Rapid dissemination of Francisella tularensisand the effect of route of infection

Ojeda, Sandra S.; Wang, Zheng J.; Mares, Chris; Chang, T. Arthur; Li, Qun; Morris, Elizabeth G.; Jerabek, Paul; Teale, Judy M.

doi:10.1186/1471-2180-8-215

Cited by 29 publications

(21 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During early stages of infection, these strains persisted at low levels in the liver and spleen, although by day 12 the levels of growth were comparable to those observed for the virulent WT Schu S4 strain at day 3 postinfection. In contrast, the lungs of mice infected with either the waaY or waaL mutant had significantly higher levels of bacterial growth than the WT strain (10 6 CFU/organ) at 3 days postinfection, with the burden in the lungs continuing to increase exponentially, to 10 11 CFU/organ by day 12 postinfection. In comparing the growth on day 3 postinfection, the trend points to the mutants having slower growth kinetics in vivo than that of the WT (Fig.…”

Section: Maldi-ms Analyses Were Also Performed On the O-lps From The mentioning

confidence: 76%

“…Francisella strains from newly streaked agar plates were inoculated into MMH broth and grown for 24 h before the OD 600 was measured and recorded. One-milliliter broth cultures were centrifuged at 8,000 ϫ g for 2 min before resuspension of each pellet in buffer A (6 mM Tris, 10 (27). In brief, bacteria were grown for ϳ16 h on chocolate agar with appropriate antibiotics at 37°C, collected in 6 mM Tris base, 10 mM EDTA, and 2.0% SDS (wt/vol), pH 6.8, containing 50 g/ml proteinase K, and incubated at 65°C for 1 h and then overnight at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…However, the organism also has important interactions with other cells, including epithelial and endothelial cells, hepatocytes, and neutrophils (5)(6)(7)(8)(9). Migration of infected leukocytes throughout the vasculature leads to seeding of sites in the lymphatic system, establishment of systemic disease, and, eventually, death by multiple-organ failure (10). Due to the extreme virulence and ease of aerosol dissemination of F. tularensis, the U.S. Centers for Disease Control and Prevention have classified this organism as a tier 1 select agent because of its potential for development into a bioweapon (11).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Francisella tularensis Schu S4 Lipopolysaccharide Core Sugar and O-Antigen Mutants Are Attenuated in a Mouse Model of Tularemia

et al. 2014

View full text Add to dashboard Cite

The virulence factors mediating Francisella pathogenesis are being investigated, with an emphasis on understanding how the organism evades innate immunity mechanisms. Francisella tularensis produces a lipopolysaccharide (LPS) that is essentially inert and a polysaccharide capsule that helps the organism to evade detection by components of innate immunity. Using an F. tularensis Schu S4 mutant library, we identified strains that are disrupted for capsule and O-antigen production. These serum-sensitive strains lack both capsule production and O-antigen laddering. Analysis of the predicted protein sequences for the disrupted genes (FTT1236 and FTT1238c) revealed similarity to those for waa (rfa) biosynthetic genes in other bacteria. Mass spectrometry further revealed that these proteins are involved in LPS core sugar biosynthesis and the ligation of O antigen to the LPS core sugars. The 50% lethal dose (LD 50 ) values of these strains are increased 100-to 1,000-fold for mice. Histopathology revealed that the immune response to the F. tularensis mutant strains was significantly different from that observed with wild-type-infected mice. The lung tissue from mutant-infected mice had widespread necrotic debris, but the spleens lacked necrosis and displayed neutrophilia. In contrast, the lungs of wild-type-infected mice had nominal necrosis, but the spleens had widespread necrosis. These data indicate that murine death caused by wild-type strains occurs by a mechanism different from that by which the mutant strains kill mice. Mice immunized with these mutant strains displayed >10-fold protective effects against virulent type A F. tularensis challenge.

show abstract

Section: Maldi-ms Analyses Were Also Performed On the O-lps From The mentioning

confidence: 76%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Francisella tularensis Schu S4 Lipopolysaccharide Core Sugar and O-Antigen Mutants Are Attenuated in a Mouse Model of Tularemia

et al. 2014

View full text Add to dashboard Cite

show abstract

“…It has been reported that redox-dependent inactivation of signaling components plays an important role in long-term homeostasis of human alveolar macrophages (27). F. tularensis encounters these cells immediately following pulmonary infection, replicates, and is rapidly disseminated to liver and spleen (28,29). F. tularensis also survives in macrophages and dendritic cells by suppressing activation of proinflammatory cytokines (6, 7 , 30, 31).…”

Section: Discussionmentioning

confidence: 99%

Francisella tularensis Antioxidants Harness Reactive Oxygen Species to Restrict Macrophage Signaling and Cytokine Production

Melillo

Bakshi

Melendez

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Francisella tularensis is the etiologic agent of the highly infectious animal and human disease tularemia. Its extreme infectivity and virulence are associated with its ability to evade immune detection, which we now link to its robust reactive oxygen species-scavenging capacity. Infection of primary human monocyte-derived macrophages with virulent F. tularensis SchuS4 prevented proinflammatory cytokine production in the presence or absence of IFN-␥ compared with infection with the attenuated live vaccine strain. SchuS4 infection also blocked signals required for macrophage cytokine production, including Akt phosphorylation, IB␣ degradation, and NF-B nuclear localization and activation. Concomitant with SchuS4-mediated suppression of Akt phosphorylation was an increase in the levels of the Akt antagonist PTEN. Moreover, SchuS4 prevented the H 2 O 2 -dependent oxidative inactivation of PTEN compared with a virulent live vaccine strain. Mutation of catalase (katG) sensitized F. tularensis to H 2 O 2 and enhanced PTEN oxidation, Akt phosphorylation, NF-B activation, and inflammatory cytokine production. Together, these findings suggest a novel role for bacterial antioxidants in restricting macrophage activation through their ability to preserve phosphatases that temper kinase signaling and proinflammatory cytokine production.Francisella tularensis is a Gram-negative intracellular bacterium that is the causative agent of the disease tularemia. F. tularensis is considered a potential biological weapon because of its extreme infectivity, ease of artificial dissemination via aerosols, and substantial capacity to cause illness and death (1). F. tularensis subsp. tularensis (strain SchuS4) is a category A biological agent and the most virulent for humans, with an estimated infectious dose of Ͻ10 colony-forming units, whereas the attenuated live vaccine strain (LVS) 2 of subsp. holarctica displays little virulence in humans. Upon infection, F. tularensis engages and rapidly tempers a number of diverse host cell signaling networks to allow for its intracellular survival and replication (2, 3). Among these is the phosphatidylinositol 3-kinase/ Akt pathway, which plays a prominent role in restricting lethal infection and inflammatory cytokine production in response to F. tularensis (4). Parsa et al. (5) demonstrated that conversion of phosphoinositol 3,4,5-triphosphate to phosphoinositol 3,4-bisphosphate by the 5Ј-phosphatase SHIP negatively regulates macrophage cytokine production in response to Francisella novicida. Thus, SHIP limits phosphoinositol 3,4,5-triphosphate production, Akt activation, and subsequent cytokine production in response to infection. Recent microarray analysis from the Tridandapani and co-workers has revealed that the activity of Akt is also suppressed by SchuS4 (6) and correlates with the production of microRNAs that target SHIP expression (7). In addition, F. tularensis infection increases the levels of the duallipid protein phosphatase and Akt antagonist PTEN (phosphatase and tensin homolog) (8). ...

show abstract

“…paratuberculosis (52), and Listeria monocytogenes (53). In another study, Ojeda et al reported early trafficking of Francisella novicida to the gastrointestinal tract following infection by both the intranasal and intratracheal routes, with viable bacteria detected in the Peyer's patches (54). Following subcutaneous infection of field voles with F. tularensis subsp.…”

Section: Figmentioning

confidence: 99%

A Bioluminescent Francisella tularensis SCHU S4 Strain Enables Noninvasive Tracking of Bacterial Dissemination and the Evaluation of Antibiotics in an Inhalational Mouse Model of Tularemia

Hall

Flick-Smith

Harding

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

bBioluminescence imaging (BLI) enables real-time, noninvasive tracking of infection in vivo and longitudinal infection studies. In this study, a bioluminescent Francisella tularensis strain, SCHU S4-lux, was used to develop an inhalational infection model in BALB/c mice. Mice were infected intranasally, and the progression of infection was monitored in real time using BLI. A bioluminescent signal was detectable from 3 days postinfection (3 dpi), initially in the spleen and then in the liver and lymph nodes, before finally becoming systemic. The level of bioluminescent signal correlated with bacterial numbers in vivo, enabling noninvasive quantification of bacterial burdens in tissues. Treatment with levofloxacin (commencing at 4 dpi) significantly reduced the BLI signal. Furthermore, BLI was able to distinguish noninvasively between different levofloxacin treatment regimens and to identify sites of relapse following treatment cessation. These data demonstrate that BLI and SCHU S4-lux are suitable for the study of F. tularensis pathogenesis and the evaluation of therapeutics for tularemia. Francisella tularensis is a Gram-negative intracellular bacterium and is the etiological agent of the disease tularemia. Tularemia has a low infectious dose by the aerosol route (50% infectious dose [ID 50 ], Ͻ10 CFU), causing a disabling illness without rapid treatment, and is considered a potential biothreat agent. The preferred treatments for tularemia are limited to a few antibiotics, including fluoroquinolones (1, 2), tetracycline (3), streptomycin (4, 5), and gentamicin (6, 7). The lack of a licensed vaccine, reported treatment failures, even with preferred antibiotics (8), and a 2% mortality rate despite treatment (5) necessitate the development and evaluation of new therapies.Conventional methods of assessing bacterial growth and dissemination in vivo require the infection of large cohorts of animals and the culling of groups of animals at set time points throughout a study. This strategy not only uses large numbers of animals but is also labor-intensive and subject to tissue sampling bias. Noninvasive imaging techniques, such as bioluminescence imaging (BLI), can report spatial and temporal aspects of infectious diseases in vivo both longitudinally and in real time (9). BLI typically relies on the detection of light produced by luciferase-catalyzed oxidation reactions, which are encoded in the pathogen of interest, by use of a sensitive charge-coupled device (CCD) camera (10). Pivotal experiments by Contag et al. have demonstrated the usefulness of BLI in the noninvasive study of bacterial pathogenesis and the evaluation of antibiotic treatments for Salmonella enterica serovar Typhimurium (11). Subsequently, bioluminescent reporters have been introduced into other bacteria, including Mycobacterium tuberculosis (10, 12), Staphylococcus aureus (13, 14), Burkholderia mallei (15), and Yersinia pestis (16,17). Further, BLI has been used to evaluate vaccines (18), antibiotics (19-21), and supportive therapies (22) for a ran...

show abstract

Rapid dissemination of Francisella tularensisand the effect of route of infection

Cited by 29 publications

References 71 publications

Francisella tularensis Schu S4 Lipopolysaccharide Core Sugar and O-Antigen Mutants Are Attenuated in a Mouse Model of Tularemia

Francisella tularensis Schu S4 Lipopolysaccharide Core Sugar and O-Antigen Mutants Are Attenuated in a Mouse Model of Tularemia

Francisella tularensis Antioxidants Harness Reactive Oxygen Species to Restrict Macrophage Signaling and Cytokine Production

A Bioluminescent Francisella tularensis SCHU S4 Strain Enables Noninvasive Tracking of Bacterial Dissemination and the Evaluation of Antibiotics in an Inhalational Mouse Model of Tularemia

Contact Info

Product

Resources

About