Virulent Type A Francisella tularensis actively suppresses cytokine responses in human monocytes

Gillette, Devyn D.; Curry, Heather M.; Cremer, Thomas; Ravneberg, David; Fatehchand, Kavin; Shah, Prexy; Wewers, Mark D.; Schlesinger, Larry S.; Butchar, Jonathan P.; Tridandapani, Susheela; Gavrilin, Mikhail A.

doi:10.3389/fcimb.2014.00045

Cited by 20 publications

(30 citation statements)

References 62 publications

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“…1). Collectively, these results demonstrate that F. tularensis LVS possesses immunosuppressive properties similar to those reported for F. tularensis SchuS4 (48). (29).…”

Section: F Tularensis Lvs Actively Suppresses Pro-inflammatory Cytoksupporting

confidence: 69%

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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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“…1). Collectively, these results demonstrate that F. tularensis LVS possesses immunosuppressive properties similar to those reported for F. tularensis SchuS4 (48). (29).…”

Section: F Tularensis Lvs Actively Suppresses Pro-inflammatory Cytoksupporting

confidence: 69%

“…SchuS4 induces a dampened pro-inflammatory cytokine response (41,47,48), and this is due to its ability to actively suppress an ongoing inflammatory response (48). However, it is not yet established whether F. tularensis LVS similarly exhibits such a phenomenon.…”

Section: F Tularensis Lvs Actively Suppresses Pro-inflammatory Cytokmentioning

confidence: 98%

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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“…All experiments involving F . tularensis Schu S4 were performed in a BSL3 facility at The Ohio State University as previously described [ 13 ].The first step, priming, was initiated by monocyte incubation with bacteria or various TLR ligands for 30 min. We used LPS from Escherichia coli strain 0111:B4 (Alexis Biochemicals, San Diego, CA), highly purified LPS from F .…”

Section: Methodsmentioning

confidence: 99%

Inflammasome Priming Is Similar for Francisella Species That Differentially Induce Inflammasome Activation

et al. 2015

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Inflammasome activation is a two-step process where step one, priming, prepares the inflammasome for its subsequent activation, by step two. Classically step one can be induced by LPS priming followed by step two, high dose ATP. Furthermore, when IL-18 processing is used as the inflammasome readout, priming occurs before new protein synthesis. In this context, how intracellular pathogens such as Francisella activate the inflammasome is incompletely understood, particularly regarding the relative importance of priming versus activation steps. To better understand these events we compared Francisella strains that differ in virulence and ability to induce inflammasome activation for their relative effects on step one vs. step two. When using the rapid priming model, i.e., 30 min priming by live or heat killed Francisella strains (step 1), followed by ATP (step 2), we found no difference in IL-18 release, p20 caspase-1 release and ASC oligomerization between Francisella strains (F. novicida, F. holarctica –LVS and F. tularensis Schu S4). This priming is fast, independent of bacteria viability, internalization and phagosome escape, but requires TLR2-mediated ERK phosphorylation. In contrast to their efficient priming capacity, Francisella strains LVS and Schu S4 were impaired in inflammasome triggering compared to F. novicida. Thus, observed differences in inflammasome activation by F. novicida, LVS and Schu S4 depend not on differences in priming but rather on their propensity to trigger the primed inflammasome.

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“…Activation of NLRP3 was recently corroborated by another study where human monocytes produced IL-1b in response to Francisella bacteria and ATP [215]; this IL-1b secretion also required K + influx, suggesting an NLRP3dependent mechanism. Perhaps a Francisella effector is able to inhibit NLRP3 activation in mice but not in humans [216], or mice and humans have other potential differences in NLRP3 regulation. Another mouse-human difference concerns Francisella activation of the pyrin inflammasome.…”

Section: Francisellamentioning

confidence: 99%

Bacterial secretion systems and regulation of inflammasome activation

Ratner

Orning

Lien

2016

Journal of Leukocyte Biology

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Innate immunity is critical for host defenses against pathogens, but many bacteria display complex ways of interacting with innate immune signaling, as they may both activate and evade certain pathways. Gram-negative bacteria can exhibit specialized nanomachine secretion systems for delivery of effector proteins into mammalian cells. Bacterial types III, IV, and VI secretion systems (T3SS, T4SS, and T6SS) are known for their impact on caspase-1-activating inflammasomes, necessary for producing bioactive inflammatory cytokines IL-1β and IL-18, key participants of anti-bacterial responses. Here, we discuss how these secretion systems can mediate triggering and inhibition of inflammasome signaling. We propose that a fine balance between secretion system-mediated activation and inhibition can determine net activation of inflammasome activity and control inflammation, clearance, or spread of the infection.

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Virulent Type A Francisella tularensis actively suppresses cytokine responses in human monocytes

Cited by 20 publications

References 62 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

Inflammasome Priming Is Similar for Francisella Species That Differentially Induce Inflammasome Activation

Bacterial secretion systems and regulation of inflammasome activation

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