Bacterial Internalization, Localization, and Effectors Shape the Epithelial Immune Response during Shigella flexneri Infection

Lippmann, Juliane; Gwinner, Frederik; Rey, Camille; Tamir, Uyanga; Law, Helen K. W.; Schwikowski, Benno; Enninga, Jost

doi:10.1128/iai.00574-15

Cited by 12 publications

(7 citation statements)

References 33 publications

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“…In agreement with previous work [ 13 ], IL-8 expression was largely restricted to uninfected cells located in the proximity of infected cells ( Fig 1B and S1 Fig ), confirming the importance of bystander cell activation in the control of inflammation during S . flexneri infection [ 13 , 21 ]. In order to identify proteins involved in the control of IL-8 expression, the assay was run in a high throughput setup to screen a commercially available genome-wide library made up of pools of 4 siRNAs per gene.…”

Section: Resultsmentioning

confidence: 99%

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ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria

et al. 2017

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During infection by invasive bacteria, epithelial cells contribute to innate immunity via the local secretion of inflammatory cytokines. These are directly produced by infected cells or by uninfected bystanders via connexin-dependent cell-cell communication. However, the cellular pathways underlying this process remain largely unknown. Here we perform a genome-wide RNA interference screen and identify TIFA and TRAF6 as central players of Shigella flexneri and Salmonella typhimurium-induced interleukin-8 expression. We show that threonine 9 and the forkhead-associated domain of TIFA are necessary for the oligomerization of TIFA in both infected and bystander cells. Subsequently, this process triggers TRAF6 oligomerization and NF-κB activation. We demonstrate that TIFA/TRAF6-dependent cytokine expression is induced by the bacterial metabolite heptose-1,7-bisphosphate (HBP). In addition, we identify alpha-kinase 1 (ALPK1) as the critical kinase responsible for TIFA oligomerization and IL-8 expression in response to infection with S. flexneri and S. typhimurium but also to Neisseria meningitidis. Altogether, these results clearly show that ALPK1 is a master regulator of innate immunity against both invasive and extracellular gram-negative bacteria.

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Section: Resultsmentioning

confidence: 99%

“…This point was further confirmed by Lippmann et al . who showed that the expression of IL-8 in bystander cells requires bacterial internalization [ 21 ]. Mechanisms explaining how HBP could therefore be detected within minutes of bacterial invasion have to be envisioned.…”

Section: Discussionmentioning

confidence: 99%

ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria

et al. 2017

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“…YopB participates in forming a pore in the host cell membrane ( 46 ), via which Yersinia can inject the pathogen effector proteins directly into the host cell. Hence yopB controls the translocation of all Yops ( 73 – 75 ). We found that yopB -deficient Y. enterocolitica and Y. pseudotuberculosis were unable to inhibit PGE2 biosynthesis from THP-1 macrophages ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Yersinia pseudotuberculosisYopJ Limits Macrophage Response by Downregulating COX-2-Mediated Biosynthesis of PGE2 in a MAPK/ERK-Dependent Manner

et al. 2021

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“…Supporting the important role of OspF in the nucleus, the ospF mutant modulates the transcription of more genes than other mutant strains tested including mxiE strain, which lacks expression of second-wave effectors (Parsot, 2009 ). In addition, affected genes are attributed to three distinct pathways: inflammation, apoptosis and stress response, going way beyond its classical role in dampening the inflammatory response (Lippmann et al, 2015 ). OspB is another effector that is located to the nucleus and that could be implicated in modulating the inflammatory response, potentially coordinating its action with OspF (Zurawski et al, 2009 ; Ambrosi et al, 2015 ).…”

Section: Recent Progresses In the Role Of Shigella mentioning

confidence: 99%

Implications of Spatiotemporal Regulation of Shigella flexneri Type Three Secretion Activity on Effector Functions: Think Globally, Act Locally

Campbell-Valois

Pontier²

2016

Front. Cell. Infect. Microbiol.

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Shigella spp. are Gram-negative bacterial pathogens that infect human colonic epithelia and cause bacterial dysentery. These bacteria express multiple copies of a syringe-like protein complex, the Type Three Secretion apparatus (T3SA), which is instrumental in the etiology of the disease. The T3SA triggers the plasma membrane (PM) engulfment of the bacteria by host cells during the initial entry process. It then enables bacteria to escape the resulting phagocytic-like vacuole. Freed bacteria form actin comets to move in the cytoplasm, which provokes bacterial collision with the inner leaflet of the PM. This phenomenon culminates in T3SA-dependent secondary uptake and vacuolar rupture in neighboring cells in a process akin to what is observed during entry and named cell-to-cell spread. The activity of the T3SA of Shigella flexneri was recently demonstrated to display an on/off regulation during the infection. While the T3SA is active when bacteria are in contact with PM-derived compartments, it switches to an inactive state when bacteria are released within the cytosol. These observations indicate that effector proteins transiting through the T3SA are therefore translocated in a highly time and space constrained fashion, likely impacting on their cellular distribution. Herein, we present what is currently known about the composition, the assembly and the regulation of the T3SA activity and discuss the consequences of the on/off regulation of T3SA on Shigella effector properties and functions during the infection. Specific examples that will be developed include the role of effectors IcsB and VirA in the escape from LC3/ATG8-positive vacuoles formed during cell-to-cell spread and of IpaJ protease activity against N-miristoylated proteins. The conservation of a similar regulation of T3SA activity in other pathogens such as Salmonella or Enteropathogenic Escherichia coli will also be briefly discussed.

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Bacterial Internalization, Localization, and Effectors Shape the Epithelial Immune Response during Shigella flexneri Infection

Cited by 12 publications

References 33 publications

ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria

ALPK1 controls TIFA/TRAF6-dependent innate immunity against heptose-1,7-bisphosphate of gram-negative bacteria

Yersinia pseudotuberculosisYopJ Limits Macrophage Response by Downregulating COX-2-Mediated Biosynthesis of PGE2 in a MAPK/ERK-Dependent Manner

Implications of Spatiotemporal Regulation of Shigella flexneri Type Three Secretion Activity on Effector Functions: Think Globally, Act Locally

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