Modulation of the host innate immune and inflammatory response by translocated bacterial proteins

Asrat, Seblewongel; Davis, Kimberly M.; Isberg, Ralph R.

doi:10.1111/cmi.12445

Cited by 44 publications

(44 citation statements)

References 109 publications

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“…Our new immunoblot data indicate that the previously observed effect of T2S on cytokine gene transcription (16) is due, at least partly, to a dampening of the macrophage's MAPK and NF-B pathways. Although it is possible that proteins secreted via T2S act directly on components of the MAPK and NF-B pathways, as has been documented following exposure to various pathogens (21,(74)(75)(76), we focused this study on discerning whether T2S diminishes the upstream event of PAMP recognition. By generating a set of human knockdown cell lines, we determined that the NLR, RLR, TRIF, and PKR pathways as well as ASC-and caspase-4-dependent inflammasomes are not required for the T2S dampening effect.…”

Section: Discussionmentioning

confidence: 99%

“…As is often the case with bacterial infections, this process is initiated in part by the recognition of pathogen-associated molecular patterns (PAMPs) by host surface or endosomal Toll-like receptors (TLRs), cytosolic nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible protein I (RIG-I)-like receptors (RLRs), and inflammasomes (21)(22)(23). Upon PAMP recognition, signal transduction events activate the nuclear factor kappa B (NF-B) and mitogenactivated protein kinase (MAPK) pathways, causing the transcriptional activators NF-B and activator protein 1 (AP-1) to induce cytokine gene transcription (23).…”

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confidence: 99%

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The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

2017

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Previously, we reported that mutants of Legionella pneumophila lacking a type II secretion (T2S) system elicit higher levels of cytokines (e.g., interleukin-6 [IL-6]) following infection of U937 cells, a human macrophage-like cell line. We now show that this effect of T2S is also manifest upon infection of human THP-1 macrophages and peripheral blood monocytes but does not occur during infection of murine macrophages. Supporting the hypothesis that T2S acts to dampen the triggering of an innate immune response, we observed that the mitogen-activated protein kinase (MAPK) and nuclear transcription factor kappa B (NF-B) pathways are more highly stimulated upon infection with the T2S mutant than upon infection with the wild type. By using short hairpin RNA to deplete proteins involved in specific pathogen-associated molecular pattern (PAMP) recognition pathways, we determined that the dampening effect of the T2S system was not dependent on nucleotide binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible protein I (RIG-I)-like receptors (RLRs), double-stranded RNA (dsRNA)-dependent protein kinase receptor (PKR), or TIR domain-containing adaptor inducing interferon beta (TRIF) signaling or an apoptosis-associated speck-like protein containing a CARD (ASC)-or caspase-4-dependent inflammasome. However, the dampening effect of T2S on IL-6 production was significantly reduced upon gene knockdown of myeloid differentiation primary response 88 (MyD88), TANK binding kinase 1 (TBK1), or Toll-like receptor 2 (TLR2). These data indicate that the L. pneumophila T2S system dampens the signaling of the TLR2 pathway in infected human macrophages. We also document the importance of PKR, TRIF, and TBK1 in cytokine secretion during L. pneumophila infection of macrophages.KEYWORDS Legionella pneumophila, TLR2, cytokine, innate immunity, macrophage, type II secretion L egionella pneumophila, a Gram-negative bacterium that is widespread in aquatic habitats, is the principal agent of Legionnaires' disease pneumonia (1-6). In the lungs, Legionella bacteria invade and grow in resident macrophages and then trigger severe inflammation (2). In macrophages, L. pneumophila evades the degradative lysosomal pathway and replicates to large numbers within a membrane-bound vacuole, the Legionella-containing vacuole (LCV) (7,8). Two protein secretion systems, Lsp type II secretion (T2S) and Dot/Icm type IV secretion (T4S), play major roles in the pathogenesis of L. pneumophila (9, 10). In T2S, protein substrates are first translocated across the inner membrane, and upon the action of the T2S pilus-like apparatus, they then exit the bacterial cell through a specific outer membrane pore (11). Using proteomics and enzymatic assays, we have shown that the T2S system of L. pneumo-

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

2017

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“…Successful bacterial pathogens have thus evolved strategies to mask these virulence factors from detection or to blunt the host response that is initiated (72)(73)(74). Indeed, a number of studies in several different systems have revealed that immune sensing of virulence factor activity promotes pathogen clearance (36,(75)(76)(77)(78)(79).…”

Section: Discussionmentioning

confidence: 99%

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

et al. 2017

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Gram-negative bacterial pathogens utilize virulence-associated secretion systems to inject, or translocate, effector proteins into host cells to manipulate cellular processes and promote bacterial replication. However, translocated bacterial products are sensed by nucleotide binding domain and leucine-rich repeat-containing proteins (NLRs), which trigger the formation of a multiprotein complex called the inflammasome, leading to secretion of interleukin-1 (IL-1) family cytokines, pyroptosis, and control of pathogen replication. Pathogenic Yersinia bacteria inject effector proteins termed Yops, as well as pore-forming proteins that comprise the translocon itself, into target cells. The Yersinia translocation regulatory protein YopK promotes bacterial virulence by limiting hyperinjection of the translocon proteins YopD and YopB into cells, thereby limiting cellular detection of Yersinia virulence activity. How hyperinjection of translocon proteins leads to inflammasome activation is currently unknown. We found that translocated YopB and YopD colocalized with the late endosomal/lysosomal protein LAMP1 and that the frequency of YopD and LAMP1 association correlated with the level of caspase-1 activation in individual cells. We also observed colocalization between YopD and Galectin-3, an indicator of endosomal membrane damage. Intriguingly, YopK limited the colocalization of Galectin-3 with YopD, suggesting that YopK limits the induction or sensing of endosomal membrane damage by components of the type III secretion system (T3SS) translocon. Furthermore, guanylate binding proteins (GBPs) encoded on chromosome 3 (Gbp Chr3 ), which respond to pathogen-induced damage or alteration of host membranes, were necessary for inflammasome activation in response to hyperinjected YopB/-D. Our findings indicate that lysosomal damage by Yersinia translocon proteins promotes inflammasome activation and implicate GBPs as key regulators of this process.

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“…These systems contribute in various ways to infection processes among clinically-important pathogens, including Helicobacter pylori , Brucella and Bartonella species, Bordetella pertussis and Legionella pneumophila (1–3). The list of pathogens employing T4SSs to subvert host cellular pathways for establishment of a replication niche continues to expand, making these machines an important subject of study for defining critical features of disease progression and development of strategies aimed at suppressing T4SS function (4).…”

Section: Introductionmentioning

confidence: 99%

“…1). Upon translocation, the effector proteins target specific physiological pathways or biochemical processes with a variety of biological consequences that benefit survival, colonization, and transmission of the invading pathogens (3, 11, 12). …”

Section: Introductionmentioning

confidence: 99%

Mechanism and Function of Type IV Secretion During Infection of the Human Host

2016

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Bacterial pathogens employ type IV secretion systems (T4SSs) for various purposes to aid in survival and proliferation in eukaryotic host. One large T4SS subfamily, the conjugation systems, confers a selective advantage to the invading pathogen in clinical settings through dissemination of antibiotic resistance genes and virulence traits. Besides their intrinsic importance as principle contributors to the emergence of multiply drug-resistant ‘superbugs’, detailed studies of these highly tractable systems have generated important new insights into the mode of action and architectures of paradigmatic T4SSs as a foundation for future efforts aimed at suppressing T4SS machine function. Over the past decade, extensive work on the second large T4SS subfamily, the effector translocators, has identified a myriad of mechanisms employed by pathogens to subvert, subdue, or bypass cellular processes and signaling pathways of the host cell. An overarching theme in the evolution of many effectors is that of molecular mimicry. These effectors carry domains similar to those of eukaryotic proteins and exert their effects through stealthy interdigitation of cellular pathways, often with the outcome not of inducing irreversible cell damage but rather of reversibly modulating cellular functions. This chapter summarizes the major developments for the actively studied pathogens with an emphasis on the structural and functional diversity of the T4SSs and the emerging common themes surrounding effector function in the human host.

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Modulation of the host innate immune and inflammatory response by translocated bacterial proteins

Cited by 44 publications

References 109 publications

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

Mechanism and Function of Type IV Secretion During Infection of the Human Host

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