Histologic and molecular diagnosis of tularemia: a potential bioterrorism agent endemic to North America

Lamps, Laura W.; Havens, Jennifer M.; Sjöstedt, Anders; Page, David L.; Scott, Margie A.

doi:10.1038/modpathol.3800087

Cited by 88 publications

(75 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…7), we used a human kidney epithelial cell line (HEK-293) to test our hypothesis. Moreover, F. tularensis is often isolated or identified in kidney tissues during natural animal infection (1,35). In contrast to the results obtained with macrophages (Fig.…”

Section: Vol 78 2010 F Tularensis Pyrf and Replication In Nonmacrocontrasting

confidence: 55%

Francisella tularensisΔpyrFMutants Show that Replication in Nonmacrophages Is Sufficient for PathogenesisIn Vivo

Horzempa¹,

O’Dee²,

Shanks

et al. 2010

Infect Immun

View full text Add to dashboard Cite

The pathogenesis of Francisella tularensis has been associated with this bacterium's ability to replicate within macrophages. F. tularensis can also invade and replicate in a variety of nonphagocytic host cells, including lung and kidney epithelial cells and hepatocytes. As uracil biosynthesis is a central metabolic pathway usually necessary for pathogens, we characterized ⌬pyrF mutants of both F. tularensis LVS and Schu S4 to investigate the role of these mutants in intracellular growth. As expected, these mutant strains were deficient in de novo pyrimidine biosynthesis and were resistant to 5-fluoroorotic acid, which is converted to a toxic product by functional PyrF. The F. tularensis ⌬pyrF mutants could not replicate in primary human macrophages. The inability to replicate in macrophages suggested that the F. tularensis ⌬pyrF strains would be attenuated in animal infection models. Surprisingly, these mutants retained virulence during infection of chicken embryos and in the murine model of pneumonic tularemia. We hypothesized that the F. tularensis ⌬pyrF strains may replicate in cells other than macrophages to account for their virulence. In support of this, F. tularensis ⌬pyrF mutants replicated in HEK-293 cells and normal human fibroblasts in vitro. Moreover, immunofluorescence microscopy showed abundant staining of wild-type and mutant bacteria in nonmacrophage cells in the lungs of infected mice. These findings indicate that replication in nonmacrophages contributes to the pathogenesis of F. tularensis.

show abstract

Section: Vol 78 2010 F Tularensis Pyrf and Replication In Nonmacrocontrasting

confidence: 55%

Francisella tularensisΔpyrFMutants Show that Replication in Nonmacrophages Is Sufficient for PathogenesisIn Vivo

Horzempa¹,

O’Dee²,

Shanks

et al. 2010

Infect Immun

View full text Add to dashboard Cite

show abstract

“…Therefore, we evaluated the role of MMP-9 in the pathogenesis of respiratory tularemia relying upon the well-characterized mouse model of infection (6,(23)(24)(25)(26). In the present study, we propose that MMP-9-mediated regulation of the matrix environment, which coordinates the influx of neutrophils, plays a more destructive than protective role in host defense against pulmonary infection with F. tularensis.…”

mentioning

confidence: 89%

Matrix Metalloproteinase 9 Activity Enhances Host Susceptibility to Pulmonary Infection with Type A and B Strains of Francisella tularensis

Malik

Bakshi

McCabe

et al. 2007

The Journal of Immunology

102

113

View full text Add to dashboard Cite

A striking feature of pulmonary infection with the Gram-negative intracellular bacterium Francisella tularensis, a category A biological threat agent, is an intense accumulation of inflammatory cells, particularly neutrophils and macrophages, at sites of bacterial replication. Given the essential role played by host matrix metalloproteinases (MMPs) in modulating leukocyte recruitment and the potentially indiscriminate destructive capacity of these cells, we investigated whether MMP-9, an important member of this protease family released by neutrophils and activated macrophages, plays a role in the pathogenesis of respiratory tularemia. We found that F. tularensis induced expression of MMP-9 in FVB/NJ mice and that the action of this protease is associated with higher bacterial burdens in pulmonary and extrapulmonary tissues, development of more extensive histopathology predominated by neutrophils, and increased morbidity and mortality compared with mice lacking MMP-9 (MMP-9−/−). Moreover, MMP-9−/− mice were able to resolve infection with either the virulence-attenuated type B (live vaccine strain) or the highly virulent type A (SchuS4) strain of F. tularensis. Disease resolution was accompanied by diminished leukocyte recruitment and reductions in both bacterial burden and proinflammatory cytokine production. Notably, neutrophilic infiltrates were significantly reduced in MMP-9−/− mice, owing perhaps to limited release of Pro-Gly-Pro, a potent neutrophil chemotactic tripeptide released from extracellular matrix through the action of MMP-9. Collectively, these results suggest that MMP-9 activity plays a central role in modulating the clinical course and severity of respiratory tularemia and identifies MMPs as novel targets for therapeutic intervention as a means of modulating neutrophil recruitment.

show abstract

“…46 The results of the histopathology evaluation of tissues collected at predetermined time points after exposure and at moribund euthanasia or death showed that the affected organs and microscopic lesions in F344 rats were similar to those observed in humans with tularemia. 1,47,48 Microscopic lesions in humans generally consist of neutrophilic and histiocytic infiltrates, which become progressively more fibrinous and necrotizing over time. After inhalation, primary lesions are described in the lungs and draining lymph nodes, with lymphohematogenous spread to organs that are rich in reticuloendothelial cells, most notably the liver, spleen, bone marrow, and lymph nodes.…”

Section: F344 Rat Model Of Inhalational Tularemiamentioning

confidence: 99%

The Natural History of Pneumonic Tularemia in Female Fischer 344 Rats after Inhalational Exposure to Aerosolized Francisella tularensis Subspecies tularensis Strain SCHU S4

Hutt

Lovchik

Dekonenko

et al. 2017

The American Journal of Pathology

View full text Add to dashboard Cite

The inbred Fischer 344 rat is being evaluated for testing novel vaccines and therapeutics against pneumonic tularemia. Although primary pneumonic tularemia in humans typically occurs by inhalation of aerosolized bacteria, the rat model has relied on intratracheal inoculation of organisms because of safety and equipment issues. We now report the natural history of pneumonic tularemia in female Fischer 344 rats after nose-only inhalational exposure to lethal doses of aerosolized Francisella tularensis subspecies tularensis, strain SCHU S4. Our results are consistent with initial uptake of aerosolized SCHU S4 from the nasal cavity, lungs, and possibly the gastrointestinal tract. Bacteremia with hematogenous dissemination was first detected 2 days after exposure. Shortly thereafter, the infected rats exhibited fever, tachypnea, and hypertension that persisted for 24 to 36 hours and then rapidly decreased as animals succumbed to infection between days 5 and 8 after exposure. Tachycardia was observed briefly, but only after the core body temperature and blood pressure began to decrease as the animals were near death. Initial neutrophilic and histiocytic inflammation in affected tissues became progressively more fibrinous and necrotizing over time. At death, as many as 10 10 colony-forming units were found in the lungs, spleen, and liver. Death was attributed to sepsis and disseminated intravascular coagulation. Overall, the pathogenesis of pneumonic tularemia in the female F344 rat model appears to replicate the disease in humans. (Am J Pathol 2017, 187: 252e267; http://dx

show abstract

Histologic and molecular diagnosis of tularemia: a potential bioterrorism agent endemic to North America

Cited by 88 publications

References 33 publications

Francisella tularensisΔpyrFMutants Show that Replication in Nonmacrophages Is Sufficient for PathogenesisIn Vivo

Francisella tularensisΔpyrFMutants Show that Replication in Nonmacrophages Is Sufficient for PathogenesisIn Vivo

Matrix Metalloproteinase 9 Activity Enhances Host Susceptibility to Pulmonary Infection with Type A and B Strains of Francisella tularensis

The Natural History of Pneumonic Tularemia in Female Fischer 344 Rats after Inhalational Exposure to Aerosolized Francisella tularensis Subspecies tularensis Strain SCHU S4

Contact Info

Product

Resources

About