title: Rickettsia massiliae and Rickettsia conorii Israeli Spotted Fever Strain Differentially Regulate Endothelial Cell Responses.
abstract: Rickettsiae primarily target microvascular endothelial cells. However, it remains elusive how endothelial cell responses to rickettsiae play a role in the pathogenesis of rickettsial diseases. In the present study, we employed two rickettsial species with high sequence homology but differing virulence to investigate the pathological endothelial cell responses. Rickettsia massiliae is a newly documented human pathogen that causes a mild spotted fever rickettsiosis. The "Israeli spotted fever" strain of R. conorii (ISF) causes severe disease with a mortality rate up to 30% in hospitalized patients. At 48 hours post infection (HPI), R. conorii (ISF) induced a significant elevation of IL-8 and IL-6 while R. massiliae induced a statistically significant elevated amount of MCP-1 at both transcriptional and protein synthesis levels. Strikingly, R. conorii (ISF), but not R. massiliae, caused a significant level of cell death or injury in HMEC-1 cells at 72 HPI, demonstrated by live-dead cell staining, annexin V staining and lactate dehydrogenase release. Monolayers of endothelial cells infected with R. conorii (ISF) showed a statistically significant decrease in electrical resistance across the monolayer compared to both R. massiliae-infected and uninfected cells at 72 HPI, suggesting increased endothelial permeability. Interestingly, pharmacological inhibitors of caspase-1 significantly reduced the release of lactate dehydrogenase by R. conorii (ISF)-infected HMEC-1 cells, which suggests the role of caspase-1 in mediating the death of endothelial cells. Taken together, our data illustrated that a distinct proinflammatory cytokine profile and endothelial dysfunction, as evidenced by endothelial cell death/injury and increased permeability, are associated with the severity of rickettsial diseases.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bechelli
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Smalley
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Natacha
authors.initials: N
authors.lastname: Milhano
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: David H
authors.initials: DH
authors.lastname: Walker
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Fang
mesh_terms: D000818:Animals; D001907:Boutonneuse Fever / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D002199:Capillary Permeability; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability; D002470:Cell Survival; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004269:DNA, Bacterial / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism* / Q000382:microbiology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012281:Rickettsia / Q000235:genetics* / Q000502:physiology; D012282:Rickettsia Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D020114:Rickettsia conorii / Q000235:genetics* / Q000502:physiology; D013045:Species Specificity; D014709:Vero Cells
chemical_list: D016207:Cytokines; D004269:DNA, Bacterial; D020170:Caspase 1