The Role of Endotoxin During Typhoid Fever and Tularemia in Man. I. Acquisition of Tolerance to Endotoxin*

Greisman, Sheldon E.; Hornick, Richard B.; Carozza, Frank A.; Woodward, Theodore E.

doi:10.1172/jci104792

Cited by 58 publications

(60 citation statements)

References 10 publications

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“…Although endotoxin levels in blood were not assayed in these patients, clinical and paraclinical findings in this subgroup can be explained on the basis of known biologic effects of endotoxin 26,27 even in the context of its role in typhoid fever. 28,29 In this study, the frequency of headache was lower than would have been expected, 19 but was higher than that reported by others. 30 In two prospective studies from India with no children, 31,32 splenomegaly was noted in more than one-third of the patients.…”

Section: Discussioncontrasting

confidence: 56%

Influence of sex on clinical features, laboratory findings, and complications of typhoid fever.

Khan

Coovadia²,

Connolly³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Clinical features, laboratory findings, and complications of typhoid fever were correlated with sex through a retrospective case note review of 102 hospitalized culture-positive patients in Durban, South Africa. Intestinal perforation (P ϭ 0.04), occult blood losses in stools (P ϭ 0.04), and a mild reticulocytosis in the absence of hemolysis (P ϭ 0.02) occurred more frequently in males than in females. A single pretreatment Widal O antibody titer Ն 1:640 was also a statistically significant occurrence in males (P ϭ 0. 006). Female patients were significantly more severely ill (P ϭ 0.0004) on admission and had chest signs consistent with bronchopneumonia (P ϭ 0.04), transverse myelitis (P ϭ 0.04), abnormal liver function test results (P ϭ 0.0003), and abnormal findings in urinalyses (P ϭ 0.02). Typhoid hepatitis (P ϭ 0.04) and glomerulonephritis (P ϭ 0.02) were present significantly more frequently in females. Whether these differences were due to differences in host's immune response to acute infection need to be determined in a prospective study.Even before the introduction of chloramphenicol in clinical practice, typhoid fever was well recognized as being extremely diverse in its clinical presentation. 1 Classic descriptions of typhoid fever in untreated cases have portrayed a multistage disease, with increasing temperature and bacteremia in the first week; rose spots, abdominal pain, and splenomegaly in the second week; abdominal complications of bleeding and perforation in the third week; and resolution or progression to death after the third week. 2 However, the pattern of disease as seen presently in many parts of the world bears little resemblance to the initial classic description. 3 Certain host-related and microbial factors have been proposed to explain this diversity. 3 It has been previously reported that the patient's age plays an important role in determining the clinical course of typhoid fever. 4 However, the role of the sex of the patient is less emphasized in the literature. On the other hand, we consider it to be an important issue in view of the fact that typhoid fever is increasingly being reported to be more common in women than men in KwaZulu, Natal. 5-7 Therefore, a retrospective study was undertaken to examine the influence of sex in determining the clinical features, laboratory findings, and complications of typhoid fever. MATERIALS AND METHODSA retrospective case note review was undertaken of 102 confirmed cases of typhoid fever treated at King Edward VIII Hospital in Durban, South Africa over a three-year period ending December 31, 1995. The study was reviewed and approved by the Ethics Committee of the University of Natal Medical School. Informed consent of the subjects was not required due to the retrospective nature of the study and because no personal identifiers were used. In all of these cases, diagnoses of typhoid fever were confirmed by isolation of Salmonella typhi from the blood. Patients' charts were reviewed for data pertaining to demographic, clinical, and labor...

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Section: Discussioncontrasting

confidence: 56%

Influence of sex on clinical features, laboratory findings, and complications of typhoid fever.

Khan

Coovadia²,

Connolly³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…Despite exponential replication and phenotypic maturation, we did not detect TNF-␣, IL-12/IL-23p40, IL-6, or IL-1␤ at any time point (24,48, or 72 h) after infection ( Fig. 3 and data not shown).…”

Section: Resultsmentioning

confidence: 71%

“…Although we did not define the mechanism of unresponsiveness in that study, it is possible that direct modulation and induction of tolerance by Francisella products contributes to the unresponsiveness. Indeed, it has been observed that humans experimentally infected with virulent F. tularensis develop in vivo tolerance to LPS from other gram-negative bacteria (24). The specific mechanism of toler- ance in humans infected with Francisella was not defined at the time of that study.…”

Section: Discussionmentioning

confidence: 99%

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

2009

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The gram-negative, facultative intracellular bacterium Francisella tularensis causes acute, lethal pneumonic disease following infection with only 10 CFU. The mechanisms used by the bacterium to accomplish this in humans are unknown. Here, we demonstrate that virulent, type A F. tularensis strain Schu S4 efficiently infects and replicates in human myeloid dendritic cells (DCs). Despite exponential replication over time, Schu S4 failed to stimulate transforming growth factor ␤, interleukin-10 (IL-10), IL-6, IL-1␤, IL-12, tumor necrosis factor alpha, alpha interferon (IFN-␣), and IFN-␤ throughout the course of infection. Schu S4 also suppressed the ability of directly infected DCs to respond to different Toll-like receptor agonists. Furthermore, we also observed functional inhibition of uninfected bystander cells. This inhibition was mediated, in part, by a heat-stable bacterial component. Lipopolysaccharide (LPS) from Schu S4 was present in Schu S4-conditioned medium. However, Schu S4 LPS was weakly inflammatory and failed to induce suppression of DCs at concentrations below 10 g/ml, and depletion of Schu S4 LPS did not significantly alleviate the inhibitory effect of Schu S4-conditioned medium in uninfected human DCs. Together, these data show that type A F. tularensis interferes with the ability of a central cell type of the immune system, DCs, to alert the host of infection both intra-and extracellularly. This suggests that immune dysregulation by F. tularensis operates on a broader and more comprehensive scale than previously appreciated.Francisella tularensis is a gram-negative, facultative intracellular bacterium and the causative agent of tularemia. Although the bacteria was identified nearly 100 years ago, the nature of its interaction with host cells and tissues has remained largely undefined until recent times. The unfortunate realization of the potential of F. tularensis as a biological weapon has resulted in a resurgence of research on tularemia. Much of our recent understanding of tularemia pathogenesis has come from manipulation of the mouse model of Francisella infections. While these murine studies have yielded many important advances in our understanding of tularemia pathogenesis, very little is understood about how Francisella, especially the most virulent type A strains such as Schu S4, interacts with human cells.Dendritic cells (DCs) serve as a central cell type in the immune system, bridging the innate and adaptive immune response to effectively eradicate invading pathogens.

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“…Exposure to high non-lethal doses of bacterial endotoxin results in a state of immune hyporesponsiveness [15,16]. This hyporesponsive innate immune state (referred by some as preconditioning) modulates cardiovascular healing following myocardial ischemia with reduced TNF-α expression and reduced infarct size [17].…”

Section: Discussionmentioning

confidence: 99%

Innate immunity has a dual effect on vascular healing: Suppression and aggravation of neointimal formation and remodeling post-endotoxin challenge

et al. 2008

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Background-Inflammation is important to vascular repair following injury, modulating neointimal proliferation and remodeling. Previously, we have shown that a low-intensity inflammatory response aggravates neointimal formation following balloon and stent injury. The present study examined whether modulation of the extent and timing of nonspecific inflammation mediates the local vascular response in an additive unidirectional or rather a bidirectional fashion.Methods and results-Rabbits subjected to denudation and balloon injury of the iliac artery were treated with low(1 µg/kg) or high (100µg/kg) doses of bacterial endotoxin (LPS) immediately after injury, or with early high-dose LPS administered 3 days prior to injury (preconditioning). Neointimal formation at 28 days was significantly increased in the low-dose group (0.537 ± 0.059mm 2 ) as compared with controls (0.3 ± 0.03mm 2 ). High-dose LPS did not significantly affect neointimal formation while early high dose significantly reduced neointima (0.296 ± 0.033 and 0.194 ± 0.025mm 2 , respectively, n = 12-14/group). Arterial wall and systemically circulating interleukin-1β levels, and monocyte CD14 activation correlated with neointimal formation. Vascular remodeling was accelerated in animals treated with low-or high-dose LPS while not affected in the preconditioned group. Remodeling index inversely correlated with arterial matrix metalloproteinase-2 levels 6 days after injury.Conclusions-The extent and timing of nonspecific inflammation that is concurrent with vascular injury can determine different and opposite vascular repair patterns.

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The Role of Endotoxin During Typhoid Fever and Tularemia in Man. I. Acquisition of Tolerance to Endotoxin*

Cited by 58 publications

References 10 publications

Influence of sex on clinical features, laboratory findings, and complications of typhoid fever.

Influence of sex on clinical features, laboratory findings, and complications of typhoid fever.

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

Innate immunity has a dual effect on vascular healing: Suppression and aggravation of neointimal formation and remodeling post-endotoxin challenge

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