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torsdag 11 oktober 2018

Legionella ja hahmontunnistajareseptorit TLR (Toll) ja NLR (Nod)

Etsin ensin NOD -kaltaisten  reseptorien ja Legionellan  yhteisiä artikkeleita ja niistä otan tähän sitaatin.
 (Mitä NOD reseptorit ja niiden kaltaiset reseptorit ovat?  Niistä on arikkeli mm tässä lähteessä: https://www.invivogen.com/review-nlr
Toll-reseptorit solupinnalla  tunnetaan tarkemmin niitä on ainakin 9.  Ne ovat patogeenin tai vaaran hahmontunnistaja reseptoreita.  Näitä NOD reseptoreita on tulehtuneen solun sisällä. NLR: 22 kpl). Koska  Legionella on solunsisällä replikoituva, etsin sen  suhteita NOD- reseptoreihin.   Löysin 21 viitettä.

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1.
[Recombinant Legionella pneumophila flagella protein A (rflaA) induces the secretion of IL-6 and IL-1β in RAW264.7 cells in vitro]. Jia L, Cao X, Yang Z.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017 May;33(5):601-605. Chinese. PMID:28502296
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Conclusion RflaA could enhance the secretion of IL-6 and IL-1β by promoting the expressions of NLRP3 and caspase-1 in RAW264.7 cells.
 
2.
The Type II Secretion System (T2SS)  of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 (TLR2)  Signaling Pathway in Infected Human Macrophages.
Mallama CA, McCoy-Simandle K, Cianciotto NP.
Infect Immun. 2017 Mar 23;85(4). pii: e00897-16. doi: 10.1128/IAI.00897-16. Print 2017 Apr. PMID:28138020
Free PMC Article
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3. Miksi useimmat ihmiset toipuvat Legionellasta? 

Tässä artikkelissa selvitetään, miten hiiri toipuu legionellasta luonnollisen immuniteetin avulla.
Innate immunity against Legionella pneumophila during pulmonary infections in mice.
Park B, Park G, Kim J, Lim SA, Lee KM. Arch Pharm Res. 2017 Feb;40(2):131-145. doi: 10.1007/s12272-016-0859-9. Epub 2017 Jan 6. Review. PMID:28063015

Tiivistelmästä suomennosta.
 Legionella pneumophila on eräs etiologinen agenssi vaikeassa legionelloosi-keuhkotulehduksessa. Tämä gram-negatiivinen bakteeri replikoi luonnossa erilaisissa makeanveden ameeboissa, mutta myös ihmisen keuhkoalveolien makrofageissa. Isäntäsolun sisällä Legionella  indusoi  ei-endosomaalisten  replikaatiokykyisten  fagosomien  tuotannon injisoimalla  effektoriproteiinejaan  solun  sytosoliin .
 Luonnolliset immuunivasteet ovat eturintamapuolustusta  (=valmiina olevaa resurssia) Legionellaa vastaan infektion varhaisvaiheessa ja tekee eroa  Legionellan ja isäntäsolun välillä käyttämällä  taudinaiheuttajan hahmon tunnistavia (PAMP)  reseptoreita (PRR)  kuten TOLL-reseptorin (TLR)   tai NOD- reseptorin kaltaisia (NLR)  tai  tai RIG-1 kaltaisia reseptoreita ( RLR). Ne pystyvät havaitsemaan patogeeneihin liittyviä molekulaarisia hahmoja (PAMP), joita kehossa , isäntäsolussa itsessään ei ole.
Keuhkojen Legionella- tulehduksen aikana rekrytoituu keuhkoihin useita erilaisia tulehdussoluja kuten makrofageja, neutrofiilejä, luonnollisia tappajasoluja (NK) , suuria mononukleaarisia soluja , B-imusoluja ja T-imusoluja: sekä CD4+ että CD8+ T-lymfosyyttisoluja ja ensisijaisesti ne  asettuvat kudossolujen väleihin,  interstitiaalisesti,  kontrolloimaan Legionellaa.
Keuhkoissa  menossa olevissa Legionella-infektioissa myös eri sytokiinien ja kemokiinien  väliset vuorovaikutukset moduloivat isäntäkehon  immuunivastetta . NK-soluilla tapahtuvasta tunnistuksesta  liipaistuu esiin  kehon  omia effektorifunktioita kuten sytokiinien ja kemokiinien  erittymistä ja niistä aiheutuu kohteena olevien solujen  lyysi, hajoaminen.  NK- solujen,  dendriittisolujne, monosyyttien ja makrofagien  keskeinen  vuorovaikutus  antaa pääasiallisen  etulinjapuolustuksen Legionellaa vastaan, kun taas  spesifinen immuunivaste,  T- ja B-solujen aktivoituminen johtaa lopulta infektion  päättymiseen ja pystyttää Legionella-spesifistä muistijälkeä isäntäkehoon.
  • Abstract
  • Legionella pneumophila is an etiological agent of the severe pneumonia known as Legionnaires' disease (LD). This gram-negative bacterium is thought to replicate naturally in various freshwater amoebae, but also replicates in human alveolar macrophages. Inside host cells, legionella induce the production of non-endosomal replicative phagosomes by injecting effector proteins into the cytosol. Innate immune responses are first line defenses against legionella during early phases of infection, and distinguish between legionella and host cells using germline-encoded pattern recognition receptors such as Toll-like receptors , NOD-like receptors, and RIG-I-like receptors, which sense pathogen-associated molecular patterns (PAMP)  that are absent in host cells.
  • During pulmonary legionella infections, the interplay between distinct cytokines and chemokines also modulates innate host responses to clear legionella from the lungs. Recognition by NK cell receptors triggers effector functions including secretion of cytokines and chemokines, and leads to lysis of target cells. Crosstalk between NK cells and dendritic cells, monocytes, and macrophages provides a major first-line defense against legionella infection, whereas activation of T and B cells resolves the infection and mounts legionella-specific memory in the host.
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4.
Yksi L. pneumophilan effektoreista on LegS2, SP1-lyaasi

 (Kommentti:  Tällainen entsyymikuuluu ihmisenkin Sfingomyeliiniaineenvaihdunnan terminaaliseen kohtaan membraani remodelling kierrossa ) . Lpn-mutantti, jolta tämä funktio puuttuu ilmentää isäntäkehossa atyyppisia mitokondrioita.  Bakterin effektori ilmeisesti pehmentää mitokondrian ulkokalvonrakennetta ja saa mitokondriat jopa fusoitumaan ja näyttämään amorfisilta).
  • The Sphingosine-1-Phosphate Lyase (LegS2) Contributes to the Restriction of Legionella pneumophila in Murine Macrophages. Abu Khweek A, Kanneganti A, Guttridge D DC, Amer AO.PLoS One. 2016 Jan 7;11(1):e0146410. doi: 10.1371/journal.pone.0146410. eCollection 2016. PMID: 26741365 L. pneumophila is the causative agent of Legionnaires’ disease, a human illness characterized by severe pneumonia. In contrast to those derived from humans, macrophages derived from most mouse strains restrict L. pneumophila replication. The restriction of L. pneumophila replication has been shown to require bacterial flagellin, a component of the type IV secretion system as well as the cytosolic NOD-like receptor (NLR) Nlrc4/ Ipaf. These events lead to caspase-1 activation which, in turn, activates caspase-7. Following caspase-7 activation, the phagosome-containing L. pneumophila fuses with the lysosome, resulting in the restriction of L. pneumophila growth. The LegS2 effector is injected by the type IV secretion system (T4SS) and functions as a sphingosine 1-phosphate lyase. It is homologous to the eukaryotic sphingosine lyase (SPL), an enzyme required in the terminal steps of sphingolipid metabolism. Herein, we show that mice Bone Marrow-Derived Macrophages (BMDMs) and human Monocyte-Derived Macrophages (hMDMs) are more permissive to L. pneumophila legS2 mutants than wild-type (WT) strains. This permissiveness to L. pneumophila legS2 is neither attributed to abolished caspase-1, caspase-7 or caspase-3 activation, nor due to the impairment of phagosome-lysosome fusion. Instead, an infection with the legS2 mutant resulted in the reduction of some inflammatory cytokines and their corresponding mRNA; this effect is mediated by the inhibition of the nuclear transcription factor kappa-B (NF-κB). Moreover, BMDMs infected with L. pneumophila legS2 mutant showed elongated mitochondria that resembles mitochondrial fusion. Therefore, the absence of LegS2 effector is associated with reduced NF-κB activation and atypical morphology of mitochondria. Free PMC Article Similar articles
 
5.
 Inflammasomi on multiproteiinikompleksi, johon kuuluu jäseninä NOD:n kaltianen reeptoriperhe(NLR) ja kaspaasi-1. 
Caspase-11 and caspase-1 differentially modulate actin polymerization via RhoA and Slingshot proteins to promote bacterial clearance. Caution K, Gavrilin MA, Tazi M, Kanneganti A, Layman D, Hoque S, Krause K, Amer AO. Sci Rep. 2015 Dec 21;5:18479. doi: 10.1038/srep18479. Inflammasomes are multiprotein complexes that include members of the NOD-like receptor family and caspase-1. Caspase-1 is required for the fusion of the Legionella vacuole with lysosomes. Caspase-11, independently of the inflammasome, also promotes phagolysosomal fusion. However, it is unclear how these proteases alter intracellular trafficking. Here, we show that caspase-11 and caspase-1 function in opposing manners to phosphorylate and dephosphorylate cofilin, respectively upon infection with Legionella. Caspase-11 targets cofilin via the RhoA GTPase, whereas caspase-1 engages the Slingshot phosphatase. The absence of either caspase-11 or caspase-1 maintains actin in the polymerized or depolymerized form, respectively and averts the fusion of pathogen-containing vacuoles with lysosomes. Therefore, caspase-11 and caspase-1 converge on the actin machinery with opposing effects to promote vesicular trafficking.
PMID:26686473 Free PMC Article
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6.
NOD:in kaltainen reseptori  (NLR) ( nukleotidiä sitovan oligomerisaatiodomeenin omaava) ja CARD- domeenin (kaspaasia rekrytoivan domeenin) omaava NLRC4  reseptori  säätelee  aerosolisen Legionella pneumofilan keuhkonsisäistä replikoitumista. 
 
7.
 NOD-reseptorit  inflammasomissa, joka  on laaja kompleksi sytoplasmassa, tunnistaa  mikrobitulehduksen ja vaaran molekyylejä ja indusoi  kaspaasi-1-aktivaatiosta  riippuvan sytokiinituotannon ja makrofagin tulehduksellisen kuoleman ( bakteerimassan kanssa lyysissä). NLRC4 tunnistaa bakteeriflagelliinia ja T4SS sekreetiosysteemin.

  • The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus (T3SS).Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, Liu L, Shao F.
    Nature. 2011 Sep 14;477(7366):596-600. doi: 10.1038/nature10510. PMID:21918512 Inflammasomes are large cytoplasmic complexes that sense microbial infections/danger molecules and induce caspase-1 activation-dependent cytokine production and macrophage inflammatory death. The inflammasome assembled by the NOD-like receptor (NLR) protein NLRC4 responds to bacterial flagellin and a conserved type III secretion system (TTSS) rod component. How the NLRC4 inflammasome detects the two bacterial products and the molecular mechanism of NLRC4 inflammasome activation are not understood. Here we show that NAIP5, a BIR-domain NLR protein required for Legionella pneumophila replication in mouse macrophages, is a universal component of the flagellin-NLRC4 pathway. NAIP5 directly and specifically interacted with flagellin, which determined the inflammasome-stimulation activities of different bacterial flagellins. NAIP5 engagement by flagellin promoted a physical NAIP5-NLRC4 association, rendering full reconstitution of a flagellin-responsive NLRC4 inflammasome in non-macrophage cells. The related NAIP2 functioned analogously to NAIP5, serving as a specific inflammasome receptor for TTSS rod proteins such as Salmonella PrgJ and Burkholderia BsaK. Genetic analysis of Chromobacterium violaceum infection revealed that the TTSS needle protein CprI can stimulate NLRC4 inflammasome activation in human macrophages. Similarly, CprI is specifically recognized by human NAIP, the sole NAIP family member in human. The finding that NAIP proteins are inflammasome receptors for bacterial flagellin and TTSS apparatus components further predicts that the remaining NAIP family members may recognize other unidentified microbial products to activate NLRC4 inflammasome-mediated innate immunity.Similar articles
 
8.
NOD-perheen reseptorista  NAIP5 inflammasomissa. Rajoittaa Legionellaa  ja tunnistaa  flagelliinia.
Global cellular changes induced by Legionella pneumophila infection of bone marrow-derived macrophages. Fortier A, Faucher SP, Diallo K, Gros P. Immunobiology. 2011 Dec;216(12):1274-85. doi: 10.1016/j.imbio.2011.06.008. Epub 2011 Jun 30. PMID:21794945
The nucleotide-binding oligomerization domain (Nod)-like receptor (NLR) family member Naip5 plays an essential role in restricting Legionella pneumophila growth inside primary macrophages. Upon interaction with bacterial flagellin, the intracellular receptor Naip5 forms a multi-protein complex, the inflammasome, which activation has a protective role against infection.
 
9.  
Legionella pneumophila  manipuloi  tehottomiksi kaksi isäntäkehon apoptoottista tietä:  sekä kanonisen apoptoottisen mitokondriaalisen tien  että  pyroptoottisen  NOD:in kaltaisten reseptorien kontrolloiman inflammasomisen tien. 
  • Striking a balance: modulation of host cell death pathways by legionella pneumophila.Luo ZQ. Front Microbiol. 2011 Feb 23;2:36. doi: 10.3389/fmicb.2011.00036. eCollection 2011.PMID: 21687427 Free PMC ArticleAbstract
    Programmed cell death is considered the ultimate solution for the host to eliminate infected cells, leading to the abolishment of the niche for microbial replication and the ablation of infection. Thus, it is not surprising that successful pathogens have evolved diverse strategies to reprogram the cell death pathways for their proliferation. Using effector proteins translocated by the Dot/Icm type IV secretion system, the facultative intracellular pathogen Legionella pneumophila manipulates multiple host cellular processes to create a niche within host cells to support its replication. Investigation in the past decade has established that in mammalian cells this bacterium actively modulates two host cell death pathways, namely the canonical apoptotic pathway controlled by the mitochondrion and the pyroptotic pathway controlled by the Nod-like receptor Naip5 and the Ipaf inflammasome. In this review, I will discuss the recent progress in understanding the mechanisms the bacterium employs to interfere with these host cell death pathways and how such modulation contribute to the intracellular life cycle of the pathogen.Similar articles
 
10. 
Lpn- infektiossa   ASC ja NLRC4 alassäätyneinä monosyyteissä. 
  • Apoptosis-associated speck-like protein (ASC) controls Legionella pneumophila infection in human monocytes. Abdelaziz DH, Gavrilin MA, Akhter A, Caution K, Kotrange S, Khweek AA, Abdulrahman BA, Grandhi J, Hassan ZA, Marsh C, Wewers MD, Amer AO.
    J Biol Chem. 2011 Feb 4;286(5):3203-8. doi: 10.1074/jbc.M110.197681. Epub 2010 Nov 19. PMID:21097506 The ability of Legionella pneumophila to cause pneumonia is determined by its capability to evade the immune system and grow within human monocytes and their derived macrophages. Human monocytes efficiently activate caspase-1 in response to Salmonella but not to L. pneumophila. The molecular mechanism for the lack of inflammasome activation during L. pneumophila infection is unknown. Evaluation of the expression of several inflammasome components in human monocytes during L. pneumophila infection revealed that the expression of the apoptosis-associated speck-like protein (ASC) and the NOD-like receptor NLRC4 are significantly down-regulated in human monocytes. Exogenous expression of ASC maintained the protein level constant during L. pneumophila infection and conveyed caspase-1 activation and restricted the growth of the pathogen. Further depletion of ASC with siRNA was accompanied with improved NF-κB activation and enhanced L. pneumophila growth. Therefore, our data demonstrate that L. pneumo phila manipulates ASC levels to evade inflammasome activation and grow in human monocytes. By targeting ASC, L. pneumophila modulates the inflammasome, the apoptosome, and NF-κB pathway simultaneously.Free PMC Article Similar articles
 
11.
PAMP reseptorit Nod1 ja Nod2  vastaavat neutrofiilien rekrytoimisesta  hiiren keuhkoon  legionella pneumophila-infektiossa.
 
12.
 Legionella pneumophilan lisääntyminen ihmissoluissa. Miksi ihminen on altis saamaan Legionella pneumophila-infektion? 
  • Replication of Legionella Pneumophila in Human Cells: Why are We Susceptible? Khweek AA, Amer A. Front Microbiol. 2010 Dec 28;1:133. doi: 10.3389/fmicb.2010.00133. eCollection 2010.PMID: 21687775 Abstract
    Legionella pneumophila is the causative agent of Legionnaires' disease, a serious and often fatal form of pneumonia. The susceptibility to L. pneumophila arises from the ability of this intracellular pathogen to multiply in human alveolar macrophages and monocytes. L. pneumophila also replicates in several professional and non-professional phagocytic human-derived cell lines. With the exception of the A/J mouse strain, most mice strains are restrictive, thus they do not support L. pneumophila replication. Mice lacking the NOD-like receptor Nlrc4 or caspase-1 are also susceptible to L. pneumophila. On the other hand, in the susceptible human hosts, L. pneumophila utilizes several strategies to ensure intracellular replication and protect itself against the host immune system. Most of these strategies converge to prevent the fusion of the L. pneumophila phagosome with the lysosome, inhibiting host cell apoptosis, activating survival pathways, and sequestering essential nutrients for replication and pathogenesis. In this review, we summarize survival mechanisms employed by L. pneumophila to maintain its replication in human cells. In addition, we highlight different human-derived cell lines that support the multiplication of this intracellular bacterium. Therefore, these in vitro models can be applicable and are reproducible when investigating L. pneumophila/phagocyte interactions at the molecular and cellular levels in the human host.KEYWORDS: NOD-like receptors; Toll-like receptors; neuronal apoptosis-inhibitory proteins; pathogen-associated molecular patterns Free PMC Article Similar articles
 
13
 Legionella pn.  moduloi kaspaaseja ja saa ne  toimimaan  ei-apoptoottisina. 
Legionella pneumofilasta on tullut mallijärjestelmä kaspaasien ei-apoptoottisten funktioiden  ja  immuunitehtävien  ratkaisemiseen.  Sallivissa soluissa Lpn-vakuolit (LCV)  välttävät endosomaalisia kuljetusteitä ja endoplasminen verkosto(ER)  muokaa vakuoleja  uuteen muotoon ( jossa replikaatio voi tapahtua). Endosomitien  evaasio välittyy Legionellan Dot/Icm- tyyppi4-sekreetiosysteemillä (T4SS). Lpn- infektiossa flagelliinia tunnistaa NOD:n kaltainen reseptori NLRC4 (IPAF) , mikä johtaa kaspaasi-1 aktivaatioon inflammasomikompleksissa.  NLRC4 inflammasomin alavirrassa aktivoituu kaspaasi-7 ja edistää ei-apoptoottisia funktioita, kuten fagosomin kypsymistä ja  bakteriaalista hajoittamista . On tehty  mielenkiintoinen havainto  kaspaasi-3:n aktivoitumisesta infektion varhaisvaiheissa permissiivisissä soluissa, sillä se ei johdakaan  apoptoosiin ja niin on   aivan infektoitumisen myöhäisvaiheisiin asti;  tähän on syynä Dot/Icm:n välittämät antiapoptoottiset signaalit, jotka tekevät  infektoituneet solut  resistenteiksi ulkopuolisille apoptoosin aiheuttajille. Sen takia kaspaasi 1:n ja exekutiivisten kaspaasien ei-apoptoottiset funktiot ovat temporaalisesti ja spatiaalisesti  moduloituja Lpn - infektion aikana, mistä määräytyy permissiivisyys (sallivuus)  solunsisäiseen bakteerireplikoitumiseen.  Artikkelissa  tehdään selkoa L. pneumophilan uusista kaspaasi- aktivoitumisteistä ja pohditaan niiden osuutta geneettisessä restriktiossa ja infektio- permissiivisyydessä.
  • Modulation of caspases and their non-apoptotic functions by Legionella pneumophila.
    Amer AO. Cell Microbiol. 2010 Feb;12(2):140-7. doi: 10.1111/j.1462-5822.2009.01401.x. Epub 2009 Oct 27. Review. PMID: 19863553Legionella pneumophila has become a model system to decipher the non-apoptotic functions of caspases and their role in immunity. In permissive cells, the L. pneumophila-containing vacuole evades endosomal traffic and is remodelled by the endoplasmic reticulum. Evasion of the endosomes is mediated by the Dot/Icm type IV secretion system. Upon L. pneumophila infection of genetically restrictive cells such as wild-type (WT) C57Bl/6J murine macrophages, flagellin is sensed by the NOD-like receptor Nlrc4 leading to caspase-1 activation by the inflammasome complex. Then, caspase-7 is activated downstream of the Nlrc4 inflammasome, promoting non-apoptotic functions such as L. pneumophila-containing phagosome maturation and bacterial degradation. Interestingly, caspase-3 is activated in permissive cells during early stages of infection. However, caspase-3 activation does not lead to apoptosis until late stages of infection because it is associated with potent Dot/Icm-mediated anti-apoptotic stimuli that render the infected cells resistant to external apoptotic inducers. Therefore, the role of caspase-1 and non-apoptotic functions of executioner caspases are temporally and spatially modulated during infection by L. pneumophila, which determine permissiveness to intracellular bacterial proliferation. This review will examine the novel activation pathways of caspases by L. pneumophila and discuss their role in genetic restriction and permissiveness to infection.Similar articles
 
14.Mitä tarvitaan legionellan restriktioon makrofagissa.
Restriction of Legionella pneumophila replication in macrophages requires concerted action of the transcriptional regulators Irf1 and Irf8 and nod-like receptors Naip5 and Nlrc4.
Fortier A, Doiron K, Saleh M, Grinstein S, Gros P. Infect Immun. 2009 Nov;77(11):4794-805. doi: 10.1128/IAI.01546-08. Epub 2009 Aug 31. PMID: 19720760
 
15. Lisätietoa  NLR reseptorista  NAIP5.
16.
NLR-perheenjäsen NLRC4 eli IPAF omaa CARD-domeenin ja NACHT- domeenin. Intrasellulaari Gram- negat. bakteeri indusoi 1-kaspaasin  IPAF välitteisesti ja infektoituneen makrofagin kuoleman ja proinflammatorisia sytokiineja. ( Useimmat ihmiset eivät sairastu  Legionella-bakteeriin,  kun immuunivaste toimii  normaalisti, tai paremminkin: useimmat ihmiset toipuvat Legionellasta, joka on diagnosoitu).
  • NLRC4/IPAF: a CARD carrying member of the NLR family.Sutterwala FS, Flavell RA. Clin Immunol. 2009 Jan;130(1):2-6. doi: 10.1016/j.clim.2008.08.011. Epub 2008 Sep 25. Review. PMID: 18819842
    The NOD-like receptor (NLR) family of proteins is involved in the regulation of innate immune responses and cell death pathways. Recent findings show that the NLR family member NLRC4 (also known as IPAF) has important roles in innate immune responses to Gram-negative bacteria. Macrophages infected with Legionella pneumophila, Salmonella typhimurium, Shigella flexneri, or Pseudomonas aeruginosa activate caspase-1 in an NLRC4-dependent manner leading to macrophage cell death and the release of proinflammatory cytokines. This review will discuss these findings as well as the role of bacterial type III and type IV secretion systems and flagellin in NLRC4-mediated caspase-1 activation.Free PMC Article Similar articles
 
17.
 
18.
NAIP and Ipaf control Legionella pneumophila replication in human cells.
Vinzing M, Eitel J, Lippmann J, Hocke AC, Zahlten J, Slevogt H, N'guessan PD, Günther S, Schmeck B, Hippenstiel S, Flieger A, Suttorp N, Opitz B.
J Immunol. 2008 May 15;180(10):6808-15. PMID:18453601
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19.
Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Nuñez G. PLoS Pathog. 2007 Aug 10;3(8):e111. PMID:17696608
Free PMC Article
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20.
TLR5 tunnistaa extrasellularisen flagelliinin ja Ipaf (NLR) tunnistaa  bakteerin, jolla on sekä flagelliinin ja viruseffektoreita.
  •    TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Miao EA, Andersen-Nissen E, Warren SE, Aderem A.
    Semin Immunopathol. 2007 Sep;29(3):275-88. Epub 2007 Aug 10. Review.PMIDAbstractThe innate immune system precisely modulates the intensity of immune activation in response to infection. Flagellin is a microbe-associated molecular pattern that is present on both pathogenic and nonpathogenic bacteria. Macrophages and dendritic cells (DC) are able to determine the virulence of flagellated bacteria by sensing whether flagellin remains outside the mammalian cell, or if it gains access to the cytosol.  Extracellular flagellin is detected by TLR5, which induces expression of proinflammatory cytokines, while flagellin within the cytosol of macrophages is detected through the Nod-like receptor (NLR) Ipaf, which activates caspase-1. In macrophages infected with Salmonella typhimurium or Legionella pneumophila, Ipaf becomes activated in response to flagellin that appears to be delivered to the cytosol via specific virulence factor transport systems (the SPI1 type III secretion system (T3SS) and the Dot/Icm type IV secretion system (T4SS), respectively). Thus, TLR5 responds more generally to flagellated bacteria, while Ipaf responds to bacteria that express both flagellin and virulence factors
21. 
Intrasellulaarisen Legionella pneumophila-kasvun  restriktioon vaaditaan Ipaf:ista riippuva  kaspaasi-1 aktivaatio ja funktionaalinen NAIP5-signalointi.
  • The Nod-like receptor family member Naip5/Birc1e restricts Legionella pneumophila growth independently of caspase-1 activation.Lamkanfi M, Amer A, Kanneganti TD, Muñoz-Planillo R, Chen G, Vandenabeele P, Fortier A, Gros P, Núñez G.J Immunol. 2007 Jun 15;178(12):8022-7. PMID: 17548639Abstract Similar to Ipaf and caspase-1, the Nod-like receptor protein Naip5 restricts intracellular proliferation of Legionella pneumophila, the causative agent of a severe form of pneumonia known as Legionnaires' disease. Thus, Naip5 has been suggested to regulate Legionella replication inside macrophages through the activation of caspase-1. In this study, we show that cytosolic delivery of recombinant flagellin activated caspase-1 in A/J macrophages carrying a mutant Naip5 allele, and in C57BL/6 (B6) macrophages congenic for the mutant Naip5 allele (B6-Naip5(A/J)), but not in Ipaf(-/-) cells. In line with these results, A/J and B6-Naip5(A/J) macrophages induced high levels of caspase-1 activation and IL-1beta secretion when infected with Legionella. In addition, transgenic expression of a functional Naip5 allele in A/J macrophages did not alter Legionella-induced caspase-1 activation and IL-1beta secretion. Notably, defective Naip5 signaling renders B6-Naip5(A/J) macrophages permissive for Legionella proliferation despite normal caspase-1 activation. These results indicate that the restriction of intracellular Legionella replication is more complex than previously appreciated and requires both Ipaf-dependent caspase-1 activation as well as functional Naip5 signaling. Free Article Similar articles

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