Host Defenses to Rickettsia rickettsii Infection Contribute to Increased Microvascular Permeability in Human Cerebral Endothelial Cells

Woods, Michael; Olano, Juan P.

doi:10.1007/s10875-007-9140-9

Cited by 52 publications

(44 citation statements)

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“…challenge with R. typhi may also argue for this hypothesis. In addition to endothelial cell damage that is mediated by the bacteria themselves, inflammatory cytokines (TNF-␣, IL-1␤, and IFN-␥) that are induced to protect against rickettsial infections have been demonstrated to contribute to enhanced microvascular permeability and, thus, could facilitate bacterial entry (66). This is in part mediated by the induction of NO production in endothelial cells (67)(68)(69)(70).…”

Section: Discussionmentioning

confidence: 99%

Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation

et al. 2016

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bRickettsioses are emerging febrile diseases caused by obligate intracellular bacteria belonging to the family Rickettsiaceae. Rickettsia typhi belongs to the typhus group (TG) of this family and is the causative agent of endemic typhus, a disease that can be fatal. In the present study, we analyzed the course of R. typhi infection in C57BL/6 RAG1 ؊/؊ mice. Although these mice lack adaptive immunity, they developed only mild and temporary symptoms of disease and survived R. typhi infection for a long period of time. To our surprise, 3 to 4 months after infection, C57BL/6 RAG1 ؊/؊ mice suddenly developed lethal neurological disorders. Analysis of these mice at the time of death revealed high bacterial loads, predominantly in the brain. This was accompanied by a massive expansion of microglia and by neuronal cell death. Furthermore, high numbers of infiltrating CD11b ؉ macrophages were detectable in the brain. In contrast to the microglia, these cells harbored R. typhi and showed an inflammatory phenotype, as indicated by inducible nitric oxide synthase (iNOS) expression, which was not observed in the periphery. Having shown that R. typhi persists in immunocompromised mice, we finally asked whether the bacteria are also able to persist in resistant C57BL/6 and BALB/c wild-type mice. Indeed, R. typhi could be recultivated from lung, spleen, and brain tissues from both strains even up to 1 year after infection. This is the first report demonstrating persistence and reappearance of R. typhi, mainly restricted to the central nervous system in immunocompromised mice.

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Section: Discussionmentioning

confidence: 99%

Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation

et al. 2016

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“…Invasion of vascular endothelium by these intracellular bacteria relying on the host cell's nutrient-rich "intracytoplasmic niche" for their metabolic requirements, replication, and intercellular spread not only contributes to the establishment and progression of infection, but also triggers a number of host defense mechanisms and deleterious effects on the barrier functions of the endothelium, leading to rickettsial vasculitis characterized by vascular inflammation and compromised permeability properties. Accordingly, salient pathological features of human rickettsioses include fluid imbalance in vital organ systems, which likely represents a major underlying cause of pulmonary and cerebral edema associated with severe rickettsial infections (13,27,36,39,40). Supported by the evidence from clinical cases and experimental models of infection, these findings imply considerable accumulation of rickettsiae in the lungs and their ability to cross the blood-brain barrier into the host's central nervous system and target the brain's vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, response to R. rickettsii infection was characterized by their inability to secrete either of the chemokines despite evidence for the activation of NF-B and p38 upstream signaling mechanisms. Infection of SV-HCECs by R. rickettsii causes a dose-dependent decrease in transendothelial electrical resistance reflecting compromised permeability, a response exacerbated by exogenous inflammatory stimuli (40). The relative inertness of SV-HCECs to secrete chemotactic activities in response to R. rickettsii infection is intriguing, because published evidence suggests augmented secretion of IL-8 and macrophage inflammatory protein 1␣ by cerebral endothelial cells infected with Anaplasma phagocytophilum and enhancement of this effect by coinfection with Borrelia burgdorferi (14).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the pulmonary microvascular ECs are among the most important targets of reactive oxygen species (ROS) in lung injury (5). In this regard, an important consideration is that prominent pathological features directly relevant to rickettsial diseases include noncardiogenic pulmonary edema and cerebral edema (13,35,36,40). Thus, keeping in mind that microvascular ECs of different origin may exhibit marked differences in their sensitivity and/or responses to infection, we have now conducted comparative studies using microvessel ECs derived from human dermis (HMEC-1), lungs (HPMEC), and brain (SV-HCEC) and macrovascular cell types, namely, human pulmonary artery endothelial cells (HPAECs) and HUVECs.…”

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confidence: 99%

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Rickettsia rickettsiiInfection of Human Macrovascular and Microvascular Endothelial Cells Reveals Activation of Both Common and Cell Type-Specific Host Response Mechanisms

2010

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Although inflammation and altered barrier functions of the vasculature, due predominantly to the infection of endothelial cell lining of small and medium-sized blood vessels, represent salient pathological features of human rickettsioses, the interactions between pathogenic rickettsiae and microvascular endothelial cells remain poorly understood. We have investigated the activation of nuclear transcription factor-kappa B (NF-B) and p38 mitogen-activated protein (MAP) kinase, expression of heme oxygenase 1 (HO-1) and cyclooxygenase 2 (COX-2), and secretion of chemokines and prostaglandins after Rickettsia rickettsii infection of human cerebral, dermal, and pulmonary microvascular endothelial cells in comparison with pulmonary artery cells of macrovascular origin. NF-B and p38 kinase activation and increased HO-1 mRNA expression were clearly evident in all cell types, along with relatively similar susceptibility to R. rickettsii infection in vitro but considerable variations in the intensities/kinetics of the aforementioned host responses. As expected, the overall activation profiles of macrovascular endothelial cells derived from human pulmonary artery and umbilical vein were nearly identical. Interestingly, cerebral endothelial cells displayed a marked refractoriness in chemokine production and secretion, while all other cell types secreted various levels of interleukin-8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) in response to infection. A unique feature of all microvascular endothelial cells was the lack of induced COX-2 expression and resultant inability to secrete prostaglandin E 2 after R. rickettsii infection. Comparative evaluation thus yields the first experimental evidence for the activation of both common and unique cell type-specific host response mechanisms in macrovascular and microvascular endothelial cells infected with R. rickettsii, a prototypical species known to cause Rocky Mountain spotted fever in humans.The obligately intracellular Alphaproteobacteria belonging to genus Rickettsia are now classified into four subgroups, which include an ancestral group and a transitional group in addition to two major antigenically defined groups comprised of spotted fever and typhus species (12). Pathogenic rickettsiae display tropism for vascular endothelial cell lining of small and mediumsized blood vessels in their mammalian hosts. As a consequence, the predominant pathological features of resultant clinical syndromes-for example, Rocky Mountain spotted fever due to Rickettsia rickettsii-are generally attributed to altered vascular functions due to preferential infection of the endothelium (27, 36). However, despite critical contributions of endothelial injury, inflammation, and dysfunction to the pathogenesis of vasculotropic rickettsioses, the biological basis of rickettsial interactions with microvascular endothelium of vertebrate hosts still remains poorly understood.An initial breakthrough in the laboratory investigations of the interplay between host cells and pathogenic rickettsiae wa...

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“…The cellular junctions maintain the vascular integrity and mediate anchorage to the actin microfilaments through the vascular endothelial cadherin and catenin proteins [Dejana et al, 1999;Bazzoni and Dejana E., 2004]. A previous study has shown that within 24 hours after R. rickettsii infection the vascular permeability is increased, and the and p120 catenin proteins dissociate from the inter-endothelial cellular junctions [Woods and Olano J. P., 2008]. One parameter to measure endothelial damage is to quantify the number of circulating endothelial cells [Brevetti et al, 2008].…”

Section: Endothelium and Pathophysiology Of Rickettsiosesmentioning

confidence: 99%