Effect of Blocking the Cxcl9/10-Cxcr3 Chemokine System in the Outcome of Endothelial-Target Rickettsial Infections

Valbuena, Gustavo; Walker, David H.

doi:10.4269/ajtmh.2004.71.393

Cited by 22 publications

(11 citation statements)

References 36 publications

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“…Endothelial cells infected with rickettsiae of the spotted fever group present antigen, in association with increased ICAM-1 expression, in the absence of chemokines to anti-rickettsial T-lymphocytes (Valbuena and Walker, 2004). These interactions activate Tlymphocytes and lead them to infected endothelial cells (Valbuena and Walker, 2004). In this context, one of the observations made during the present study -that D. andersoni SGE significantly downregulated ICAM-1 expression -is particularly interesting.…”

Section: Ticks and Endothelial-cell Adhesion Moleculessupporting

confidence: 50%

“…Activated endothelial cells infected with Rickettsia conorii not only express elevated levels of E-selectin, ICAM-1 and VCAM-1 but also display increased adhesiveness for leucocytes (Valbuena et al, 2002). Endothelial cells infected with rickettsiae of the spotted fever group present antigen, in association with increased ICAM-1 expression, in the absence of chemokines to anti-rickettsial T-lymphocytes (Valbuena and Walker, 2004). These interactions activate Tlymphocytes and lead them to infected endothelial cells (Valbuena and Walker, 2004).…”

Section: Ticks and Endothelial-cell Adhesion Moleculesmentioning

confidence: 99%

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Tick modulation of the in-vitro expression of adhesion molecules by skin-derived endothelial cells

Maxwell

Stoklasek

Dash

et al. 2005

Annals of Tropical Medicine & Parasitology

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As a tick feeds, its saliva induces innate and acquired immune responses in the host, including leucocyte infiltration into the bite site. Tick salivary glands produce molecules, however, that counteract many host defences against blood feeding. The effects of salivary-gland extracts (SGE) of Dermacentor andersoni and Ixodes scapularis on the expression of various adhesion molecules [E-selectin, P-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)] by the sEND.1 cell line (which is based on cells from the subcutaneous tissue of mice) have now been investigated in vitro. The effects were found to differ with the tick species. The SGE of D. andersoni significantly down-regulated the expression of ICAM-1, whereas a similar extract prepared from I. scapularis significantly reduced the expression of P-selectin and VCAM-1. Tick salivary proteins therefore appear to have direct effects on adhesion-molecule expression, in addition to their previously established roles in down-regulating the pro-inflammatory cytokines that activate endothelial cells. It remains unclear exactly how the reduction of adhesion-molecule expression in the host's endothelial cells benefits the feeding tick but it may alter leucocyte migration to the bite site and/or reduce antigen presentation by the endothelial cells. It may also modulate the interactions between the host's leucocytes and any tick-borne pathogens, during initial infection of the endothelium.

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Section: Ticks and Endothelial-cell Adhesion Moleculessupporting

confidence: 50%

Section: Ticks and Endothelial-cell Adhesion Moleculesmentioning

confidence: 99%

Tick modulation of the in-vitro expression of adhesion molecules by skin-derived endothelial cells

Maxwell

Stoklasek

Dash

et al. 2005

Annals of Tropical Medicine & Parasitology

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“…PGE 2 and PGI 2 released by EC are vasodilatory PGs and may synergize with other vasoactive mediators to cause increased vascular permeability and edema, which are thought to be the cardinal features of inflammation during rickettsial infections. Among the major organ systems of the host affected are the lungs and brain, manifesting as interstitial pneumonia, acute respiratory distress syndrome, and neurological deficits leading to seizures and coma (44)(45)(46). It is essential to keep in mind in this context that treatment of brain microvascular endothelial cells with PGE 2 and PGF 2␣ induces significant increases in permeability and changes in cytoskeletal organization (25).…”

Section: Discussionmentioning

confidence: 99%

Infection of Human Endothelial Cells with Spotted Fever Group Rickettsiae Stimulates Cyclooxygenase 2 Expression and Release of Vasoactive Prostaglandins

Rydkina¹,

Sahni²,

Baggs

et al. 2006

Infect Immun

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Rickettsiae, a diverse group of obligately intracellular gram-negative bacteria, include etiologic agents of the spotted fever and typhus groups of diseases. Rocky Mountain spotted fever and boutonneuse fever, due to Rickettsia rickettsii and R. conorii, respectively, are characterized by widespread infection of the vascular endothelium, microvascular injury, and vasculitis. Cultured human endothelial cells (EC) are highly susceptible to infection and respond by altering the expression of adhesion molecules, regulatory cytokines, and the antioxidant enzyme heme oxygenase (HO). In the vasculature, HO regulates the cyclooxygenase (COX) enzymes, among which the inducible isozyme COX-2 facilitates the synthesis of prostaglandins (PGs). Using in vitro and ex vivo models of infection, we demonstrate here that R. rickettsii infection of human EC causes robust induction of COX-2 mRNA and protein expression but has no apparent effect on the constitutive COX-1 isoform. Cells infected with viable rickettsiae consistently displayed significantly increased secretion of 6-keto-PGF 1␣ and PGE 2 . R. rickettsii-induced COX-2 was sensitive to inhibitors of de novo transcription and the pyridinylimidazole-based compound SB 203580, suggesting that this transcriptional host cell response involves signaling through p38 mitogen-activated protein kinase. PG production by infected cells was abrogated by NS 398 (a selective COX-2 inhibitor) and indomethacin (a pan-COX inhibitor). Immunohistochemical staining of sections of infected umbilical cords and corresponding uninfected controls revealed comparatively more intense and abundant staining for COX-2 in infected endothelia. Induction of the endothelial COX-2 system and the resultant enhanced release of vasoactive PGs may contribute to the regulation of inflammatory responses and vascular permeability changes during spotted fever rickettsioses.Pathogenic species of the genus Rickettsia include gramnegative bacteria capable of causing mild to severe diseases in humans. Spotted fever group (SFG) organisms, which represent one of the two major groups of rickettsiae, are found globally in their characteristic arthropod vectors and are often classified to reflect the location of their predominant geographic distribution, for example, Rickettsia sibirica and R. australis, or the resultant human disease, such as Rocky Mountain spotted fever and Mediterranean spotted fever, caused by R. rickettsii and R. conorii, respectively (27, 47). Rocky Mountain spotted fever is a life-threatening illness and can be fatal in children, the elderly, and immunodeficient individuals if there is a lack of early detection and timely intervention with suitable antibiotic therapy. Yet another recently realized and alarming epidemiologic aspect of this disease is that tick-to-human transmission can occur not only through the previously identified principal vectors of Dermacentor species, but also through the more commonly distributed brown dog tick, Rhipicephalus sanguineus, suggesting the capability of this obliga...

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“…Similarly, intravenous administration of R. australis , the causative agent of Queensland tick typhus, results in disseminated endothelial infection of BALB/c and C57BL/6 mice with involvement of nearly all vital organ systems including the lungs, liver, testes, kidneys and spleen [106]. Surprisingly, neutralization of CXCL9 and CXCL10 through function blocking antibodies or infection of CXCR3 knockout mice suggests no survival advantage or beneficial effects on tissue bacterial titers during R. conorii or R. australis infection [107]. Capable of recapitulating alterations in the expression of antioxidant enzymes, infection of the pine vole ( Microtus pinetorum ) has also been recognized as a valuable in vivo experimental model for studying the pathogenesis of RMSF [108], but a direct and more convenient murine model of R. rickettsii infection facilitating the use of well-characterized knockout strains deficient in a particular gene locus has yet to be established.…”

Section: Pathogenesis In Established In Vivo Models Of Infectionmentioning

confidence: 99%

Host-Cell Interactions with Pathogenic Rickettsia Species

2009

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Pathogenic Rickettsia species are Gram-negative, obligate intracellular bacteria responsible for the spotted fever and typhus groups of diseases around the world. It is now well established that a majority of sequelae associated with human rickettsioses are the outcome of the pathogen's affinity for endothelium lining the blood vessels, the consequences of which are vascular inflammation, insult to vascular integrity and compromised vascular permeability, collectively termed ‘Rickettsial vasculitis’. Signaling mechanisms leading to transcriptional activation of target cells in response to Rickettsial adhesion and/or invasion, differential activation of host-cell signaling due to infection with spotted fever versus typhus subgroups of Rickettsiae, and their contributions to the host's immune responses and determination of cell fate are the major subtopics of this review. Also included is a succinct analysis of established in vivo models and their use for understanding Rickettsial interactions with host cells and pathogenesis of vasculotropic rickettsioses. Continued progress in these important but relatively under-explored areas of bacterial pathogenesis research should further highlight unique aspects of Rickettsial interactions with host cells, elucidate the biological basis of endothelial tropism and reveal novel chemotherapeutic and vaccination strategies for debilitating Rickettsial diseases.

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Effect of Blocking the Cxcl9/10-Cxcr3 Chemokine System in the Outcome of Endothelial-Target Rickettsial Infections

Cited by 22 publications

References 36 publications

Tick modulation of the in-vitro expression of adhesion molecules by skin-derived endothelial cells

Tick modulation of the in-vitro expression of adhesion molecules by skin-derived endothelial cells

Infection of Human Endothelial Cells with Spotted Fever Group Rickettsiae Stimulates Cyclooxygenase 2 Expression and Release of Vasoactive Prostaglandins

Host-Cell Interactions with Pathogenic Rickettsia Species

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