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Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent Legionella pneumophila.

Fontana MF, Banga S, Barry KC, Shen X, Tan Y, Luo ZQ, Vance RE - PLoS Pathog. (2011)

Bottom Line: Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor.L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR.Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, California, USA.

ABSTRACT
The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires' Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis.

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Related in: MedlinePlus

Model of NF-κB activation and superinduction by translation inhibitors.(A) NF-κB activation by TLR signaling, via the adaptor Myd88, or Nod signaling, via Rip2, normally leads to synthesis of inhibitory proteins, including IκB and A20, which act to shut off NF-κB signaling. (B) When translation is inhibited, IκB and A20 fail to be synthesized, allowing sustained activation of NF-κB and subsequent robust transcription of a subset of target genes.
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ppat-1001289-g006: Model of NF-κB activation and superinduction by translation inhibitors.(A) NF-κB activation by TLR signaling, via the adaptor Myd88, or Nod signaling, via Rip2, normally leads to synthesis of inhibitory proteins, including IκB and A20, which act to shut off NF-κB signaling. (B) When translation is inhibited, IκB and A20 fail to be synthesized, allowing sustained activation of NF-κB and subsequent robust transcription of a subset of target genes.

Mentions: NF-κB signaling is also inhibited by other de novo expressed proteins such as A20 [29]. We therefore used A20−/− macrophages, which exhibit prolonged NF-κB activation in response to TLR signaling [29], to further test the hypothesis that sustained NF-κB signaling can induce targets of the ETR. Strikingly, we found that the defective induction of Il23a and Csf2 by Δ5 was rescued in A20−/− macrophages (Figure 5E). Taken together, these observations suggest a model in which disrupted protein synthesis, and the subsequent failure to synthesize inhibitors of NF-κB signaling (e.g. IκB and A20), leads to sustained activation of NF-κB (Figure 6). In turn, we suggest that this prolonged activation of NF-κB results in enhanced transcription of a specific subset of genes.


Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent Legionella pneumophila.

Fontana MF, Banga S, Barry KC, Shen X, Tan Y, Luo ZQ, Vance RE - PLoS Pathog. (2011)

Model of NF-κB activation and superinduction by translation inhibitors.(A) NF-κB activation by TLR signaling, via the adaptor Myd88, or Nod signaling, via Rip2, normally leads to synthesis of inhibitory proteins, including IκB and A20, which act to shut off NF-κB signaling. (B) When translation is inhibited, IκB and A20 fail to be synthesized, allowing sustained activation of NF-κB and subsequent robust transcription of a subset of target genes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040669&req=5

ppat-1001289-g006: Model of NF-κB activation and superinduction by translation inhibitors.(A) NF-κB activation by TLR signaling, via the adaptor Myd88, or Nod signaling, via Rip2, normally leads to synthesis of inhibitory proteins, including IκB and A20, which act to shut off NF-κB signaling. (B) When translation is inhibited, IκB and A20 fail to be synthesized, allowing sustained activation of NF-κB and subsequent robust transcription of a subset of target genes.
Mentions: NF-κB signaling is also inhibited by other de novo expressed proteins such as A20 [29]. We therefore used A20−/− macrophages, which exhibit prolonged NF-κB activation in response to TLR signaling [29], to further test the hypothesis that sustained NF-κB signaling can induce targets of the ETR. Strikingly, we found that the defective induction of Il23a and Csf2 by Δ5 was rescued in A20−/− macrophages (Figure 5E). Taken together, these observations suggest a model in which disrupted protein synthesis, and the subsequent failure to synthesize inhibitors of NF-κB signaling (e.g. IκB and A20), leads to sustained activation of NF-κB (Figure 6). In turn, we suggest that this prolonged activation of NF-κB results in enhanced transcription of a specific subset of genes.

Bottom Line: Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor.L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR.Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, Berkeley, California, USA.

ABSTRACT
The intracellular bacterial pathogen Legionella pneumophila causes an inflammatory pneumonia called Legionnaires' Disease. For virulence, L. pneumophila requires a Dot/Icm type IV secretion system that translocates bacterial effectors to the host cytosol. L. pneumophila lacking the Dot/Icm system is recognized by Toll-like receptors (TLRs), leading to a canonical NF-κB-dependent transcriptional response. In addition, L. pneumophila expressing a functional Dot/Icm system potently induces unique transcriptional targets, including proinflammatory genes such as Il23a and Csf2. Here we demonstrate that this Dot/Icm-dependent response, which we term the effector-triggered response (ETR), requires five translocated bacterial effectors that inhibit host protein synthesis. Upon infection of macrophages with virulent L. pneumophila, these five effectors caused a global decrease in host translation, thereby preventing synthesis of IκB, an inhibitor of the NF-κB transcription factor. Thus, macrophages infected with wildtype L. pneumophila exhibited prolonged activation of NF-κB, which was associated with transcription of ETR target genes such as Il23a and Csf2. L. pneumophila mutants lacking the five effectors still activated TLRs and NF-κB, but because the mutants permitted normal IκB synthesis, NF-κB activation was more transient and was not sufficient to fully induce the ETR. L. pneumophila mutants expressing enzymatically inactive effectors were also unable to fully induce the ETR, whereas multiple compounds or bacterial toxins that inhibit host protein synthesis via distinct mechanisms recapitulated the ETR when administered with TLR ligands. Previous studies have demonstrated that the host response to bacterial infection is induced primarily by specific microbial molecules that activate TLRs or cytosolic pattern recognition receptors. Our results add to this model by providing a striking illustration of how the host immune response to a virulent pathogen can also be shaped by pathogen-encoded activities, such as inhibition of host protein synthesis.

Show MeSH
Related in: MedlinePlus