Rapid local expression of interleukin-12, tumor necrosis factor alpha, and gamma interferon after cutaneous Francisella tularensis infection in tularemia-immune mice.
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Francisella tularensis LVS is an effective live vaccine strain used for cutaneous vaccination against tularemia in man. In mice, injection of LVS causes invasive disease and subsequent development of immunity that is characterized by effective control of otherwise lethal doses of the organism. In the present investigation, it is shown that LVS-immune mice controlled an intradermal infection much more effectively than did naive mice; bacterial counts in skin samples were 1.5 to 2.0 log10 lower 24 h after injection and 6 log10 lower 72 h after injection in immune mice. Moreover, in contrast to naive mice, no bacteria were demonstrated in samples from livers and spleens of immune mice. By immunohistochemistry, skin samples from immune mice showed an intense staining for interleukin-12 (IL-12) and a moderate staining for tumor necrosis factor alpha (TNF-alpha) at 24 h postinoculation, after which staining for both cytokines faded. In naive mice, the staining for IL-12 was weak at all time points and no staining for TNF-alpha was observed. No staining for gamma interferon (IFN-gamma) was observed in any group before 72 h. At that time point, skin samples from immune mice showed moderate staining and skin samples from naive mice showed weak staining. Reverse transcriptase PCR showed an induction of mRNA of the three cytokines in the skin within the first day after injection. A quantitative analysis demonstrated higher IFN-gamma and TNF-alpha mRNA levels in immune mice at 24 h postinoculation. In conclusion, immunization with F. tularensis LVS conferred a capability to respond to cutaneous reinfection, with rapid local expression of IL-12, TNF-alpha, and IFN-gamma, and this expression was paralleled by containment and mitigation of the infection. The cytokine response may be part of a local barrier function of the skin, important to host protection against tularemia. (+info)
Tularemia--an unusual cause of a solitary pulmonary nodule in the post-transplant setting.
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We report a case of tularemia presenting as a solitary pulmonary nodule following syngeneic PBSC transplant. Seven months after undergoing a syngeneic PBSC transplant for AML, our patient presented with fever without localizing signs. Chest X-ray revealed a solitary pulmonary nodule. Culture of a CT guided needle aspiration revealed Francisella tularensis. The patient was successfully treated with ciprofloxacin. His fever resolved and clearance of the nodule was documented on a CT scan 2 months after diagnosis and initiation of treatment. To our knowledge, this is the only reported case of tularemia occurring in the post-transplant setting. The possible relationship between transplant-induced immune dysfunction and the occurrence of this rare infection is discussed. (+info)
Repeated administration of synthetic oligodeoxynucleotides expressing CpG motifs provides long-term protection against bacterial infection.
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Synthetic oligodeoxynucleotides (ODN) expressing unmethylated CpG motifs stimulate an innate immune response characterized by the production of polyreactive immunoglobulin M antibodies and immunomodulatory cytokines. This immune response has been shown to protect mice from challenge by Listeria monocytogenes and Francisella tularensis for up to 2 weeks. By repeatedly administering CpG ODN two to four times/month, we found that this protection could be maintained indefinitely. Protection was associated with a significant increase in the number of spleen cells that could be triggered by subsequent pathogen exposure to secrete gamma interferon and interleukin-6 in vivo (P < 0.01). ODN-treated animals remained healthy and developed neither macroscopic nor microscopic evidence of tissue damage or inflammation. Thus, repeated administration of CpG ODN may provide a safe means of conferring long-term protection against infectious pathogens. (+info)
Treatment of tularemia with fluoroquinolones: two cases and review.
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Streptomycin, gentamicin, and tetracycline are currently considered the antimicrobials of choice for the treatment of tularemia. Preliminary data suggest that quinolones may be effective alternative agents; however, clinical experience is limited, and their role in treating severe disease is uncertain. We recently treated two acutely ill immunocompromised patients who had presumed "atypical" pneumonia with levofloxacin. Both patients had an excellent clinical response and were diagnosed with tularemia only when blood cultures subsequently yielded Francisella tularensis. Neither patient relapsed during 12 months of follow-up. Including our two cases, a total of 10 cases of tularemia treated with quinolones have been reported. In all 10 cases, a favorable clinical response was documented, and no relapses occurred. We conclude that the quinolones appear promising for the treatment of even severe tularemia, and they should be considered efficacious alternative agents for patients who do not require parenteral therapy or are intolerant of more standard treatment regimens. (+info)
Comparative analysis of PCR versus culture for diagnosis of ulceroglandular tularemia.
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PCR and culture were comparatively evaluated for their abilities to demonstrate Francisella tularensis in wound specimens from tularemia patients during an outbreak in Sweden in 1998. For transport of the specimens used for PCR, a buffer solution containing a nuclease inhibitor was used, and for transport of the specimens used for culture, a commercial transport system was selected after experimental comparison of various systems. Of 40 patients with culture- and/or serology-verified ulceroglandular tularemia, PCR detected F. tularensis DNA in 30 (75%) patients, whereas culture detected bacterial growth in 25 (62%) patients. Compared to data from a previous study, the present inclusion of a nuclease inhibitor in the transport medium did not improve the sensitivity of the PCR, whereas the sensitivity of the culture procedure was significantly increased by selection of the system used for transport. Among eight patients with clinically suspected tularemia but with negative serology and culture, specimens from four patients showed detectable DNA. In three of these patients the diagnosis was verified by the demonstration of an F. tularensis-specific T-cell response in vitro. In conclusion, PCR was more sensitive than culture for demonstration of F. tularensis in wound specimens. Besides, we showed that tularemia may proceed without development of serum antibodies, and in these patients, PCR may be of special importance for verification of the diagnosis. (+info)
Influence of the bcg locus on natural resistance to primary infection with the facultative intracellular bacterium Francisella tularensis in mice.
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The implication of the Bcg locus in the control of natural resistance to infection with a live vaccine strain (LVS) of the intracellular pathogen Francisella tularensis was studied. Analysis of phenotypic expression of natural resistance and susceptibility was performed using mouse strains congenic at the Bcg locus. Comparison of the kinetics of bacterial colonization of spleen showed that B10.A.Bcg(r) mice were extremely susceptible during early phases of primary sublethal infection, while their congenic C57BL/10N [Bcg(s)] counterparts could be classified as resistant to F. tularensis LVS infection according to the 2-log-lower bacterial CFU within the tissue as long as 5 days after infection. Different phenotypes of Bcg congenic mice were associated with differential expression of the cytokines tumor necrosis factor alpha, interleukin-10, and gamma interferon and production of reactive oxygen intermediates. These results strongly suggest that the Bcg locus, which is close or identical to the Nramp1 gene, controls natural resistance to infection by F. tularensis and that its effect is the opposite of that observed for other Bcg-controlled pathogens. (+info)
The pathology of untreated and antibiotic-treated experimental tularaemia in monkeys.
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Grivet monkeys were infected intranasally with the virulent Schu-S4 strain of F. tularensis. One group of animals remained untreated and two other groups received a 7-day course of kanamycin therapy starting on either the third or fourth day after infection. Untreated monkeys developed pyrexia and mucopurulent oculonasal discharge and died 5--7 days after infection. All had pyogranulomatous lesions in the liver, spleen, respiratory tract and lymph nodes. Electron microscopy of liver and spleen showed phagocytosis of F. tularensis organisms by macrophages and polymorphonuclear leucocytes, but many bacteria survived phagocytosis and were released on destruction of the cells. Kanamycin therapy enabled most monkeys to survive the disease, but it did not prevent the development of persistent lesions in all animals. Caseous nodules were larger and more widespread in the organs of monkeys in which treatment was delayed until the fourth day of infection. (+info)
Changes in whole blood and serum components of grivet monkeys with experimental respiratory Francisella tularensis infection.
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Grivet monkeys infected with virulent Francisella tularensis Strain Schu S4 showed significant early changes in serum levels of trace metals, triglycerides and activities of alkaline phosphatase, lactate dehydrogenase and alpha-hydroxybutyrate dehydrogenase. Free amino acid levels decreased slightly and there was a marked increase in the phenylalanine: tyrosine ratio. Serum lysozyme activity and seromucoid levels also increased. Kanamycin therapy produced remission of overt signs but the changes in blood constituents were less readily affected. Immunization with the live vaccine strain of F. tularensis induced transient responses similar to those resulting from Schut S4 infection. Immunized monkeys subsequently challenged with the virulent Schu S4 strain showed no clinical signs or marked changes in blood constituents. (+info)