An improved vaccine for prevention of respiratory tularemia caused by Francisella tularensis SchuS4 strain

Bakshi, Chandra Shekhar; Malik, Meenakshi; Mahawar, Manish; Kirimanjeswara, Girish S.; Hazlett, Karsten R. O.; Palmer, Lance E.; Furie, Martha B.; Singh, Rajendra; Melendez, J. Andrés; Sellati, Timothy J.; Metzger, Dennis W.

doi:10.1016/j.vaccine.2008.07.051

Cited by 69 publications

(83 citation statements)

References 52 publications

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“…Furthermore, we have shown that these Fpt mutant strains are severely attenuated for virulence in mice and protective against high-level challenge with parental LVS and that the protection is long lasting. There have been limited reports of live vaccine strains conferring protection against a type A challenge (1,27). Future studies will determine if these LVS Fpt mutants or the corresponding mutants in the Schu S4 background can protect against a type A challenge.…”

Section: Discussionmentioning

confidence: 99%

Members of the Francisella tularensis Phagosomal Transporter Subfamily of Major Facilitator Superfamily Transporters Are Critical for Pathogenesis

et al. 2012

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ABSTRACTFrancisella tularensisis the causative agent of tularemia. Due to its aerosolizable nature and low infectious dose,F. tularensisis classified as a category A select agent and, therefore, is a priority for vaccine development. Survival and replication in macrophages and other cell types are critical toF. tularensispathogenesis, and impaired intracellular survival has been linked to a reduction in virulence. TheF. tularensisgenome is predicted to encode 31 major facilitator superfamily (MFS) transporters, and the nine-memberFrancisellaphagosomal transporter (Fpt) subfamily possesses homology with virulence factors in other intracellular pathogens. We hypothesized that these MFS transporters may play an important role inF. tularensispathogenesis and serve as good targets for attenuation and vaccine development. Here we show altered intracellular replication kinetics and attenuation of virulence in mice infected with three of the nine Fpt mutant strains compared with wild-type (WT)F. tularensisLVS. The vaccination of mice with these mutant strains was protective against a lethal intraperitoneal challenge. Additionally, we observed pronounced differences in cytokine profiles in the livers of mutant-infected mice, suggesting that alterations inin vivocytokine responses are a major contributor to the attenuation observed for these mutant strains. These results confirm that this subset of MFS transporters plays an important role in the pathogenesis ofF. tularensisand suggest that a focus on the development of attenuated Fpt subfamily MFS transporter mutants is a viable strategy toward the development of an efficacious vaccine.

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Section: Discussionmentioning

confidence: 99%

Members of the Francisella tularensis Phagosomal Transporter Subfamily of Major Facilitator Superfamily Transporters Are Critical for Pathogenesis

et al. 2012

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“…Mice were deeply anesthetized by intraperitoneal injection of ketamine/xylazine mixture and inoculated intranasally with 2 ϫ 10 3 cfu of sodBC mutant or F. tularensis LVS in a 20-l volume of PBS. Mice were sacrificed on days 1, 5, and 7 postinfection, and homogenates of lungs were prepared for quantitation of bacterial burden and pro-inflammatory cytokines following our previously published protocols (43,44).…”

Section: Methodsmentioning

confidence: 99%

Antioxidant Defenses of Francisella tularensis Modulate Macrophage Function and Production of Proinflammatory Cytokines

Rabadi

Sanchez

Varanat

et al. 2016

Journal of Biological Chemistry

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Francisella tularensis, the causative agent of a fatal human disease known as tularemia, has been used in the bioweapon programs of several countries in the past, and now it is considered a potential bioterror agent. Extreme infectivity and virulence of F. tularensis is due to its ability to evade immune detection and to suppress the host's innate immune responses. However, Francisella-encoded factors and mechanisms responsible for causing immune suppression are not completely understood. Macrophages and neutrophils generate reactive oxygen species (ROS)/reactive nitrogen species as a defense mechanism for the clearance of phagocytosed microorganisms. ROS serve a dual role; at high concentrations they act as microbicidal effector molecules that destroy intracellular pathogens, and at low concentrations they serve as secondary signaling messengers that regulate the expression of various inflammatory mediators. We hypothesized that the antioxidant defenses of F. tularensis maintain redox homeostasis in infected macrophages to prevent activation of redox-sensitive signaling components that ultimately result in suppression of pro-inflammatory cytokine production and macrophage microbicidal activity. We demonstrate that antioxidant enzymes of F. tularensis prevent the activation of redox-sensitive MAPK signaling components, NF-B signaling, and the production of pro-inflammatory cytokines by inhibiting the accumulation of ROS in infected macrophages. We also report that F. tularensis inhibits ROS-dependent autophagy to promote its intramacrophage survival. Collectively, this study reveals novel pathogenic mechanisms adopted by F. tularensis to modulate macrophage innate immune functions to create an environment permissive for its intracellular survival and growth.Francisella tularensis is a Gram-negative intracellular pathogen and the causative agent of a fatal human disease known as tularemia. F. tularensis is classified into four subspecies as follows: F. tularensis subspecies tularensis; F. tularensis subspecies holarctica; F. tularensis subspecies mediasiatica, and F. tularensis subspecies novicida. All classifications are based on virulence, genetics, and metabolic characteristics. F. tularensis subspecies tularensis (type A) is the most virulent of all four Francisella subspecies. About 70% of tularemia cases in North America are a result of type A Francisella with an infectivity dose of less than 10 colony-forming units (cfu) in humans (1). The live vaccine strain (LVS) 3 is a derivative of Russian S15 strain of F. tularensis subspecies holarctica (type B). F. tularensis LVS is not approved for mass vaccinations in the United States due to adverse reactions in vaccinated individuals (2). F. tularensis LVS is relatively avirulent in humans and therefore commonly used as a surrogate for the more virulent SchuS4 strain to study tularemia pathogenesis. F. tularensis subspecies mediasiatica and novicida are rarely associated with human tularemia and have been isolated in Asia and in North America and Australia, re...

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“…Like many pathogens, Francisella can directly detoxify ROS using proteins, including catalase (134,151,214) and superoxide dismutases (15,16,151), whose specific mechanisms of action are reviewed extensively elsewhere (135). In addition to these well-known mechanisms of ROS resistance, we identified a previously uncharacterized protein, FTN_1133, that is required for virulence and resistance to organic hydroperoxides (135).…”

Section: Inhibition Of Reactive Oxygen Speciesmentioning

confidence: 99%

Subversion of Host Recognition and Defense Systems by Francisella spp

Jones

Napier

Sampson

et al. 2012

Microbiol Mol Biol Rev

123

151

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SUMMARY Francisella tularensis is a Gram-negative intracellular pathogen and the causative agent of the disease tularemia. Inhalation of as few as 10 bacteria is sufficient to cause severe disease, making F. tularensis one of the most highly virulent bacterial pathogens. The initial stage of infection is characterized by the “silent” replication of bacteria in the absence of a significant inflammatory response. Francisella achieves this difficult task using several strategies: (i) strong integrity of the bacterial surface to resist host killing mechanisms and the release of inflammatory bacterial components (pathogen-associated molecular patterns [PAMPs]), (ii) modification of PAMPs to prevent activation of inflammatory pathways, and (iii) active modulation of the host response by escaping the phagosome and directly suppressing inflammatory pathways. We review the specific mechanisms by which Francisella achieves these goals to subvert host defenses and promote pathogenesis, highlighting as-yet-unanswered questions and important areas for future study.

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An improved vaccine for prevention of respiratory tularemia caused by Francisella tularensis SchuS4 strain

Cited by 69 publications

References 52 publications

Members of the Francisella tularensis Phagosomal Transporter Subfamily of Major Facilitator Superfamily Transporters Are Critical for Pathogenesis

Members of the Francisella tularensis Phagosomal Transporter Subfamily of Major Facilitator Superfamily Transporters Are Critical for Pathogenesis

Antioxidant Defenses of Francisella tularensis Modulate Macrophage Function and Production of Proinflammatory Cytokines

Subversion of Host Recognition and Defense Systems by Francisella spp

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