Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain–containing proteins

Cirl, Christine; Wieser, Andreas; Yadav, Manisha; Duerr, Susanne; Schubert, Sören; Fischer, Hans; Stappert, Dominik; Wantia, Nina; Rodríguez, Núria; Wagner, Hermann; Svanborg, Catharina; Miethke, Thomas

doi:10.1038/nm1734

Cited by 356 publications

(479 citation statements)

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“…As bacterial TIR proteins down‐modulate NF‐κB activation (Newman et al , 2006; Cirl et al , 2008; Salcedo et al , 2008, 2013; Spear et al , 2012; Askarian et al , 2014; Zou et al , 2014), we infected the lung carcinoma epithelial cell line A549, a well‐established cellular model for Pseudomonas infection and analysed NF‐κB translocation into the nucleus after one hour of infection by confocal microscopy. We developed an automated analysis of p65/RelA fluorescence in relation to DAPI labelling using a specific ImageJ plugin from images obtained by confocal microscopy (Fig EV1A) which allowed us to clearly differentiate between TNFα‐treated and mock‐infected cells (Figs 2A and EV1B).…”

Section: Resultsmentioning

confidence: 99%

“…Bacterial targeting of TLRs has been best described for uropathogenic E. coli TcpC (Cirl et al , 2008) and Brucella BtpA, also known as TcpB (Cirl et al , 2008; Salcedo et al , 2008), even though their molecular mode of action remains elusive. Brucella relies on an additional TIR protein, BtpB to down‐modulate inflammation during infection (Salcedo et al , 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Brucella relies on an additional TIR protein, BtpB to down‐modulate inflammation during infection (Salcedo et al , 2013). TcpC was shown to interfere with MyD88‐dependent and independent pathways to down‐modulate TLR signalling and contribute to kidney pathology (Cirl et al , 2008; Yadav et al , 2010). In the case of Brucella , BtpA/TcpB has been described as a mimic of TIRAP, since it can directly bind specific phosphoinositides of the plasma membrane (Radhakrishnan et al , 2009).…”

Section: Discussionmentioning

confidence: 99%

“…No direct imaging of bacterial TIR proteins has been described. In the case of TcpC, internalization into host cells was observed but the export mechanism was not identified (Cirl et al , 2008), whereas no data are available regarding Salmonella , Yersinia, Staphyloccocus and Enteroccoccus . In the case of Brucella , depending on the fusion tags, translocation into host cells of BtpA/TcpB or BtpB was dependent or independent of the T4SS (Salcedo et al , 2013) whereas a separate group has proposed that BtpA/TcpB is cell permeable and may enter host cells in a passive manner (Radhakrishnan & Splitter, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, few examples of direct blocking at the level of initial receptor–adaptor complexes are known. Some bacterial pathogens rely on TIR domain‐containing proteins to perturb TIR‐dependent interactions (Newman et al , 2006; Cirl et al , 2008; Salcedo et al , 2008, 2013), essential in innate immune signalling. The growing number of bacterial TIR proteins recently identified in both Gram‐negative and Gram‐positive human pathogens (Spear et al , 2012; Askarian et al , 2014; Zou et al , 2014) highlights the importance of this immune evasion strategy in disease.…”

Section: Introductionmentioning

confidence: 99%

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A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors

et al. 2017

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Bacterial pathogens often subvert the innate immune system to establish a successful infection. The direct inhibition of downstream components of innate immune pathways is particularly well documented but how bacteria interfere with receptor proximal events is far less well understood. Here, we describe a Toll/interleukin 1 receptor (TIR) domain‐containing protein (PumA) of the multi‐drug resistant Pseudomonas aeruginosa PA7 strain. We found that PumA is essential for virulence and inhibits NF‐κB, a property transferable to non‐PumA strain PA14, suggesting no additional factors are needed for PumA function. The TIR domain is able to interact with the Toll‐like receptor (TLR) adaptors TIRAP and MyD88, as well as the ubiquitin‐associated protein 1 (UBAP1), a component of the endosomal‐sorting complex required for transport I (ESCRT‐I). These interactions are not spatially exclusive as we show UBAP1 can associate with MyD88, enhancing its plasma membrane localization. Combined targeting of UBAP1 and TLR adaptors by PumA impedes both cytokine and TLR receptor signalling, highlighting a novel strategy for innate immune evasion.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors

et al. 2017

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Immune Defence: Microbial Interference

Merino

2010

Encyclopedia of Life Sciences

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The immune system controls the host–microbe interactions, the outcome of which can range from symbiotic coexistence with commensally microbiota, to mild asymptomatic infections, to highly virulent infectious diseases. This control is achieved by two defence mechanisms: the innate immune defence, which consists in a nonspecific mechanism, and the adaptive immunity defence, acquired over time following infections or vaccination. Despite the sophisticated immune system, extracellular and intracellular pathogens have developed numerous, and often ingenious strategies, to evade, interfere or eradicate the effectiveness of host immune defences. Although the strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms shared between these microbial pathogens. The success of each pathogen depends on the coordinated activities of its virulence factors to overcome host barriers to colonisation and its ability to mount an effective anti‐immune response within the infected host, which can ultimately result in acute disease or chronic infection. Key Concepts: Immunoglobulin proteases cleave antibodies rendering them nonfunctional and leading to deficiencies in the immune system. Complement regulators prevent complement activation and cell destruction. Interference with major histocompatibility complexes overcomes T‐cell recognition. Microbial interference with cytokines modulates intracellular signalling critical to the regulation, proliferation and differentiation of lymphocytes, which drive inflammation. Intracellular resistance allows microorganisms to circumvent humoral defence mechanisms and spread within the host. Immunosuppresion reduces T or B lymphocytes’ defence.

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Immune Defence: Microbial Interference

Merino

Tomás

2015

Encyclopedia of Life Sciences

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To cause diseases, pathogens must first breach physical barriers and then successfully replicate and disseminate while avoiding destruction by immune system. The immune system control is achieved by two defence mechanisms: the innate immune defence, which consists in a non‐specific mechanism present in organisms across all kingdoms, and the adaptive immunity defence, acquired over time following infections or vaccination. Despite the sophisticated immune system, extracellular and intracellular pathogens have developed numerous, and often ingenious strategies, to evade, interfere or eradicate the effectiveness of host immune defences. Although the strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms shared between these microbial pathogens. The success of each pathogen depends on the coordinated activities of its virulence factors to overcome host barriers to colonisation and its ability to mount an effective anti‐immune response within the infected host, which can ultimately result in acute disease or chronic infection. Key Concepts Immunoglobulin proteases cleave antibodies rendering them non‐functional and leading to deficiencies in the immune system. Complement regulators prevent complement activation and cell destruction. Interference with major histocompatibility complexes overcomes T‐cell recognition. Microbial interference with cytokines modulates intracellular signalling critical to the regulation, proliferation and differentiation of lymphocytes, which drive inflammation. Intracellular resistance allows microorganisms to circumvent humoral defence mechanisms and spread within the host. Immunosuppression reduces T or B lymphocytes' defence.

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Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain–containing proteins

Cited by 356 publications

References 32 publications

A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors

A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors

Immune Defence: Microbial Interference

Immune Defence: Microbial Interference

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