Modulation of host cell apoptotic pathways by intracellular pathogens

Friedrich, Anja; Pechstein, Julian; Berens, Christian; Lührmann, Anja

doi:10.1016/j.mib.2017.03.001

Cited by 33 publications

(19 citation statements)

References 80 publications

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“…These features are considered very attractive to be explored by intracellular pathogens as a vast source of cellular resources that can be rapidly remodeled (Eisenreich et al, 2015, 2017; Van den Bossche et al, 2017). Along with the capacity to hijack a wide range of host signaling pathways to their own benefit (Ashida et al, 2014; Reddick and Alto, 2014; Friedrich et al, 2017), it has been reported that several intracellular pathogens are also able to induce distinct host cell metabolic signatures in macrophages to suit their replication requirements (Eisele et al, 2013; Xavier et al, 2013). The altered metabolic state of M2 macrophages, which has also been associated with reduced antimicrobial capacity, seems to be a beneficial factor that supports the survival and proliferation of several intracellular pathogens (Benoit et al, 2008; Mege et al, 2011; Eisele et al, 2013; Buchacher et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

A Pathogen and a Non-pathogen Spotted Fever Group Rickettsia Trigger Differential Proteome Signatures in Macrophages

Curto

Santa

Allen³

et al. 2019

Front. Cell. Infect. Microbiol.

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We have previously reported that Rickettsia conorii and Rickettsia montanensis have distinct intracellular fates within THP-1 macrophages, suggesting that the ability to proliferate within macrophages may be a distinguishable factor between pathogenic and non-pathogenic Spotted fever group (SFG) members. To start unraveling the molecular mechanisms underlying the capacity (or not) of SFG Rickettsia to establish their replicative niche in macrophages, we have herein used quantitative proteomics by SWATH-MS to profile the alterations resulted by the challenge of THP-1 macrophages with R. conorii and R. montanensis. We show that the pathogenic, R. conorii, and the non-pathogenic, R. montanensis, member of SFG Rickettsia trigger differential proteomic signatures in macrophage-like cells upon infection. R. conorii specifically induced the accumulation of several enzymes of the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid β-oxidation, and glutaminolysis, as well as of several inner and outer membrane mitochondrial transporters. These results suggest a profound metabolic rewriting of macrophages by R. conorii toward a metabolic signature of an M2-like, anti-inflammatory activation program. Moreover, several subunits forming the proteasome and immunoproteasome are found in lower abundance upon infection with both rickettsial species, which may help bacteria to escape immune surveillance. R. conorii-infection specifically induced the accumulation of several host proteins implicated in protein processing and quality control in ER, suggesting that this pathogenic Rickettsia may be able to increase the ER protein folding capacity. This work reveals novel aspects of macrophage-Rickettsia interactions, expanding our knowledge of how pathogenic rickettsiae explore host cells to their advantage.

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Section: Introductionmentioning

confidence: 99%

A Pathogen and a Non-pathogen Spotted Fever Group Rickettsia Trigger Differential Proteome Signatures in Macrophages

Curto

Santa

Allen³

et al. 2019

Front. Cell. Infect. Microbiol.

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“…The CCV retains the low pH and hydrolytic features of a lysosome but is also modified by the pathogen to facilitate replication. Key features of the mature CCV include significant expansion, through interaction with intracellular vesicles including autophagosomes, clathrin-coated vesicles, and endocytic vesicles, and a strong antiapoptotic influence on the host cell (5,6).…”

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confidence: 99%

Lysosomal degradation products induce Coxiella burnetii virulence

Newton

Thomas

Reed

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Coxiella burnetiiis an intracellular pathogen that replicates in a lysosome-like vacuole through activation of a Dot/Icm-type IVB secretion system and subsequent translocation of effectors that remodel the host cell. Here a genome-wide small interfering RNA screen and reporter assay were used to identify host proteins required for Dot/Icm effector translocation. Significant, and independently validated, hits demonstrated the importance of multiple protein families required for endocytic trafficking of theC. burnetii-containing vacuole to the lysosome. Further analysis demonstrated that the degradative activity of the lysosome created by proteases, such as TPP1, which are transported to the lysosome by receptors, such as M6PR and LRP1, are critical forC. burnetiivirulence. Indeed, theC. burnetiiPmrA/B regulon, responsible for transcriptional up-regulation of genes encoding the Dot/Icm apparatus and a subset of effectors, induced expression of a virulence-associated transcriptome in response to degradative products of the lysosome. Luciferase reporter strains, and subsequent RNA-sequencing analysis, demonstrated that particular amino acids activate theC. burnetiiPmrA/B two-component system. This study has further enhanced our understanding ofC. burnetiipathogenesis, the host–pathogen interactions that contribute to bacterial virulence, and the different environmental triggers pathogens can sense to facilitate virulence.

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“…Apoptosis is part of the arsenal of defense mechanisms used to prevent infection. However, pathogens themselves have evolved numerous ways to modulate cell death pathways, and intracellular microorganisms can subvert nearly all steps of the apoptotic cascade (Gao and Kwaik, 2000; Friedrich et al, 2017). THP-1 cells infected with R. conorii showed a striking difference in the number of DE genes grouped to the negative regulation of the apoptotic process (GO:0043066), with 16 out of the 19 DE genes showing altered abundance in R. conorii -infected cells only (Figure 5; Table S9).…”

Section: Resultsmentioning

confidence: 99%

“…Another strategy that intracellular pathogens have developed to establish a niche of infection is the ability to control host cell apoptosis to their advantage (Friedrich et al, 2017). Our results revealed that R. conorii promoted an increased abundance of several transcripts whose products have been implicated in pro-survival pathways.…”

Section: Discussionmentioning

confidence: 99%

Macrophages Infected by a Pathogen and a Non-pathogen Spotted Fever Group Rickettsia Reveal Differential Reprogramming Signatures Early in Infection

Curto

Riley

Simões

et al. 2019

Front. Cell. Infect. Microbiol.

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Despite their high degree of genomic similarity, different spotted fever group (SFG) Rickettsia are often associated with very different clinical presentations. For example, Rickettsia conorii causes Mediterranean spotted fever, a life-threatening disease for humans, whereas Rickettsia montanensis is associated with limited or no pathogenicity to humans. However, the molecular basis responsible for the different pathogenicity attributes are still not understood. Although killing microbes is a critical function of macrophages, the ability to survive and/or proliferate within phagocytic cells seems to be a phenotypic feature of several intracellular pathogens. We have previously shown that R. conorii and R. montanensis exhibit different intracellular fates within macrophage-like cells. By evaluating early macrophage responses upon insult with each of these rickettsial species, herein we demonstrate that infection with R. conorii results in a profound reprogramming of host gene expression profiles. Transcriptional programs generated upon infection with this pathogenic bacteria point toward a sophisticated ability to evade innate immune signals, by modulating the expression of several anti-inflammatory molecules. Moreover, R. conorii induce the expression of several pro-survival genes, which may result in the ability to prolong host cell survival, thus protecting its replicative niche. Remarkably, R. conorii -infection promoted a robust modulation of different transcription factors, suggesting that an early manipulation of the host gene expression machinery may be key to R. conorii proliferation in THP-1 macrophages. This work provides new insights into the early molecular processes hijacked by a pathogenic SFG Rickettsia to establish a replicative niche in macrophages, opening several avenues of research in host-rickettsiae interactions.

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Modulation of host cell apoptotic pathways by intracellular pathogens

Cited by 33 publications

References 80 publications

A Pathogen and a Non-pathogen Spotted Fever Group Rickettsia Trigger Differential Proteome Signatures in Macrophages

A Pathogen and a Non-pathogen Spotted Fever Group Rickettsia Trigger Differential Proteome Signatures in Macrophages

Lysosomal degradation products induce Coxiella burnetii virulence

Macrophages Infected by a Pathogen and a Non-pathogen Spotted Fever Group Rickettsia Reveal Differential Reprogramming Signatures Early in Infection

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