Working toward the Future: Insights into<i>Francisella tularensis</i>Pathogenesis and Vaccine Development

Pechous, Roger D.; McCarthy, Travis R.; Zahrt, Thomas C.

doi:10.1128/mmbr.00028-09

Cited by 128 publications

(147 citation statements)

References 223 publications

(290 reference statements)

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“…Although F. tularensis infection is uncommon in the general population, the extreme virulence and relatively high mortality rate of F. tularensis infection have led to the classification of F. tularensis as a probable biological warfare agent (3,4). As evidence of its extreme virulence, F. tularensis infection can be initiated with as few as 10 organisms and if left untreated has mortality rates of 30 -60% (5).…”

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confidence: 99%

“…The archetype of an acyl protein thioesterase is human acyl protein thioesterase 1 (hAPT1), 5 which controls essential cellular functions including signal transduction, ion transport, and neural development (16 -18). hAPT1 was recently confirmed as a target for cancer therapeutics, where inhibition of hAPT1 led to partial phenotypic reversion of Ras-dependent cancers (18).…”

mentioning

confidence: 99%

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Large Scale Structural Rearrangement of a Serine Hydrolase from Francisella tularensis Facilitates Catalysis

Filippova

Weston

Kuhn

et al. 2013

Journal of Biological Chemistry

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Background: Acyl protein thioesterases control protein S-acylation at cellular membranes. Results: FTT258 is a serine hydrolase with broad substrate specificity that binds to bacterial membranes and exists in two distinct conformations. Conclusion: Conformational changes in FTT258 are correlated with catalytic activity. Significance: Structural rearrangement dually regulates the membrane binding and catalytic activity of acyl protein thioesterases.

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confidence: 99%

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confidence: 99%

Large Scale Structural Rearrangement of a Serine Hydrolase from Francisella tularensis Facilitates Catalysis

Filippova

Weston

Kuhn

et al. 2013

Journal of Biological Chemistry

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“…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).…”

mentioning

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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“…95). Although human disease is shown to occur via zoonotic transmission from arthropods or other infected animals, F. tularensis has gained increasing attention because of its potential use in bioterrorism (96).…”

Section: Franciscellamentioning

confidence: 99%

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

Stifter¹,

Feng²

2015

The Journal of Immunology

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Type I IFNs are known to inhibit viral replication and mediate protection against viral infection. However, recent studies revealed that these cytokines play a broader and more fundamental role in host responses to infections beyond their well-established antiviral function. Type I IFN induction, often associated with microbial evasion mechanisms unique to virulent microorganisms, is now shown to increase host susceptibility to a diverse range of pathogens, including some viruses. This article presents an overview of the role of type I IFNs in infections with bacterial, fungal, parasitic, and viral pathogens and discusses the key mechanisms mediating the regulatory function of type I IFNs in pathogen clearance and tissue inflammation.

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Working toward the Future: Insights intoFrancisella tularensisPathogenesis and Vaccine Development

Cited by 128 publications

References 223 publications

Large Scale Structural Rearrangement of a Serine Hydrolase from Francisella tularensis Facilitates Catalysis

Large Scale Structural Rearrangement of a Serine Hydrolase from Francisella tularensis Facilitates Catalysis

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

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

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