scholarly journals Toxoplasma gondiibradyzoites induce transcriptional changes to host cells and prevent IFNγ-mediated cell death

2019 ◽  
Author(s):  
Simona Seizova ◽  
Alexandra L Garnham ◽  
Michael J Coffey ◽  
Lachlan W Whitehead ◽  
Kelly L Rogers ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Stage ◽  
Effector Proteins ◽  
Host Cells ◽  
Host Manipulation ◽  
Parasite Protein ◽  
Congenital Birth Defects ◽  
Transcriptional Changes ◽  
Disease Reactivation ◽  
Transcriptional Landscape

SummaryToxoplasma gondii, the causative agent of toxoplasmosis, lies dormant for life and is a reservoir for disease reactivation, causing blindness, encephalitis and congenital birth defects. Acute-stage tachyzoites extensively manipulate their host cell by exporting a repertoire of proteins across the parasitophorous vacuolar membrane (PVM). This interferes with the hosts transcriptional program, allowing for persistence during immune attack. It is unknown how bradyzoites persist and what role host manipulation plays in latency. Here we show that bradyzoite-containing host cells have a unique transcriptional landscape when compared to tachyzoite infection. We demonstrate that many of these changes are dependent parasite protein export. Furthermore, we show that bradyzoite effector proteins protect host cell’s from IFNγ-mediated cell death, thus highlighting the functional importance of host manipulation. Together, our work provides the first understanding of howToxoplasmasets up latency to persist in its host.

Toxoplasma Gondii Bradyzoites Elicit Transcriptional Changes in Host Cells to Prevent IFNγ-Mediated Cell Death

2019 ◽  
Author(s):  
Simona Seizova ◽  
Alexandra L Garnham ◽  
Michael J Coffey ◽  
Lachlan W Whitehead ◽  
Kelly L Rogers ◽  
...  
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Host Cells ◽  
Transcriptional Changes

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

2017 ◽  
Vol 214 (11) ◽  
pp. 3171-3182 ◽  
Author(s):  
Lance W. Peterson ◽  
Naomi H. Philip ◽  
Alexandra DeLaney ◽  
Meghan A. Wynosky-Dolfi ◽  
Kendra Asklof ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Activity ◽  
Cytokine Production ◽  
Mapk Signaling ◽  
Immune Defense ◽  
Effector Proteins ◽  
Host Cells ◽  
Effector Triggered Immunity ◽  
Induced Apoptosis

Many pathogens deliver virulence factors or effectors into host cells in order to evade host defenses and establish infection. Although such effector proteins disrupt critical cellular signaling pathways, they also trigger specific antipathogen responses, a process termed “effector-triggered immunity.” The Gram-negative bacterial pathogen Yersinia inactivates critical proteins of the NF-κB and MAPK signaling cascade, thereby blocking inflammatory cytokine production but also inducing apoptosis. Yersinia-induced apoptosis requires the kinase activity of receptor-interacting protein kinase 1 (RIPK1), a key regulator of cell death, NF-κB, and MAPK signaling. Through the targeted disruption of RIPK1 kinase activity, which selectively disrupts RIPK1-dependent cell death, we now reveal that Yersinia-induced apoptosis is critical for host survival, containment of bacteria in granulomas, and control of bacterial burdens in vivo. We demonstrate that this apoptotic response provides a cell-extrinsic signal that promotes optimal innate immune cytokine production and antibacterial defense, demonstrating a novel role for RIPK1 kinase–induced apoptosis in mediating effector-triggered immunity to circumvent pathogen inhibition of immune signaling.

scholarly journals Diversion at the ER: How Plasmodium falciparum exports proteins into host erythrocytes

F1000Research ◽  
2012 ◽  
Vol 1 ◽  
pp. 12 ◽  
Author(s):  
Karin Römisch
Keyword(s):  
Plasmodium Falciparum ◽  
Host Cell ◽  
Protein Transport ◽  
Effector Proteins ◽  
Host Cells ◽  
Cell Targeting ◽  
Parasite Protein ◽  
Starting Point ◽  
Targeting Signal

Malaria is caused by parasites which live in host erythrocytes and remodel these cells to provide optimally for the parasites’ needs by exporting effector proteins into the host cells. Eight years ago the discovery of a host cell targeting sequence present in both soluble and transmembrane P. falciparum exported proteins generated a starting point for investigating the mechanism of parasite protein transport into infected erythrocytes. Since then many confusing facts about this targeting signal have emerged. In this paper, I try to make sense of them.

scholarly journals The Secreted Effector Protein EspZ Is Essential for Virulence of Rabbit Enteropathogenic Escherichia coli

2015 ◽  
Vol 83 (3) ◽  
pp. 1139-1149 ◽  
Author(s):  
John Scott Wilbur ◽  
Wyatt Byrd ◽  
Shylaja Ramamurthy ◽  
Hannah E. Ledvina ◽  
Khaldoon Khirfan ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Cell Death ◽  
Epithelial Cell ◽  
Host Cell ◽  
Bacterial Colonization ◽  
Clinical Signs ◽  
Effector Proteins ◽  
Host Cells ◽  
Tunel Staining

Attaching and effacing (A/E) pathogens adhere intimately to intestinal enterocytes and efface brush border microvilli. A key virulence strategy of A/E pathogens is the type III secretion system (T3SS)-mediated delivery of effector proteins into host cells. The secreted protein EspZ is postulated to promote enterocyte survival by regulating the T3SS and/or by modulating epithelial signaling pathways. To explore the role of EspZ in A/E pathogen virulence, we generated an isogenicespZdeletion strain (ΔespZ) and correspondingcis-complemented derivatives of rabbit enteropathogenicEscherichia coliand compared their abilities to regulate the T3SS and influence host cell survivalin vitro. For virulence studies, rabbits infected with these strains were monitored for bacterial colonization, clinical signs, and intestinal tissue alterations. Consistent with data from previous reports,espZ-transfected epithelial cells were refractory to infection-dependent effector translocation. Also, the ΔespZstrain induced greater host cell death than did the parent and complemented strains. In rabbit infections, fecal ΔespZstrain levels were 10-fold lower than those of the parent strain at 1 day postinfection, while the complemented strain was recovered at intermediate levels. In contrast to the parent and complemented mutants, ΔespZmutant fecal carriage progressively decreased on subsequent days. ΔespZmutant-infected animals gained weight steadily over the infection period, failed to show characteristic disease symptoms, and displayed minimal infection-induced histological alterations. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining of intestinal sections revealed increased epithelial cell apoptosis on day 1 after infection with the ΔespZstrain compared to animals infected with the parent or complemented strains. Thus, EspZ-dependent host cell cytoprotection likely prevents epithelial cell death and sloughing and thereby promotes bacterial colonization.

scholarly journals Impact of Host Membrane Pore Formation by the Yersinia pseudotuberculosis Type III Secretion System on the Macrophage Innate Immune Response

2013 ◽  
Vol 81 (3) ◽  
pp. 905-914 ◽  
Author(s):  
Laura Kwuan ◽  
Walter Adams ◽  
Victoria Auerbuch
Keyword(s):  
Cell Death ◽  
Type Iii Secretion ◽  
Mammalian Cells ◽  
Yersinia Pseudotuberculosis ◽  
Effector Proteins ◽  
Innate Immune ◽  
Host Cells ◽  
Content Type ◽  
Host Cell Death ◽  
Tnf Α

ABSTRACTType III secretion systems (T3SSs) are used by Gram-negative pathogens to form pores in host membranes and deliver virulence-associated effector proteins inside host cells. In pathogenicYersinia, the T3SS pore-forming proteins are YopB and YopD. Mammalian cells recognize theYersiniaT3SS, leading to a host response that includes secretion of the inflammatory cytokine interleukin-1β (IL-1β), Toll-like receptor (TLR)-independent expression of the stress-associated transcription factor Egr1 and the inflammatory cytokine tumor necrosis factor alpha (TNF-α), and host cell death. The knownYersiniaT3SS effector proteins are dispensable for eliciting these responses, but YopB is essential. Three models describe how theYersiniaT3SS might trigger inflammation: (i) mammalian cells sense YopBD-mediated pore formation, (ii) innate immune stimuli gain access to the host cytoplasm through the YopBD pore, and/or (iii) the YopB-YopD translocon itself or its membrane insertion is proinflammatory. To test these models, we constructed aYersinia pseudotuberculosismutant expressing YopD devoid of its predicted transmembrane domain (YopDΔTM) and lacking the T3SS cargo proteins YopHEMOJTN. This mutant formed pores in macrophages, but it could not mediate translocation of effector proteins inside host cells. Importantly, this mutant did not elicit rapid host cell death, IL-1β secretion, or TLR-independent Egr1 and TNF-α expression. These data suggest that YopBD-mediated translocation of unknown T3SS cargo leads to activation of host pathways influencing inflammation, cell death, and response to stress. As the YopDΔTMY. pseudotuberculosismutant formed somewhat smaller pores with delayed kinetics, an alternative model is that the wild-type YopB-YopD translocon is specifically sensed by host cells.

The ways of a killer: how does Entamoeba histolytica elicit host cell death?

2011 ◽  
Vol 51 ◽  
pp. 193-210 ◽  
Author(s):  
Katherine S. Ralston ◽  
William A. Petri
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Entamoeba Histolytica ◽  
Calcium Influx ◽  
Protozoan Parasite ◽  
Basic Mechanism ◽  
Effector Proteins ◽  
Host Cells ◽  
Host Cell Death ◽  
Cytotoxic Effector

Entamoeba histolytica is the causative agent of amoebiasis in humans and is responsible for an estimated 100 000 deaths annually, making it the second leading cause of death due to a protozoan parasite after Plasmodium. Pathogenesis appears to result from the potent cytotoxic activity of the parasite, which kills host cells within minutes. The mechanism is unknown, but progress has been made in determining that cytotoxicity requires parasite Gal (galactose)/GalNAc (N-acetylgalactosamine) lectin-mediated adherence, target cell calcium influx, dephosphorylation and activation of caspase 3. Putative cytotoxic effector proteins such as amoebapores, proteases and various parasite membrane proteins have also been identified. Nonetheless the bona fide cytotoxic effector molecules remain unknown and it is unclear how the lethal hit is delivered. To better understand the basic mechanism of pathogenesis and to enable the development of new therapeutics, more work will be needed in order to determine how the parasite elicits host cell death.

scholarly journals Importin-αs are required for the nuclear localization and function of the Plasmopara viticola effector PvAVH53

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Tingting Chen ◽  
Jing Peng ◽  
Xiao Yin ◽  
Meijie Li ◽  
Gaoqing Xiang ◽  
...  
Keyword(s):  
Cell Death ◽  
Nuclear Localization ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
Plasmopara Viticola ◽  
Effector Proteins ◽  
Host Cells ◽  
Virus Induced Gene Silencing ◽  
Oomycete Pathogen ◽  
And Function

AbstractPlant pathogenic oomycetes deliver a troop of effector proteins into the nucleus of host cells to manipulate plant cellular immunity and promote colonization. Recently, researchers have focused on identifying how effectors are transferred into the host cell nucleus, as well as the identity of the nuclear targets. In this study, we found that the RxLR effector PvAVH53 from the grapevine (Vitis vinifera) oomycete pathogen Plasmopara viticola physically interacts with grapevine nuclear import factor importin alphas (VvImpα and VvImpα4), localizes to the nucleus and triggers cell death when transiently expressed in tobacco (Nicotiana benthamiana) cells. Deletion of a nuclear localization signal (NLS) sequence from PvAVH53 or addition of a nuclear export signal (NES) sequence disrupted the nuclear localization of PvAVH53 and attenuated its ability to trigger cell death. Suppression of two tobacco importin-α genes, namely, NbImp-α1 and NbImp-α2, by virus-induced gene silencing (VIGS) also disrupted the nuclear localization and ability of PvAVH53 to induce cell death. Likewise, we transiently silenced the expression of VvImpα/α4 in grape through CRISPR/Cas13a, which has been reported to target RNA in vivo. Finally, we found that attenuating the expression of the Importin-αs genes resulted in increased susceptibility to the oomycete pathogen Phytophthora capsici in N. benthamiana and P. viticola in V. vinifera. Our results demonstrate that importin-αs are required for the nuclear localization and function of PvAVH53 and are essential for host innate immunity. The findings provide insight into the functions of importin-αs in grapevine against downy mildew.

scholarly journals Interaction of Phytophthora sojae Effector Avr1b With E3 Ubiquitin Ligase GmPUB1 Is Required for Recognition by Soybeans Carrying Phytophthora Resistance Rps1-b and Rps1-k Genes

2021 ◽  
Vol 12 ◽  
Author(s):  
Shan Li ◽  
Regina Hanlon ◽  
Hua Wise ◽  
Narinder Pal ◽  
Hargeet Brar ◽  
...  
Keyword(s):  
Cell Death ◽  
Phytophthora Sojae ◽  
Effector Proteins ◽  
Host Cells ◽  
Bimolecular Fluorescence Complementation ◽  
Yeast Two Hybrid ◽  
Synonymous Mutations ◽  
Rxlr Effectors ◽  
C Terminus ◽  
Two Hybrid

Phytophthora sojae is an oomycete that causes stem and root rot disease in soybean. P. sojae delivers many RxLR effector proteins, including Avr1b, into host cells to promote infection. We show here that Avr1b interacts with the soybean U-box protein, GmPUB1-1, in yeast two-hybrid, pull down, and bimolecular fluorescence complementation (BIFC) assays. GmPUB1-1, and a homeologous copy GmPUB1-2, are induced by infection and encode 403 amino acid proteins with U-Box domains at their N-termini. Non-synonymous mutations in the Avr1b C-terminus that abolish suppression of cell death also abolished the interaction of Avr1b with GmPUB1-1, while deletion of the GmPUB1-1 C-terminus, but not the U box, abolished the interaction. BIFC experiments suggested that the GmPUB1-1-Avr1b complex is targeted to the nucleus. In vitro ubiquitination assays demonstrated that GmPUB1-1 possesses E3 ligase activity. Silencing of the GmPUB1 genes in soybean cotyledons resulted in loss of recognition of Avr1b by gene products encoded by Rps1-b and Rps1-k. The recognition of Avr1k (which did not interact with GmPUB1-1) by Rps1-k plants was not, however, affected following GmPUB1-1 silencing. Furthermore, over-expression of GmPUB1-1 in particle bombardment experiments triggered cell death suggesting that GmPUB1 may be a positive regulator of effector-triggered immunity. In a yeast two-hybrid system, GmPUB1-1 also interacted with a number of other RxLR effectors including Avr1d, while Avr1b and Avr1d interacted with a number of other infection-induced GmPUB proteins, suggesting that the pathogen uses a multiplex of interactions of RxLR effectors with GmPUB proteins to modulate host immunity.

scholarly journals Transcriptional landscape of PTEN loss in primary prostate cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Eddie Luidy Imada ◽  
Diego Fernando Sanchez ◽  
Wikum Dinalankara ◽  
Thiago Vidotto ◽  
Ericka M. Ebot ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Meta Analysis ◽  
Pten Loss ◽  
Primary Prostate Cancer ◽  
Expression Atlas ◽  
Transcriptomic Signature ◽  
Transcriptional Changes ◽  
New Biomarkers ◽  
Adaptive Immune Systems ◽  
Transcriptional Landscape

Abstract Background PTEN is the most frequently lost tumor suppressor in primary prostate cancer (PCa) and its loss is associated with aggressive disease. However, the transcriptional changes associated with PTEN loss in PCa have not been described in detail. In this study, we highlight the transcriptional changes associated with PTEN loss in PCa. Methods Using a meta-analysis approach, we leveraged two large PCa cohorts with experimentally validated PTEN and ERG status by Immunohistochemistry (IHC), to derive a transcriptomic signature of PTEN loss, while also accounting for potential confounders due to ERG rearrangements. This signature was expanded to lncRNAs using the TCGA quantifications from the FC-R2 expression atlas. Results The signatures indicate a strong activation of both innate and adaptive immune systems upon PTEN loss, as well as an expected activation of cell-cycle genes. Moreover, we made use of our recently developed FC-R2 expression atlas to expand this signature to include many non-coding RNAs recently annotated by the FANTOM consortium. Highlighting potential novel lncRNAs associated with PTEN loss and PCa progression. Conclusion We created a PCa specific signature of the transcriptional landscape of PTEN loss that comprises both the coding and an extensive non-coding counterpart, highlighting potential new players in PCa progression. We also show that contrary to what is observed in other cancers, PTEN loss in PCa leads to increased activation of the immune system. These findings can help the development of new biomarkers and help guide therapy choices.

scholarly journals Xyloglucan processing machinery in Xanthomonas pathogens and its role in the transcriptional activation of virulence factors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Plinio S. Vieira ◽  
Isabela M. Bonfim ◽  
Evandro A. Araujo ◽  
Ricardo R. Melo ◽  
Augusto R. Lima ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Model Organism ◽  
Citrus Canker ◽  
Effector Proteins ◽  
Glycoside Hydrolases ◽  
Host Cells ◽  
System A ◽  
Enzymatic Machinery

AbstractXyloglucans are highly substituted and recalcitrant polysaccharides found in the primary cell walls of vascular plants, acting as a barrier against pathogens. Here, we reveal that the diverse and economically relevant Xanthomonas bacteria are endowed with a xyloglucan depolymerization machinery that is linked to pathogenesis. Using the citrus canker pathogen as a model organism, we show that this system encompasses distinctive glycoside hydrolases, a modular xyloglucan acetylesterase and specific membrane transporters, demonstrating that plant-associated bacteria employ distinct molecular strategies from commensal gut bacteria to cope with xyloglucans. Notably, the sugars released by this system elicit the expression of several key virulence factors, including the type III secretion system, a membrane-embedded apparatus to deliver effector proteins into the host cells. Together, these findings shed light on the molecular mechanisms underpinning the intricate enzymatic machinery of Xanthomonas to depolymerize xyloglucans and uncover a role for this system in signaling pathways driving pathogenesis.

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