Type IV Secretion-dependent Activation of Host MAP Kinases Induces an Increased Proinflammatory Cytokine Response to Legionella Pneumophila

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2008 Dec 2

PMID 19043549

Citations 79

Authors

Sunny Shin

Christopher L Case

Kristina A Archer

Catarina V Nogueira

Koichi S Kobayashi

Richard A Flavell

Craig R Roy

Dario S Zamboni

Affiliations

Soon will be listed here.

Abstract

The immune system must discriminate between pathogenic and nonpathogenic microbes in order to initiate an appropriate response. Toll-like receptors (TLRs) detect microbial components common to both pathogenic and nonpathogenic bacteria, whereas Nod-like receptors (NLRs) sense microbial components introduced into the host cytosol by the specialized secretion systems or pore-forming toxins of bacterial pathogens. The host signaling pathways that respond to bacterial secretion systems remain poorly understood. Infection with the pathogen Legionella pneumophila, which utilizes a type IV secretion system (T4SS), induced an increased proinflammatory cytokine response compared to avirulent bacteria in which the T4SS was inactivated. This enhanced response involved NF-kappaB activation by TLR signaling as well as Nod1 and Nod2 detection of type IV secretion. Furthermore, a TLR- and RIP2-independent pathway leading to p38 and SAPK/JNK MAPK activation was found to play an equally important role in the host response to virulent L. pneumophila. Activation of this MAPK pathway was T4SS-dependent and coordinated with TLR signaling to mount a robust proinflammatory cytokine response to virulent L. pneumophila. These findings define a previously uncharacterized host response to bacterial type IV secretion that activates MAPK signaling and demonstrate that coincident detection of multiple bacterial components enables immune discrimination between virulent and avirulent bacteria.

Citing Articles

The effector PieF modulates mRNA stability through association with eukaryotic CCR4-NOT.

Mount H, Urbanus M, Zangari F, Gingras A, Ensminger A mSphere. 2024; 10(1):e0089124.

PMID: 39699231 PMC: 11774319. DOI: 10.1128/msphere.00891-24.

Different infant formulas can activate toll-like receptor 9 in vitro and inhibit interleukin 6 in human primary intestinal epithelial cells.

Hedegger K, Hommel T, Schaubeck M, Gimpfl M, Dahlhoff M Eur J Nutr. 2024; 64(1):16.

PMID: 39567370 PMC: 11579199. DOI: 10.1007/s00394-024-03507-7.

Muropeptides and muropeptide transporters impact on host immune response.

Orsini Delgado M, Gamelas Magalhaes J, Morra R, Cultrone A Gut Microbes. 2024; 16(1):2418412.

PMID: 39439228 PMC: 11509177. DOI: 10.1080/19490976.2024.2418412.

Genetic evidence for a regulated cysteine protease catalytic triad in LegA7, a protein that impinges on a stress response pathway.

Hershkovitz D, Chen E, Ensminger A, Dugan A, Conway K, Joyce A mSphere. 2024; 9(9):e0022224.

PMID: 39166849 PMC: 11423584. DOI: 10.1128/msphere.00222-24.

Role of Type 4B Secretion System Protein, IcmE, in the Pathogenesis of .

Palanisamy R, Zhang Y, Zhang G Pathogens. 2024; 13(5).

PMID: 38787259 PMC: 11123719. DOI: 10.3390/pathogens13050405.

References

Chien M, Morozova I, Shi S, Sheng H, Chen J, Gomez S . The genomic sequence of the accidental pathogen Legionella pneumophila. Science. 2004; 305(5692):1966-8. DOI: 10.1126/science.1099776. View

Coers J, Kagan J, Matthews M, Nagai H, Zuckman D, Roy C . Identification of Icm protein complexes that play distinct roles in the biogenesis of an organelle permissive for Legionella pneumophila intracellular growth. Mol Microbiol. 2000; 38(4):719-36. DOI: 10.1046/j.1365-2958.2000.02176.x. View

Girardin S, Boneca I, Carneiro L, Antignac A, Jehanno M, Viala J . Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003; 300(5625):1584-7. DOI: 10.1126/science.1084677. View

Park J, Greten F, Wong A, Westrick R, Arthur J, Otsu K . Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis--CREB and NF-kappaB as key regulators. Immunity. 2005; 23(3):319-29. DOI: 10.1016/j.immuni.2005.08.010. View

Leber J, Crimmins G, Raghavan S, Meyer-Morse N, Cox J, Portnoy D . Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen. PLoS Pathog. 2008; 4(1):e6. PMC: 2186359. DOI: 10.1371/journal.ppat.0040006. View

Mintz C, Chen J, Shuman H . Isolation and characterization of auxotrophic mutants of Legionella pneumophila that fail to multiply in human monocytes. Infect Immun. 1988; 56(6):1449-55. PMC: 259420. DOI: 10.1128/iai.56.6.1449-1455.1988. View

Akira S, Uematsu S, Takeuchi O . Pathogen recognition and innate immunity. Cell. 2006; 124(4):783-801. DOI: 10.1016/j.cell.2006.02.015. View

Hawn T, Smith K, Aderem A, Skerrett S . Myeloid differentiation primary response gene (88)- and toll-like receptor 2-deficient mice are susceptible to infection with aerosolized Legionella pneumophila. J Infect Dis. 2006; 193(12):1693-702. DOI: 10.1086/504525. View

Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L . An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003; 4(7):702-7. DOI: 10.1038/ni945. View

10.

Lightfield K, Persson J, Brubaker S, Witte C, von Moltke J, Dunipace E . Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat Immunol. 2008; 9(10):1171-8. PMC: 2614210. DOI: 10.1038/ni.1646. View

11.

Segal G, Purcell M, Shuman H . Host cell killing and bacterial conjugation require overlapping sets of genes within a 22-kb region of the Legionella pneumophila genome. Proc Natl Acad Sci U S A. 1998; 95(4):1669-74. PMC: 19142. DOI: 10.1073/pnas.95.4.1669. View

12.

Amer A, Franchi L, Kanneganti T, Body-Malapel M, Ozoren N, Brady G . Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf. J Biol Chem. 2006; 281(46):35217-23. DOI: 10.1074/jbc.M604933200. View

13.

Tada H, Aiba S, Shibata K, Ohteki T, Takada H . Synergistic effect of Nod1 and Nod2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun. 2005; 73(12):7967-76. PMC: 1307098. DOI: 10.1128/IAI.73.12.7967-7976.2005. View

14.

ORiordan M, Yi C, Gonzales R, Lee K, Portnoy D . Innate recognition of bacteria by a macrophage cytosolic surveillance pathway. Proc Natl Acad Sci U S A. 2002; 99(21):13861-6. PMC: 129788. DOI: 10.1073/pnas.202476699. View

15.

Berger K, Isberg R . Two distinct defects in intracellular growth complemented by a single genetic locus in Legionella pneumophila. Mol Microbiol. 1993; 7(1):7-19. DOI: 10.1111/j.1365-2958.1993.tb01092.x. View

16.

Molofsky A, Byrne B, Whitfield N, Madigan C, Fuse E, Tateda K . Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J Exp Med. 2006; 203(4):1093-104. PMC: 1584282. DOI: 10.1084/jem.20051659. View

17.

Stockinger S, Materna T, Stoiber D, Bayr L, Steinborn R, Kolbe T . Production of type I IFN sensitizes macrophages to cell death induced by Listeria monocytogenes. J Immunol. 2002; 169(11):6522-9. DOI: 10.4049/jimmunol.169.11.6522. View

18.

Kobayashi K, Inohara N, Hernandez L, Galan J, Nunez G, Janeway C . RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature. 2002; 416(6877):194-9. DOI: 10.1038/416194a. View

19.

Park J, Greten F, Li Z, Karin M . Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science. 2002; 297(5589):2048-51. DOI: 10.1126/science.1073163. View

20.

Huffman D, Abrami L, Sasik R, Corbeil J, van der Goot F, Aroian R . Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins. Proc Natl Acad Sci U S A. 2004; 101(30):10995-1000. PMC: 503732. DOI: 10.1073/pnas.0404073101. View