RIPK1-dependent apoptosis bypasses pathogen blockade of innate signaling to promote immune defense

Peterson, Lance W.; Philip, Naomi H.; DeLaney, Alexandra; Wynosky-Dolfi, Meghan A.; Asklof, Kendra; Gray, Falon; Choa, Ruth; Bjånes, Elisabet; Buza, Elisabeth L.; Hu, Baofeng; Dillon, Christopher P.; Green, Douglas R.; Berger, Scott B.; Gough, Peter J.; Bertin, John; Brodsky, Igor E.

doi:10.1084/jem.20170347

Cited by 98 publications

(109 citation statements)

References 62 publications

(120 reference statements)

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“…Yersinia pseudotuberculosis replicates within deep tissue sites to form clonal extracellular clusters of bacteria called microcolonies (or pyogranulomas) (16–18). Within the spleen, neutrophils are recruited to sites of bacterial replication and directly contact bacteria at the periphery of microcolonies.…”

Section: Introductionmentioning

confidence: 99%

“…A layer of monocytes is recruited immediately around the layer of neutrophils. Recruited monocytes develop characteristics of dendritic cells and macrophages (16–18), and expresses inducible nitric oxide synthase (iNOS), which produces antimicrobial nitric oxide (NO) that diffuses towards the microcolony. Bacteria at the periphery of the microcolony respond to NO by expressing the NO-detoxifying gene, hmp (18).…”

Section: Introductionmentioning

confidence: 99%

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Subpopulations of stressed Y. pseudotuberculosis preferentially survive doxycycline treatment within host tissues

Raneses

Ellison

Liu

et al. 2020

Preprint

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Severe systemic bacterial infections result in colonization of deep tissues, which can be very difficult to eliminate with antibiotics. It remains unclear if this is because antibiotics are not reaching inhibitory concentrations within tissues, if subsets of bacteria are less susceptible to antibiotics, or if both contribute to limited treatment efficacy. To determine the concentration of doxycycline (Dox) present within deep tissues following treatment, we generated a fluorescent transcriptional reporter derived from the tet operon to specifically detect intracellular tetracycline exposure at the single bacterial cell level. Dox exposure was detected in the spleen 2 hours after intraperitoneal injection, and by 4 hours post-injection, this treatment resulted in a significant decrease in viable Yersinia pseudotuberculosis in the spleen. Nitric oxide-stressed bacteria preferentially survived treatment, suggesting stress was sufficient to alter Dox susceptibility. Many bacteria (~10%) survived a single dose of Dox, and the antibiotic accumulated at the periphery of microcolonies to growth inhibitory concentrations until 48 hours post-treatment. After this timepoint, antibiotic concentrations decreased and bacterial growth resumed. Dox-treated mice eventually succumbed to the infection, albeit with significantly prolonged survival relative to untreated mice. These results indicate that Dox delivery by intraperitoneal injection results in rapid diffusion of inhibitory concentrations of antibiotic into the spleen, but stressed cells preferentially survive drug treatment, and bacterial growth resumes once drug concentrations decrease. This fluorescent reporter strategy for antibiotic detection could easily be modified to detect the concentration of additional antimicrobial compounds within host tissues following drug administration.ImportanceBacterial infections are very difficult to treat when bacteria spread into the bloodstream and begin to replicate within deep tissues, such as the spleen. Subsets of bacteria can survive antibiotic treatment, but it remains unclear if this survival is because of limited drug diffusion into tissues, or if something has changed within the bacteria, promoting survival of some bacterial cells. Here, we have developed a fluorescent reporter to detect doxycycline (Dox) diffusion into host tissues, and show that Dox impacts the bacterial population within hours of administration, and inhibits bacterial growth for 48 hours. However, bacterial growth resumes when antibiotic concentrations decrease. Subsets of bacteria, stressed by the host response to infection, survive Dox treatment at a higher rate. These results provide critical information about the dynamics that occur within deep tissues following antibiotic administration, and suggests subsets of bacteria are predisposed to survive inhibitory concentrations of antibiotic before exposure.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Subpopulations of stressed Y. pseudotuberculosis preferentially survive doxycycline treatment within host tissues

Raneses

Ellison

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…The resulting potassium efflux triggers NLRP3 and caspase‐1 activation, and release of IL‐1β (Philip et al, ; Orning et al, ) (Figure f). In addition, blockade of TNF‐mediated pro‐survival NF‐κB and MAPK signalling by YopJ can also lead to RIPK1‐dependent apoptosis (Weng et al, ; Peterson et al, ; Peterson et al, ). Further, YopJ‐mediated inhibition of the Nod2 pathway has also been linked to Nod2‐dependent activation of caspase‐1 and IL‐1β release from Peyer's patches, and loss of intestinal barrier function in mice (Meinzer et al, ).…”

Section: Yersinia Spp and Inflammasome Manipulationmentioning

confidence: 99%

“…Further, YopJ‐mediated inhibition of the Nod2 pathway has also been linked to Nod2‐dependent activation of caspase‐1 and IL‐1β release from Peyer's patches, and loss of intestinal barrier function in mice (Meinzer et al, ). During Y. pseudotuberculosis infection in vivo , YopJ‐driven cell death pathways promote bacterial clearance and host survival, seemingly counteracting the pathogen‐mediated blockade of inflammatory signalling (Meinzer et al, ; Philip et al, ; Peterson et al, ).…”

Section: Yersinia Spp and Inflammasome Manipulationmentioning

confidence: 99%

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Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

Sanchez‐Garrido

Slater

Clements

et al. 2020

Cellular Microbiology

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Enteric pathogen–host interactions occur at multiple interfaces, including the intestinal epithelium and deeper organs of the immune system. Microbial ligands and activities are detected by host sensors that elicit a range of immune responses. Membrane‐bound toll‐like receptors and cytosolic inflammasome pathways are key signal transducers that trigger the production of pro‐inflammatory molecules, such as cytokines and chemokines, and regulate cell death in response to infection. In recent years, the inflammasomes have emerged as a key frontier in the tussle between bacterial pathogens and the host. Inflammasomes are complexes that activate caspase‐1 and are regulated by related caspases, such as caspase‐11, ‐4, ‐5 and ‐8. Importantly, enteric bacterial pathogens can actively engage or evade inflammasome signalling systems. Extracellular, vacuolar and cytosolic bacteria have developed divergent strategies to subvert inflammasomes. While some pathogens take advantage of inflammasome activation (e.g. Listeria monocytogenes, Helicobacter pylori), others (e.g. E. coli, Salmonella, Shigella, Yersinia sp.) deploy a range of virulence factors, mainly type 3 secretion system effectors, that subvert or inhibit inflammasomes. In this review we focus on inflammasome pathways and their immune functions, and discuss how enteric bacterial pathogens interact with them. These studies have not only shed light on inflammasome‐mediated immunity, but also the exciting area of mammalian cytosolic immune surveillance.

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Yersinia pseudotuberculosis: Cultivation, Storage, and Methods for Introducing DNA

Davidson

Davis

2020

CP Microbiology

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Yersinia pseudotuberculosis has been studied for many decades, and research on this microbe has taught us a great deal about host-pathogen interactions, bacterial manipulation of host cells, virulence factors, and the evolution of pathogens. This microbe should not be cultivated at 37°C because this is a trigger that the bacterium uses to sense its presence within a mammalian host and results in expression of genes necessary to colonize a mammalian host. Prolonged growth at this temperature can result in accumulation of mutations that reduce the virulence of the strain, so all protocols need to be modified for growth at room temperature, or 26°C. This article describes protocols for cultivating this microbe and for its long-term storage and its genetic manipulation by transformation and conjugation.

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RIPK1-dependent apoptosis bypasses pathogen blockade of innate signaling to promote immune defense

Cited by 98 publications

References 62 publications

Subpopulations of stressed Y. pseudotuberculosis preferentially survive doxycycline treatment within host tissues

Subpopulations of stressed Y. pseudotuberculosis preferentially survive doxycycline treatment within host tissues

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

Yersinia pseudotuberculosis: Cultivation, Storage, and Methods for Introducing DNA

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