Innate Immune Pathways Triggered by Listeria monocytogenes and Their Role in the Induction of Cell-Mediated Immunity.

Graduate Group in Microbiology, University of California, Berkeley, Berkeley, California, USA.

Acquired cell-mediated immunity to Listeria monocytogenes is induced by infection with live, replicating bacteria that grow in the host cell cytosol, whereas killed bacteria, or those trapped in a phagosome, fail to induce protective immunity. In this chapter, we focus on how L. monocytogenes is sensed by the innate immune system, with the presumption that innate immunity affects the development of acquired immunity. Infection by L. monocytogenes induces three innate immune pathways: an MyD88-dependent pathway emanating from a phagosome leading to expression of inflammatory cytokines; a STING/IRF3-dependent pathway emanating from the cytosol leading to the expression of IFN-ß and coregulated genes; and very low levels of a Caspase-1-dependent, AIM2-dependent inflammasome pathway resulting in proteolytic activation and secretion of IL-1ß and IL-18 and pyroptotic cell death. Using a combination of genetics and biochemistry, we identified the listerial ligand that activates the STING/IRF3 pathway as secreted cyclic diadenosine monophosphate, a newly discovered conserved bacterial signaling molecule. We also identified L. monocytogenes mutants that caused robust inflammasome activation due to bacteriolysis in the cytosol, release of DNA, and activation of the AIM2 inflammasome. A strain was constructed that ectopically expressed and secreted a fusion protein containing Legionella pneumophila flagellin that robustly activated the Nlrc4-dependent inflammasome and was highly attenuated in mice, also in an Nlrc4-dependent manner. Surprisingly, this strain was a poor inducer of adaptive immunity, suggesting that inflammasome activation is not necessary to induce cell-mediated immunity and may even be detrimental under some conditions. To the best of our knowledge, no single innate immune pathway is necessary to mount a robust acquired immune response to L. monocytogenes infection.

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Legionella secreted effectors and innate immune responses

Legionella secreted effectors and innate immune responses - Luo - 2011 - Cellular Microbiology - Wiley Online LibrarySkip to Main Content

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DOI: 10.1111/j.1462-5822.2011.01713.x

© 2011 Blackwell Publishing Ltd

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Cellular MicrobiologyEarly View (Online Version of Record published before inclusion in an issue)

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How to CiteLuo, Z.-Q. (2011), Legionella secreted effectors and innate immune responses. Cellular Microbiology. doi: 10.1111/j.1462-5822.2011.01713.x

Author Information

Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, IN 47907, USA

*Correspondence: Zhao-Qing Luo,

*Correspondence: E-mail luoz@purdue.edu; Tel. (+1) 765 496 6697; Fax (+1) 765 494 0876.

Publication HistoryArticle first published online: 10 NOV 2011Accepted manuscript online: 11 OCT 2011 03:50AM ESTReceived 1 August, 2011; revised 3 October, 2011; accepted 5 October, 2011. SEARCH Search Scope All contentPublication titlesIn this journalIn this issue Search String Advanced >Saved Searches > SEARCH BY CITATION Volume: Issue: Page: ARTICLE TOOLSGet PDF (300K)Save to My ProfileE-mail Link to this ArticleExport Citation for this ArticleGet Citation AlertsRequest Permissions AbstractArticleReferencesCited By View Full Article (HTML) Get PDF (300K) Summary

Legionella pneumophila is a facultative intracellular pathogen capable of replicating in a wide spectrum of cells. Successful infection by Legionella requires the Dot/Icm type IV secretion system, which translocates a large number of effector proteins into infected cells. By co-opting numerous host cellular processes, these proteins function to establish a specialized organelle that allows bacterial survival and proliferation. Even within the vacuole, L. pneumophila triggers robust immune responses. Recent studies reveal that a subset of Legionella effectors directly target some basic components of the host innate immunity systems such as phagosome maturation. Others play essential roles in engaging the host innate immune surveillance system. This review will highlight recent progress in our understanding of these interactions and discuss implications for the study of the immune detection mechanisms.

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Two signal models in innate immunity

Summary: Two-signal models have a rich history in immunology. In the classic two-signal model of T-cell activation, signal one consists of engagement of the T-cell receptor by antigen/major histocompatibility complex, whereas signal two arises from costimulatory ligands on antigen-presenting cells. A requirement for two independent signals helps to ensure that T-cell responses are initiated only in response to bona fide infectious threats. Our studies have led us to conclude that initiation of innate immune responses to pathogens also often requires two signals: signal one is initiated by a microbe-derived ligand, such as lipopolysaccharide (LPS) or flagellin, whereas signal two conveys additional contextual information that often accompanies infectious microbes. Although ...

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