Mouse Macrophages Are Permissive to Motile<i>Legionella</i>Species That Fail To Trigger Pyroptosis

Whitfield, Natalie N.; Byrne, Brenda; Swanson, Michele S.

doi:10.1128/iai.00070-09

Cited by 23 publications

(20 citation statements)

References 83 publications

(126 reference statements)

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“…Lightfield and colleagues demonstrated that transduction of BMMs with a retroviral construct that encodes bacterial flagellin renders cytotoxicity to BMMs (35). Indeed, it was recently demonstrated that transfection of flagellin from L. parisiensis and L. tucsonensis triggers cytotoxicity to BMMs (56). Collectively, these data indicate that bacterial internalization and phagosome formation are not required for pyroptosis.…”

Section: Discussionmentioning

confidence: 59%

Pore Formation Triggered byLegionellaspp. Is an Nlrc4 Inflammasome-Dependent Host Cell Response That Precedes Pyroptosis

Silveira

Zamboni

2010

Infect Immun

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Legionella pneumophila, the etiological agent of Legionnaires disease, is known to trigger pore formation in bone marrow-derived macrophages (BMMs) by mechanisms dependent on the type IVB secretion system known as Dot/Icm. Here, we used several mutants of L. pneumophila in combination with knockout mice to assess the host and bacterial factors involved in pore formation in BMMs. We found that regardless of Dot/Icm activity, pore formation does not occur in BMMs deficient in caspase-1 and Nlrc4/Ipaf. Pore formation was temporally associated with interleukin-1␤ secretion and preceded host cell lysis and pyroptosis. Pore-forming ability was dependent on bacterial Dot/Icm but independent of several effector proteins, multiplication, and de novo protein synthesis. Flagellin, which is known to trigger the Nlrc4 inflammasome, was required for pore formation as flaA mutant bacteria failed to induce cell permeabilization. Accordingly, transfection of purified flagellin was sufficient to trigger pore formation independent of infection. By using 11 different Legionella species, we found robust pore formation in response to L. micdadei, L. bozemanii, L. gratiana, L. jordanis, and L. rubrilucens, and this trait correlated with flagellin expression by these species. Together, the results suggest that pore formation is neither L. pneumophila specific nor the result of membrane damage induced by Dot/Icm activity; instead, it is a highly coordinated host cell response dependent on host Nlrc4 and caspase-1 and on bacterial flagellin and type IV secretion system.

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Section: Discussionmentioning

confidence: 59%

Pore Formation Triggered byLegionellaspp. Is an Nlrc4 Inflammasome-Dependent Host Cell Response That Precedes Pyroptosis

Silveira

Zamboni

2010

Infect Immun

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“…The NLRC4-dependent and caspase-1-dependent response, known as NLRC4 inflammasome, has been extensively characterized and accounts for pore formation, pyroptosis, and modulation of phagosome maturation as well as restriction of L. pneumophila replication in macrophages (20,21,(23)(24)(25)(47)(48)(49)(50). Besides the NLRC4 inflammasome, we demonstrated that NLRC4 also uses caspase-1-independent signaling in the restriction of L. pneumophila replication.…”

Section: Discussionmentioning

confidence: 90%

Activation of NLRC4 by Flagellated Bacteria Triggers Caspase-1–Dependent and –Independent Responses To Restrict Legionella pneumophila Replication in Macrophages and In Vivo

Pereira

Morgantetti

Massis

et al. 2011

The Journal of Immunology

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Although NLRC4/IPAF activation by flagellin has been extensively investigated, the downstream signaling pathways and the mechanisms responsible for infection clearance remain unclear. In this study, we used mice deficient for the inflammasome components in addition to wild-type (WT) Legionella pneumophila or bacteria deficient for flagellin (flaA) or motility (fliI) to assess the pathways responsible for NLRC4-dependent growth restriction in vivo and ex vivo. By comparing infections with WT L. pneumophila, fliI, and flaA, we found that flagellin and motility are important for the colonization of the protozoan host Acanthamoeba castellanii. However, in macrophages and mammalian lungs, flagellin expression abrogated bacterial replication. The flagellin-mediated growth restriction was dependent on NLRC4, and although it was recently demonstrated that NLRC4 is able to recognize bacteria independent of flagellin, we found that the NLRC4-dependent restriction of L. pneumophila multiplication was fully dependent on flagellin. By examining infected caspase-1−/− mice and macrophages with flaA, fliI, and WT L. pneumophila, we could detect greater replication of flaA, which suggests that caspase-1 only partially accounted for flagellin-dependent growth restriction. Conversely, WT L. pneumophila multiplied better in macrophages and mice deficient for NLRC4 compared with that in macrophages and mice deficient for caspase-1, supporting the existence of a novel caspase-1–independent response downstream of NLRC4. This response operated early after macrophage infection and accounted for the restriction of bacterial replication within bacteria-containing vacuoles. Collectively, our data indicate that flagellin is required for NLRC4-dependent responses to L. pneumophila and that NLRC4 triggers caspase-1–dependent and –independent responses for bacterial growth restriction in macrophages and in vivo.

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“…Legionella parisensis and Legionella tusconensis do not induce pyroptosis or IL‐1β secretion in mouse macrophages. However, purified flagellin from these two species does induce pyroptosis and IL‐1β secretion when delivered directly to the cytosol (107). These two species lack type IV secretion system‐dependent characteristics, so it appears that lack of functional secretion prevents flagellin delivery to the cytosol and subsequent NLRC4 inflammasome activation.…”

Section: Nlrc4mentioning

confidence: 99%

Intracellular sensing of microbes and danger signals by the inflammasomes

Horváth

Schrum

Nardo

et al. 2011

Immunological Reviews

114

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Summary The cells of the innate immune system mobilize a coordinated immune response towards invading microbes and after disturbances in tissue homeostasis. These immune responses typically lead to infection control and tissue repair. Exaggerated or uncontrolled immune responses, however, can also induce acute of chronic inflammatory pathologies that are characteristic for many common diseases such as sepsis, arthritis, atherosclerosis or Alzheimer’s disease. In recent years the concerted efforts of many scientists have uncovered numerous mechanisms by which immune cells detect foreign or changed self-substances that appear in infections or during tissue damage. These substances stimulate signaling receptors, which leads to cellular activation and the induction of effector mechanisms. Here, we review the role of inflammasomes, a family of signaling molecules that form multi-molecular signaling platforms and activate inflammatory caspases and IL-1β cytokines.

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Mouse Macrophages Are Permissive to MotileLegionellaSpecies That Fail To Trigger Pyroptosis

Cited by 23 publications

References 83 publications

Pore Formation Triggered byLegionellaspp. Is an Nlrc4 Inflammasome-Dependent Host Cell Response That Precedes Pyroptosis

Pore Formation Triggered byLegionellaspp. Is an Nlrc4 Inflammasome-Dependent Host Cell Response That Precedes Pyroptosis

Activation of NLRC4 by Flagellated Bacteria Triggers Caspase-1–Dependent and –Independent Responses To Restrict Legionella pneumophila Replication in Macrophages and In Vivo

Intracellular sensing of microbes and danger signals by the inflammasomes

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