Endothelial Cell Proteomic Response to Rickettsia conorii Infection Reveals Activation of the Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT)-Inferferon Stimulated Gene (ISG)15 Pathway and Reprogramming Plasma Membrane Integrin/Cadherin Signaling

Zhao, Yingxin; Valbuena, Gustavo; Walker, David H.; Gaži, Michal; Hidalgo, Marylin; DeSousa, Rita; Oteo, José A.; Góez, Yenny; Brasier, Allan R.

doi:10.1074/mcp.m115.054361

Cited by 16 publications

(15 citation statements)

References 44 publications

(29 reference statements)

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“…30,31 Rickettsia conorii infection activates the Janus kinaseeSTAT1eubiquitin-like protein ISG15 pathway and induces the reprogramming of plasma membrane integrin/ cadherin signaling. 20 Analysis of the endothelial secretome identified enhanced secretion of cytokines and chemokines, IL-6, CXCL8, CXCL1, and CXCL3 in a manner consistent with previous studies. 60 In vivo, CXCL8 secretion is responsible for neutrophil recruitment, and IL-6 is involved in monocyte activation and stimulation of the hepatic acutephase response.…”

Section: Discussionsupporting

confidence: 86%

“…The culture of HUVECs and R. conorii infection were conducted, as described previously. 20 The culture medium was supplemented EGM-Plus endothelial cell growth medium (Lonza, Walkersville, MD; catalog number CC-5035) without the addition of gentamicin sulfate and amphotericin-B or fetal bovine serum. For infection, 15 Â 10 6 primary HUVECs were infected with R. conorii in biosafety level 3 containment, and subsequently the conditioned medium was collected 24 hours after infection.…”

Section: Cell Cultures and Infection With R Conoriimentioning

confidence: 99%

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Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as Diagnostic of Acute Rickettsial Spotted Fever Infections

Zhao

Fang

Zhang

et al. 2020

The American Journal of Pathology

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Mediterranean spotted fever is a reemerging acute tick-borne infection produced by the a-proteobacterium, Rickettsia conorii. Rickettsia conorii infects vascular endothelial cells producing disseminated plasma leakage, manifesting as nonspecific fever, headache, and maculopapular rash. Because there are no available tests of early infection, Mediterranean spotted fever is often undiagnosed and untreated, resulting in significant mortality. To address this critical need, we have applied a quantitative proteomics pipeline for analyzing the secretome of primary human umbilical vein endothelial cells. Of the 104 proteins whose abundance changed significantly in the R. conoriieinfected human umbilical vein endothelial cells' secretome, 46 proteins were up-regulated: 45 were host secreted proteins (including cytokines), and 1 was a rickettsial protein, the putative N-acetylmuramoyl-L-alanine amidase RC0497. Proteins with sequence highly homologous to RC0497 were found to be shared by many species of the spotted fever group rickettsiae, but not typhus group rickettsiae. Quantitative targeted proteomics studies of plasma from a mouse model of sublethal and lethal R. conorii identified RC0497 in the blood, and its circulating levels were proportionally associated with infection outcome. Finally, the presence of RC0497 in the serum samples from a cohort of humans presenting with acute rickettsioses was confirmed. The detection of RC0497 has the potential to be a sensitive and specific marker for acute rickettsial spotted rickettsioses. (Am J Pathol 2020, 190: 306e322; https://doi.

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Section: Discussionsupporting

confidence: 86%

Section: Cell Cultures and Infection With R Conoriimentioning

confidence: 99%

Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as Diagnostic of Acute Rickettsial Spotted Fever Infections

Zhao

Fang

Zhang

et al. 2020

The American Journal of Pathology

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“…Therefore, it is not surprising that a plethora of pathogens utilize specialized strategies to interact with and exploit the host ubiquitin system to their advantage. An important consideration in this regard is that the host ubiquitinome is one of the major determinants of actin cytoskeleton, NF-κB response, and autophagy pathways, all of which have been shown to contribute to host–pathogen interactions during rickettsial infections [52,53,54,55,56]. Further investigation of an interplay with host mechanisms regulated by ubiquitination will add a new dimension to the biology of rickettsial infections.…”

Section: Discussionmentioning

confidence: 99%

Global Transcriptomic Profiling of Pulmonary Gene Expression in an Experimental Murine Model of Rickettsia conorii Infection

Narra

Sahni

Khanipov

et al. 2019

Genes

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Mediterranean spotted fever develops from an infection with Rickettsia conorii, an obligate intracellular, Gram-negative, endotheliotropic, and tick-transmitted bacterial pathogen, and is an acute, febrile illness that can progress to life-threatening complications if not diagnosed and treated early with effective antibiotics. Despite significant morbidity and mortality, little is known about changes in gene expression that determine the host responses during in vivo infection. We have investigated the transcriptional landscape of host lungs as a prominently affected organ system in an established murine model of infection by RNA-sequencing. Ingenuity pathway analysis resulted in the identification of 1332 differentially expressed genes and 292 upstream regulators. Notably, genes encoding for ubiquitin D, aconitate decarboxylase, antimicrobial peptides, calgranulins, cytokines and chemokines, and guanylate binding proteins were highly up-regulated, whereas those involved in hemoglobin biosynthesis and heme homeostasis were significantly down-regulated. Amongst response regulators, nucleotide-binding oligomerization domain-containing protein 2 and killer cell lectin-like receptors were differentially expressed, and gene clustering revealed eukaryotic initiation factor-2, oxidative phosphorylation, and ubiquitination as the predominantly activated biological pathways. Collectively, this first global transcriptomic profiling has identified R. conorii-induced regulation of novel genes and pathways in the host lungs, further in-depth investigation of which will strengthen our understanding of the pathogenesis of human rickettsioses.

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“…HUVEC comprise the same ontogenetic type of cells which rickettsiae parasitize in vivo. Consequently, these cells are widely used as a model system for studying rickettsia–host cell interactions in vitro [31] , [32] , [33] , [34] , [35] , [36] , but they have been little used for isolating rickettsia species [37] .…”

Section: Discussionmentioning

confidence: 99%

Isolation of Rickettsia amblyommatis in HUVEC line

Santibáñez

Portillo

Palomar

et al. 2018

New Microbes and New Infections

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Rickettsia amblyommatis, formerly named Rickettsia amblyommii and ‘Candidatus Rickettsia amblyommii’ is an intracellular bacterium belonging to the spotted fever group Rickettsia. It is highly prevalent in Amblyomma americanum and in other Amblyomma spp. throughout the Western Hemisphere. R. amblyommatis has been cultivated in chicken fibroblast, primary embryonated chicken eggs, Vero cells and arthropod-derived cells. Because of the affinity of rickettsiae to invade vascular endothelial cells, we tried to isolate R. amblyommatis from a nymph of Amblyomma cajennense s.l. collected in Saltillo (Coahulia, Mexico) using human umbilical vein endothelial cells (HUVEC). One tick half was analysed by ompA PCR and was found to be positive for R. amblyommatis. The other half was selected for in vitro culture of Rickettsia spp. It was triturated in 1 mL of endothelial cell growth medium with 1% antibiotic–antimycotic solution, and the homogenate was inoculated into a HUVEC line. Culture was maintained at 33°C in endothelial cell growth medium plus 2 mM l-glutamine and 2% fetal calf serum, with 5% CO2. The medium was changed weekly. Culture was checked by Gimenez stain for Rickettsia-like intracellular organisms. After 48 days of incubation, Rickettsia-like organisms were observed in HUVEC. PCR assays and sequencing of ompA gene in the culture suspension showed 100% identity with R. amblyommatis. This isolate was successfully established in HUVEC, and it has been deposited in the collection of the Center of Rickettsioses and Arthropod-Borne Diseases, Infectious Diseases Department, Hospital San Pedro–Center of Biomedical Research from La Rioja, Logroño, Spain. The HUVEC line is a useful tool for the isolation of R. amblyommatis.

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Endothelial Cell Proteomic Response to Rickettsia conorii Infection Reveals Activation of the Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT)-Inferferon Stimulated Gene (ISG)15 Pathway and Reprogramming Plasma Membrane Integrin/Cadherin Signaling

Cited by 16 publications

References 44 publications

Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as Diagnostic of Acute Rickettsial Spotted Fever Infections

Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as Diagnostic of Acute Rickettsial Spotted Fever Infections

Global Transcriptomic Profiling of Pulmonary Gene Expression in an Experimental Murine Model of Rickettsia conorii Infection

Isolation of Rickettsia amblyommatis in HUVEC line

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