Identification of
            <i>Francisella tularensis</i>
            Live Vaccine Strain CuZn Superoxide Dismutase as Critical for Resistance to Extracellularly Generated Reactive Oxygen Species

Melillo, Amanda A.; Mahawar, Manish; Sellati, Timothy J.; Malik, Meenakshi; Metzger, Dennis W.; Melendez, J. Andrés; Bakshi, Chandra Shekhar

doi:10.1128/jb.00534-09

Cited by 57 publications

(57 citation statements)

References 33 publications

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“…The iron-containing superoxide dismutase (SodB) is constitutively expressed and secreted (26,27); and the copper-zinc-containing SodC is located in the periplasmic space. Previous studies from our laboratory with mutants of F. tularensis LVS in genes encoding for the antioxidant enzymes sodB, sodC, sodBC, and those of Lindgren et al (28)., with catalase (katG), have shown that these antioxidant enzymes are required for intramacrophage survival and virulence in mice (26,29,30). We have also demonstrated that the sodBC mutant of F. tularensis LVS, which carries a point mutation in the sodB gene and a clean in-frame deletion of the sodC gene, exhibits enhanced sensitivity toward ROS and RNS, attenuated survival in macrophages, and virulence in mice (30).…”

mentioning

confidence: 83%

“…Bacterial Strains-F. tularensis LVS used in this study was obtained from BEI Resources, Manassas, VA. A sodBC double gene mutant previously reported from our laboratory (30), which carries a point mutation in sodB gene and deleted sodC gene, was used in this study. The transcomplemented strain of sodBC mutant (sodBCϩpsodC) was generated by providing a copy of the sodC gene in trans in the sodBC mutant.…”

Section: Methodsmentioning

confidence: 99%

“…sodBC Mutant Induces Significantly Higher Levels of TNF-␣ and IL-6 in Vivo Which Are Dependent on NADPH Oxidasegenerated ROS-Previously, we have reported that sodBC mutant of F. tularensis is attenuated for intramacrophage survival (30). To establish that higher levels of TNF-␣ observed in macrophages infected with the sodBC mutant were not due to ) on a C57BL/6 background were infected intranasally with sublethal (2 ϫ 10 3 cfu) doses of F. tularensis LVS or the sodBC mutant.…”

Section: F Tularensis Lvs Actively Suppresses Pro-inflammatory Cytokmentioning

confidence: 99%

“…Previous studies from our laboratory with mutants of F. tularensis LVS in genes encoding for the antioxidant enzymes sodB, sodC, sodBC, and those of Lindgren et al (28)., with catalase (katG), have shown that these antioxidant enzymes are required for intramacrophage survival and virulence in mice (26,29,30). We have also demonstrated that the sodBC mutant of F. tularensis LVS, which carries a point mutation in the sodB gene and a clean in-frame deletion of the sodC gene, exhibits enhanced sensitivity toward ROS and RNS, attenuated survival in macrophages, and virulence in mice (30). In addition to these primary antioxidant enzymes, a moxR family ATPase encoded by the FTL_0200 gene and two additional genes present on the moxR locus of F. tularensis LVS are required for resistance against oxidative and pH stresses (31).…”

mentioning

confidence: 99%

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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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mentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Section: F Tularensis Lvs Actively Suppresses Pro-inflammatory Cytokmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…For construction of the ⌬FTT0831c mutant, the entire coding region of the FTT0831c gene was deleted by employing an approach described earlier (25,26). For transcomplementation, the full-length FTT0831c gene was amplified by PCR and cloned in pKK214 vector downstream of GroEL promoter of F. tularensis following our recently published protocol (26,27). The plasmid constructs, bacterial strains, and the primer sequences used in this study are shown in supplemental Table S1.…”

Section: Methodsmentioning

confidence: 99%

Identification of a Novel Francisella tularensis Factor Required for Intramacrophage Survival and Subversion of Innate Immune Response

Mahawar

Atianand

Dotson

et al. 2012

Journal of Biological Chemistry

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Background:The mechanism of immune suppression caused by Francisella tularensis SchuS4 strain, a category A agent, are yet unknown. Results: FTL_0325/FTT0831c genes of F. tularensis suppress proinflammatory cytokines by preventing activation of NF-B signaling. Conclusion: FTL_0325/FTT0831c of Francisella is a key virulence factor and functions as an immunosuppressant. Significance: Understanding of such pathogenic mechanisms will define vaccine candidates to prevent tularemia acquired naturally or through an act of bioterrorism.

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Microbial Proteomics Using Mass Spectrometry

Hines

2012

Microbial Systems Biology

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Proteomic analyses involve a series of intricate, interdependent steps involving approaches and technical issues that must be fully coordinated to obtain the optimal amount of required information about the test subject. Fortunately, many of these steps are common to most test subjects, requiring only modifications to or, in some cases, substitution of some of the steps to ensure they are relevant to the desired objective of a study. This fortunate occurrence creates an essential core of proteomic approaches and techniques that are consistently available for most studies, regardless of test subject. In this chapter, an overview of some of these core approaches, techniques, and mass spectrometric instrumentation is given, while indicating how such steps are useful for and applied to bacterial investigations. To exemplify how such proteomic concepts and techniques are applicable to bacterial investigations, a practical, quantitative method useful for bacterial proteomic analysis is presented with a discussion of possibilities, pitfalls, and some emerging technology to provide a compilation of information from the diverse literature that is intermingled with experimental experience.

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Identification of Francisella tularensis Live Vaccine Strain CuZn Superoxide Dismutase as Critical for Resistance to Extracellularly Generated Reactive Oxygen Species

Cited by 57 publications

References 33 publications

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

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

Identification of a Novel Francisella tularensis Factor Required for Intramacrophage Survival and Subversion of Innate Immune Response

Microbial Proteomics Using Mass Spectrometry

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