHP1; also known as PTPN6); this suppresses the phosphorylation of phosphoinositide 3-kinase (PI3K) and downstream activation of the AKT-mediated pro-inflammatory pathway. b | Serotypes of Group B Streptococcus (GBS) bind sialic acid-binding immunoglobulin-like lectins (Siglecs), either through molecular mimicry of host sialylated glycans or through a cell wall-anchored protein. The activation of ITIM-bearing Siglec-5 or Siglec-9 by GBS activates inhibitory SHP2 (also known as PTPN11)-dependent signals that interfere with TLR-mediated cellular activation and antimicrobial functions. c | Staphylococcus aureus uses the ITIM-containing paired immunoglobulin-like receptor B (PIRB) to crosstalk with and inhibit the TLR2-induced inflammatory response, possibly by inhibiting the PI3KAKT pathway. d | Human cytomegalovirus (HCMV) expresses an MHC class I homologue, UL18, which interacts with immunoglobulin-like transcript 2 (ILT2; also known as LIR1) and activates ITIM-dependent and SHP1-mediated signalling. This inhibits natural killer (NK) cell activating receptors, such as the NK group 2, member C (NKG2C)CD94 complex, and interferes with NK cell-mediated cytolysis of the HCMV-infected cell. e | Upon activation by viruses, the ITIM-bearing DC immunoreceptor (DCIR; also known as CLEC4A) becomes internalized into endosomes and inhibits endosomal TLR signalling specifically, it inhibits production of TLR8-induced interleukin-12 (IL-12) and TLR9-induced interferon- (IFN) in conventional and plasmacytoid dendritic cells, respectively. f | Escherichia coli evades macrophage receptor with collagenous structure (MARCO)-dependent phagocytic killing through inhibitory crosstalk with Fc receptor III (FcRIII; also known as CD16). Specifically, non-opsonized E. coli binds with low affinity to FcRIII and induces partial phosphorylation of the FcR common -chain (FcR) ITAM (ITAMi), leading to weak mobilization of spleen tyrosine kinase (SYK) but strong recruitment of SHP1. SHP1 dephosphorylates PI3K and impairs MARCO-dependent phagocytosis. TNF, tumour necrosis factor. a | The indicated pathogens express mannose-containing ligands that bind DC-specific ICAM3-grabbing non-integrin (DC-SIGN; also known as CD209) and induce crosstalk with Toll-like receptors (TLRs) through RAF1. Induction of RAF1 signalling involves the participation of the LSP1KSR1CNK scaffolding complex and upstream activators (LARG, RAS and RHOA), and this pathway then mediates the phosphorylation and acetylation of TLR-activated nuclear factor-B (NF-B) p65 subunit. This results in increased transcription of the interleukin-10 (IL10), IL12A and IL12B genes owing to the enhanced DNA-binding affinity and transcriptional activity of acetylated p65. b | Helicobacter pylori binds DC-SIGN through fucose-containing lipopolysaccharide Lewis antigens and activates leukocyte-specific protein 1 (LSP1)-dependent (but RAF1-independent) signalling, leading to increased IL-10 production, decreased IL-12 production and the inhibition of T helper 1 (TH1) cell development The crosstalk between Toll-like receptors (TLRs) and anaphylatoxin receptors (particularly C5a receptor (C5aR)) or other complement receptors (such as complement receptor 3 (CR3; also known as M2 integrin or CD11bCD18), gC1q receptor (gC1qR) and CD46) selectively inhibits the induction of interleukin-12 (IL-12) production. Relatively little is known regarding the pathways that mediate this selective inhibition; signalling molecules that have been implicated, such as extracellular signal-regulated kinase 1 (ERK1), ERK2 and phosphoinositide 3-kinase (PI3K), are shown downstream of the corresponding receptors. At least for ERK1 and ERK2, the selectivity of IL-12 inhibition is attributed to the suppression of a crucial transcription factor, interferon regulatory factor 1 (IRF1). Post-transcriptional mechanisms might also contribute to IL-12 inhibition. Activation of the complement receptors by their natural ligands might have a homeostatic function, and this is also a possibility for other innate immune receptors (such as CD36, mannose receptor and CD150 (also known as SLAM)) that share the ability to downregulate IL-12 production. However, these same receptors can be activated by bacterial, viral or parasitic pathogens, which can thereby downregulate TLR-induced IL-12 production to interfere with host defences (such as the inhibition of T helper 1 (TH1) cell-mediated immunity). Although microbial molecules that function as ligands for C5aR have been described, this receptor can also come under pathogen control through the enzymatic generation of high levels of C5a by microbial C5 convertase-like enzymes. P. falciparum, Plasmodium falciparum; PRR, pattern recognition receptor. Disruption of the pathways for activation of nitric oxide production by mycobacteria
The activation of myeloid differentiation primary response protein 88 (MYD88) signalling by mycobacteria (at least in part through Toll-like receptor 2 (TLR2)) induces CCAAT/enhancer-binding protein- (C/EBP)-mediated induction of interleukin-6 (IL-6), IL-10 and granulocyte colony-stimulating factor (G-CSF) production. These signal transducer and activator of transcription 3 (STAT3)-activating cytokines function in both autocrine and paracrine manners to induce arginase 1 (ARG1) expression, which is partially dependent on C/EBP. The ARG1 that is produced can inhibit inducible nitric oxide synthase (iNOS) activity through competition for their common substrate, arginine. The MYD88-dependent pathway for arginase production was shown to confer a survival benefit for mycobacteria in vivo and is thought to counteract pathways that activate nitric oxide production, such as TLR4 signalling. CR3 mediated uptake of bacterial cells that help them avoid intracellular killing
Certain bacteria (such as Porphyromonas gingivalis, Mycobacterium tuberculosis and Bacillus anthracis) bind CD14 and induce Toll-like receptor 2 (TLR2)TLR1 inside-out signalling for activating and binding complement receptor 3 (CR3; also known as M2 integrin or CD11bCD18), which leads to a relatively 'safe' uptake of these organisms by macrophages. The signalling pathway that activates the high-affinity state of CR3 is mediated by RAC1, phosphoinositide 3-kinase (PI3K) and cytohesin 1 (CYT1). Enterococcus faecalis and Bordetella pertussis stimulate their uptake by CR3 through an alternative inside-out signalling pathway. This mechanism is activated by the interaction of these bacteria with a receptor complex comprising V3 integrin and CD47, and is dependent on PI3K signalling. Similarly, CR3-mediated uptake of these bacteria prevents their intracellular killing and promotes their persistence in the mammalian host. Bacterial effector molecules go everywhere to help overcome the immune response PAMPS & DAMPs are ok, what is cSADD???
The cellular surveillance-activated detoxification and defenses (cSADD) theory postulates the presence of host surveillance mechanisms that monitor the integrity of common cellular processes and components targeted by pathogen effectors. Being organelles essential for multiple cellular processes, including innate immune responses, mitochondria represent an attractive target for pathogens Mitochondrial anti viral signalling protein (MAVS)
Cytosolic viral RNA is recognized by the RIG-I-like receptors (RLRs) retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), which activate mitochondrial antiviral signalling protein (MAVS) through caspase-recruitment domain (CARD)CARD interactions. MAVS then recruits various signalling molecules to transduce downstream signalling, such as TNF receptor-associated factor 6 (TRAF6) and TRAF5. TRAF6, along with TNFR1-associated death domain protein (TRADD), activates canonical nuclear factor-B (NF-B) signalling via receptor-interacting protein 1 (RIP1) and FAS-associated death domain protein (FADD). Canonical NF-B signalling occurs as the IB kinase (IKK) complex consisting of IKK, IKK and IKK phosphorylates NF-B inhibitor- (IB), resulting in the proteasomal degradation of IB and thus liberating NF-B to translocate into the nucleus and initiate pro-inflammatory cytokine gene expression. MAVS also interacts with various molecules that activate interferon regulatory factor (IRF) signalling (such as stimulator of interferon genes (STING)). These molecules, together with the translocon-associated protein (TRAP) complex and the SEC61 translocon, mediate the activation of TANK-binding kinase 1 (TBK1), which phosphorylates IRF3 and IRF7. In addition, MAVS interacts with translocase of the outer membrane 70 (TOM70), which also interacts with heat shock protein 90 (HSP90) and thereby localizes TBK1 and IRF3 in proximity to the MAVS signalosome. Finally, MAVS binds TRAF2 and TRAF3 and, through TRADD and TRAF family member-associated NF-B activator (TANK) interactions, promotes IKK- and/or TBK1-mediated phosphorylation of IRF3. This promotes IRF3 nuclear translocation, leading to the expression of type I interferon (IFN) genes. b | MAVS signalling can also be inhibited by various molecules. For example, hepatitis C virus (HCV) encodes a serine protease, termed NS34A, that inhibits MAVS by cleaving it from the outer mitochondrial membrane and preventing the formation of MAVSIKK signalling complexes. Hepatitis A virus (HAV) and GB virus B (GBV-B) also encode proteases that disrupt the mitochondrial targeting of MAVS, and hepatitis B virus (HBV) X protein was shown to promote polyubiquitin conjugation to MAVS, leading to its degradation. Endogenous molecules such as poly(rC)-binding protein 2 (PCBP2) and the 20S proteasomal subunit PSMA7 can negatively regulate MAVS signalling during viral infection by promoting its degradation. Other molecules, such as mitofusin 2 (MFN2), receptor for globular head domain of complement component 1q (gC1qR) and NLR family member X1 (NLRX1) are also thought to inhibit MAVS signalling by direct interaction, although gC1qR and NLRX1 are thought to localize predominately to the mitochondrial matrix. Therefore, the mechanisms by which these molecules inhibit MAVS signalling remain under investigation (dashed lines). ER, endoplasmic reticulum; MAM, mitochondria-associated membrane. Disarming of MAVS by Vibrio cholerae The three innate recognition systems
Recognition of Pathogens by Host Cell Surveillance (A) Schematic drawing of Vibrio cholerae disarmament of mitochondrial immune surveillance through the T3SS effector VopE resulting in inhibition of mitochondrial perinuclear clustering and immune activation. (B) Models of pathogen recognition by host cell surveillance machinery. PAMP recognition: results in indiscriminate recognition of pathogens and commensals. DAMP recognition: results in time-dependent, indiscriminate response to cell death. Guard hypothesis: results in specific recognition of pathogens and not commensal microbes. p53 and its role in the immune response to various cellular inputs
It can activateDNA repairproteins when DNA has sustained damage. Thus, it may be an important factor inaging.[30] It can arrest growth by holding thecell cycleat theG1/S regulation pointon DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle). It can initiateapoptosis(i.e., programmed cell death) if DNA damage proves to be irreparable. The tumour suppressor p53 has many functions and has roles in genomic stability control, apoptosis, metabolism and antioxidant defence. p53 is polyubiquitylated by the E3 ubiquitin ligase human double minute 2 (HDM2), which results in its proteasomal degradation. However, in response to certain extracellular and intracellular stimuli (such as oxidative stress, hypoxia, oncogene activation and DNA damage), p53 becomes post-translationally modified and stabilized. p53 can activate multiple pathways in response to cellular stress, through activation or repression of genes encoding a wide range of regulatory proteins. Depending on the severity of DNA damage, p53 can induce cell cycle arrest, senescence or apoptosis (which additionally involves direct proteinprotein interactions of p53 with apoptotic proteins in the cytoplasm), and several metabolic pathways, including glycolysis, the pentose phosphate pathway and oxidative phosphorylation, are also regulated by p53. Moreover, p53 upregulates antioxidant defence genes encoding reactive oxygen species (ROS)-removing enzymes that are important for cellular and genetic stability and thus contribute to the antitumour function of p53. Ac, acetylation; AIF, apoptosis-inducing factor; ALDH4, aldehyde dehydrogenase 4; DDB2, DNA damage-binding protein 2; GADD45, growth arrest and DNA damage-inducible protein 45; GLS2, glutaminase 2; GPX1, glutathione peroxidase 1; Me, methylation; MnSOD, manganese superoxide dismutase; mTOR, mammalian target of rapamycin; P, phosphorylation; p53R2, p53-inducible ribonucleotide reductase small subunit 2-like protein (also known as RRM2B); PAI, plasminogen activator inhibitor; PML, promyelocytic leukaemia; SCO2, synthesis of cytochromecoxidase 2; TIGAR, TP53-induced glycolysis and apoptosis regulator; TRIM22, tripartite motif-containing protein 22; Ub, ubiquitylation. Deactivation of p53 by various bacterial pathogens
To prevent the induction of apoptosis and other p53-regulated pathways that are detrimental to bacterial growth and dissemination, bacterial pathogens such asShigella flexneri,Helicobacter pylori,Chlamydia trachomatisandNeisseria gonorrhoeaeuse different strategies to deactivate p53.S. flexneriuses both the cellular calpain system and phosphoinositide 3-kinase (PI3K)AKT signalling to induce degradation of p53. In the early stages of infection, theS. flexnerieffector IpgD induces proteasomal degradation of p53 through human double minute 2 (HDM2), which is activated by PI3KAKT signalling. In the later stages of infection, another effector, VirA, induces proteolysis of calpastatin, a host protein that inhibits calpain. As a result of this loss of inhibition, calpain degrades p53 by cleaving its amino terminus. TheH. pylorieffector cytotoxin-associated protein A (CagA) induces PI3KAKT signalling to activate HDM2, which results in proteasomal degradation of p53, whereasC. trachomatisalso activates the PI3KAKT pathway, but does so by engaging ephrin receptor A2 (EPHA2) and epidermal growth factor receptor (EGFR) at the host cell surface.N. gonorrhoeaedownregulates protein levels of p53, but the mechanism by which it does so is still poorly understood, and also delays progression through the cell cycle by upregulating p21 and p27 (encoded byCDKN1AandCDKN1B, respectively), most likely at the transcriptional level. In contrast to these pathogens, theSalmonella entericasubsp.entericaserovar Typhimurium effector AvrA induces acetylation of p53, which is a stabilizing modification that is associated with cell cycle arrest in infected cells. Ac, acetylation; T3SS, type III secretion system; T4SS, type IV secretion system. SUMO and SUMOYLATION Small Ubiquitin-like Modifier (or SUMO) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. SUMOylation is a post-translational modification involved in various cellular processes, such as nuclear-cytosolic transport, transcriptional regulation, apoptosis, protein stability, response to stress, and progression through the cell cycle.[1] SUMO proteins are similar to ubiquitin, and SUMOylation is directed by an enzymatic cascade analogous to that involved in ubiquitination. In contrast to ubiquitin, SUMO is not used to tag proteins for degradation. Mature SUMO is produced when the last four amino acids of the C-terminus have been cleaved off to allow formation of an isopeptide bond between the C-terminal glycine residue of SUMO and an acceptor lysine on the target protein. SUMOylation/deSUMOylation dynamics:
Fig. 1. SUMOylation/deSUMOylation dynamics: the SUMO pathway in eukaryotes, depicting SUMO activation by E1, SUMO ligation by the E2 and E3 enzymes onto target proteins, and subsequent SUMO deconjugation by SUMO proteases, which also process SUMO to its active form. Influence of pathogens on the host SUMOylation pathway
Fig. 2. The functions of XopD in bacterial infection of plant cells: the injection of XopD into host plant cells by the TTSS of X. campestris pathovar vesicatoria . Upon delivery, XopD translocates to the nucleus and deSUMOylates nuclear SUMOylated proteins, presumably turning off the transcription of genes required for plant defense mechanisms. It is currently unclear if XopD performs additional deSUMOylating activities in the plant cytosol or whether XopD can cleave SUMO chains. Fig. 3. The influence of pathogens on the host SUMOylation pathway: examples of a viral protein [Gam1 from adenovirus CELO (in blue)] and a bacterial virulence factor [lysteriolysin O from L. monocytogenes (in pink)] influencing the SUMO pathway of host cells upon infection, resulting in global hypoSUMOylation of target proteins. Lyme Disease pathogen Borrelia burgdorferi s.l. Activation of complement by three different pathways in response to borrelial infection
Complement activation pathways leading to the common terminal pathway. Complement can be activated on the outer membrane of Borrelia through three pathways: the classical (CP), lectin (LP), and alternative (AP) pathways. The classical pathway is activated when complement protein C1q binds to the pathogen surface, which activates complement C4 and C2. In the lectin pathway, mannose-binding lectin (MBL) or ficolin (FCN), in complex with serine protease MASP-1/-2/-3 (mannose-binding lectin-associated serine protease-1/-2/-3) and small mannose-binding lectin-associated protein (sMAP), binds to polysaccharide structures on a pathogen surface, leading to the autoactivation of MASP-2, permitting the cleavage of C2 and C4. Both pathways converge to produce C3 convertase consisting of C4b and C2a. C3 convertase can either cleave additional C3 into C3b, or bind to C3b, producing the C3/C5 convertase (C4bC2aC3b). MASP-1 and MASP-3 of the lectin pathway can activate the alternative pathway directly. The contribution of this bypass activation route in complement activation on Borrelia is yet to be determined. The alternative pathway involves the continuous spontaneous hydrolysis of C3 into C3-H2O, which binds to factor B, producing Bb and Ba through the action of factor D. Properdin binds and stabilizes the alternative C3 convertase C3bBb. The latter can either cleave more C3 components or bind to C3b, producing the C5 convertase (C3bBbC3b). C5 convertase of either the alternative pathway, the classical or lectin pathways can go on to produce the membrane attack complex (MAC) through the terminal assembly of complement components C5b through C9, leading to cell lysis and death. In addition to MAC formation, activation of the complement cascade results in leukocyte chemotaxis and opsonization of the invading pathogen, leading to enhanced phagocytosis. Impairment of immune function by tick saliva
Compounds in tick saliva impair DC functions on various levels. Borrelia-infected ticks secrete saliva as well as Borrelia into the skin during a blood meal. Borrelia is recognised and phagocytosed by skin dendritic cells (DCs), dermal DCs (DDCs), and Langerhans cells (LCs). However, certain immunomodulatory compounds in tick saliva (in orange boxes) have been reported to interfere with this interaction and impair the DC response to Borrelia on various levels. Studies have shown that tick saliva impairs phagocytosis by DCs [59] and inhibits upregulation of maturation markers, proteins expressed upon DC maturation which aid in T cell activation, and MHC class II 60, 61, 62, 64and65. Furthermore, there is less production of proinflammatory cytokines IL-6, IL-12, TNF-, and IL-1, and greater IL-10 production 33, 59, 61, 62, 63, 64and65. Tick saliva was reported to impair migration of DCs from the skin to lymph nodes [60]. Finally, DCT cell interactions are impeded as antigen presentation and DC-induced T cell proliferation are affected 33, 59, 60, 61and62, and there is a shift towards T helper (TH)2 polarisation 60, 79and80. Various factors that help Borrelia evade complement activation
Molecular mechanisms that contribute to complement evasion by Borrelia. Borrelia spirochetes have evolved several strategies to evade complement activation by co-opting mammalian host (a) and tick (c) complement regulators/inhibitors and by protecting itself (b) directly against complement-mediated killing. (a) Serum-resistant Borrelia isolates recruit host complement regulators that are part of the factor H family such as complement factor H (CFH), factor H-like 1 (CFHL), and factor H-related (CFHR) proteins by expressing Erps and Csps on their outer membrane. These Erps and Csps are collectively called complement regulator-acquiring surface proteins (CRASPs) and, to date, five CRASPs have been identified. CFH binds to all five CRASPs, whereas CHFL only binds to CRASP-1 and -2, and CFHR proteins solely bind to CRASP-3, -4, and -5. This figure illustrates binding interactions between CRASPs from Borrelia burgdorferi sensu stricto to factor H family proteins. These interactions are slightly different for certain other Borrelia genospecies as discussed in the text. In addition to recruiting factory H family proteins, Borrelia has also shown to bind C4-binding protein of the host. (b)Borrelia expresses CD59-like protein that inhibits the formation of the lytic membrane attack complex (MAC, left panel). Studies by Kochi et al. 54and55 showed that altering the borrelial cell surface by means of anti-Borrelia IgG or IgG Fab fragments allowed effective MAC formation, suggesting that the borrelial membrane composition sterically inhibits formation of lytic MAC (right panel). (c)Borrelia co-opts the tick salivary protein TSLPI (Tick Salivary Lectin Pathway Inhibitor) to evade clearance mediated by the lectin pathway of complement activation (left panel). Tick salivary proteins from the Ixodes Anti-Complement (IxAC) family, including salivary protein (Salp)20 bind and neutralize host-derived properdin, a positive regulator of the alternative pathway of complement. Neutralization of properdin has been shown to inhibit complement-mediated killing of Borrelia by early degradation of unstable C3bBb (middle panel). Direct binding of tick salivary protein Salp15 to the outer surface protein C (OspC) protects Borrelia against MAC formation and lysis of the spirochetes (right panel). Tick Innate Immune system
Various tick proteins that are shown to be involved in pathogen acquisition, transmission or persistence within the tick Immunity against helminths
(TH2 response) Immunity against helminths
(function of eosinophils) Inhibitory molecules that play a role in the evasion of the immune response by helminths
Overview to helminth and DC interactions. Helminth products are recognized by receptors such as TLRs, CLRs or Scavenger receptors. These cells remain in an immature state and unresponsive to further TLR stimuli probably due to interaction and signalling of parasite molecules through CLRs. Signalling pathways that implicate ERK phosphorylation, c-Fos up-regulation and expression of SOCS proteins may play a role in downregulation of DC responses particularly by suppressing IL-12 production. Once again, interactions of helminth molecules with CLRs but also with TLRs may be involved in these inhibitory effects. Finally, these helminth-conditioned DC induce a Th2 or Treg lymphocyte responses. Inhibitory molecules that play a role in the evasion of the immune response by protozoa
Overview to protozoan and DC interactions. Protozoan parasites and their products interact with TLRs on DC leading to their activation and release of proinflammatory cytokines and up-regulation of costimulatory molecules promoting a Th1 responses and the control of the infection. However, in some cases (T. gondii infection), this response can be later impaired by the same parasites through mechanisms that involve enhancement of SOCS proteins expression and downregulation of IL-12 production. In addition, interactions of parasite molecules with Siglecs and CLRs may be responsible of maintaining DC in an immature state and refractory to TLR stimuli, diminishing their proinflammatory response likely by using ERK and PI3K-dependent pathways. These DC may lead to activation of Treg responses that presumably favour parasite survival. Thanks