Modulation of the host transcriptome by Coxiella burnetii nuclear effector Cbu1314

Weber, Mary M.; Faris, Robert; McLachlan, Juanita; Tellez, Andres; Wright, William U.; Galván, Gloria C.; Luo, Zhao‐Qing; Samuel, James E.

doi:10.1016/j.micinf.2016.01.003

Cited by 26 publications

(22 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, a significant number of C. burnetii T4BSS effectors are translocated into the host cell cytoplasm when expressed in a surrogate L. pneumophila system (Pan et al, 2008; Voth et al, 2009; Chen et al, 2010; Toman et al, 2012; van Schaik et al, 2013). Distinct T4BSS effectors associate with the PV membrane, microtubules, mitochondria, and the nucleus (Pan et al, 2008; Voth et al, 2009; Chen et al, 2010; Toman et al, 2012; Larson et al, 2013, 2015; Weber et al, 2013; van Schaik et al, 2013: Weber et al, 2016). However, the specific function of the vast majority of confirmed and putative C. burnetii T4BSS effectors remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Coxiella burnetii Employs the Dot/Icm Type IV Secretion System to Modulate Host NF-κB/RelA Activation

Mahapatra

Gallaher

Smith

et al. 2016

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Coxiella burnetii is the causative agent of Q fever and an obligate intracellular pathogen in nature that survives and grows in a parasitophorous vacuole (PV) within eukaryotic host cells. C. burnetii promotes intracellular survival by subverting apoptotic and pro-inflammatory signaling pathways that are typically regulated by nuclear transcription factor-κB (NF-κB). We and others have demonstrated that C. burnetii NMII proteins inhibit expression of pro-inflammatory cytokines and induce expression of anti-apoptotic genes during infection. Here, we demonstrate that C. burnetii promotes intracellular survival by modulating NF-κB subunit p65 (RelA) phosphorylation, and thus activation, in a Type Four B Secretion System (T4BSS)-dependent manner. Immunoblot analysis of RelA phosphorylated at serine-536 demonstrated that C. burnetii increases NF-κB activation via the canonical pathway. However, RelA phosphorylation levels were even higher in infected cells where bacterial protein or mRNA synthesis was inhibited. Importantly, we demonstrate that inhibition of RelA phosphorylation impairs PV formation and C. burnetii growth. We found that a T4BSS-defective mutant (CbΔdotA) elicited phosphorylated RelA levels similar to those of wild type C. burnetii infection treated with Chloramphenicol. Moreover, cells infected with CbΔdotA or wild type C. burnetii treated with Chloramphenicol showed similar levels of GFP-RelA nuclear localization, and significantly increased localization compared to wild type C. burnetii infection. These data indicate that without de novo protein synthesis and a functional T4BSS, C. burnetii is unable to modulate NF-κB activation, which is crucial for optimal intracellular growth.

show abstract

Section: Discussionmentioning

confidence: 99%

Coxiella burnetii Employs the Dot/Icm Type IV Secretion System to Modulate Host NF-κB/RelA Activation

Mahapatra

Gallaher

Smith

et al. 2016

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

show abstract

“…However, detection of native effectors is exceedingly difficult; thus, ectopic expression of effector-fluorescent protein chimeras has been extensively used for trafficking studies, despite known artifacts of this procedure [120]. Effectors traffic to mitochondria [87,92,94,121], endoplasmic reticulum [91,94,96,122], Golgi apparatus [87], lysosomes [87,92,107,122], autophagosomes [91,93], endocytic vesicles [73,107], nucleus [87,94,[121][122][123], microtubules [92,122] and ubiquitinated proteins [91,93]. An interesting subset of five effectors designated Cvp (Coxiella vacuolar protein) also traffic to the CCV [73,107].…”

Section: The Hard Part: Effector Functionmentioning

confidence: 99%

Right on Q: Genetics begin to Unravel Coxiella Burnetii host cell Interactions

et al. 2016

View full text Add to dashboard Cite

Invasion of macrophages and replication within an acidic and degradative phagolysosomelike vacuole are essential for disease pathogenesis by Coxiella burnetii, the bacterial agent of human Q fever. Previous experimental constraints imposed by the obligate intracellular nature of Coxiella limited knowledge of pathogen strategies that promote infection. Fortunately, new genetic tools facilitated by axenic culture now allow allelic exchange and transposon mutagenesis approaches for virulence gene discovery. Phenotypic screens have illuminated the critical importance of Coxiella's type 4B secretion system in host cell subversion and discovered genes encoding translocated effector proteins that manipulate critical infection events. Here, we highlight the cellular microbiology and genetics of Coxiella and how recent technical advances now make Coxiella a model organism to study macrophage parasitism.

show abstract

“…The nuclear effector CBU1314 modulates the host transcription response [ 88 ], but with scant Y2H interaction data we could only identify nuclear host protein interactions related to focal adhesion (the Rho GTPase activating ARHGAP5 gene) and proteasome subunit interactions involved in the NF-κB immune-response pathway.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of action of Coxiella burnetii effectors inferred from host-pathogen protein interactions

et al. 2017

View full text Add to dashboard Cite

Coxiella burnetii is an obligate Gram-negative intracellular pathogen and the etiological agent of Q fever. Successful infection requires a functional Type IV secretion system, which translocates more than 100 effector proteins into the host cytosol to establish the infection, restructure the intracellular host environment, and create a parasitophorous vacuole where the replicating bacteria reside. We used yeast two-hybrid (Y2H) screening of 33 selected C. burnetii effectors against whole genome human and murine proteome libraries to generate a map of potential host-pathogen protein-protein interactions (PPIs). We detected 273 unique interactions between 20 pathogen and 247 human proteins, and 157 between 17 pathogen and 137 murine proteins. We used orthology to combine the data and create a single host-pathogen interaction network containing 415 unique interactions between 25 C. burnetii and 363 human proteins. We further performed complementary pairwise Y2H testing of 43 out of 91 C. burnetii-human interactions involving five pathogen proteins. We used the combined data to 1) perform enrichment analyses of target host cellular processes and pathways, 2) examine effectors with known infection phenotypes, and 3) infer potential mechanisms of action for four effectors with uncharacterized functions. The host-pathogen interaction profiles supported known Coxiella phenotypes, such as adapting cell morphology through cytoskeletal re-arrangements, protein processing and trafficking, organelle generation, cholesterol processing, innate immune modulation, and interactions with the ubiquitin and proteasome pathways. The generated dataset of PPIs—the largest collection of unbiased Coxiella host-pathogen interactions to date—represents a rich source of information with respect to secreted pathogen effector proteins and their interactions with human host proteins.

show abstract

Modulation of the host transcriptome by Coxiella burnetii nuclear effector Cbu1314

Cited by 26 publications

References 36 publications

Coxiella burnetii Employs the Dot/Icm Type IV Secretion System to Modulate Host NF-κB/RelA Activation

Coxiella burnetii Employs the Dot/Icm Type IV Secretion System to Modulate Host NF-κB/RelA Activation

Right on Q: Genetics begin to Unravel Coxiella Burnetii host cell Interactions

Mechanisms of action of Coxiella burnetii effectors inferred from host-pathogen protein interactions

Contact Info

Product

Resources

About