Subversion of innate immune responses by<i>Francisella</i>involves the disruption of TRAF3 and TRAF6 signalling complexes

Putzová, Daniela; Panda, Swarupa; Härtlová, Anetta; Stulı́k, Jiřı́; Gekara, Nelson O.

doi:10.1111/cmi.12769

Cited by 12 publications

(18 citation statements)

References 55 publications

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“…In this light, it is interesting that components of cytosolic DNA-sensing pathways are not among phosphoproteins differentially regulated between WTand ⌬dsbA-infected DCs. It was previously shown that ⌬dsbA of LVS background stimulates the higher production of IFN-␤ than its WT counterpart (70). In contrast, the expression of Ifnb1 in DCs infected by FSC200 WT and ⌬dsbA is lower than in LVS-infected DCs and virtually indistinguishable from uninfected cells.…”

Section: Discussionmentioning

confidence: 90%

The Early Dendritic Cell Signaling Induced by Virulent Francisella tularensis Strain Occurs in Phases and Involves the Activation of Extracellular Signal-Regulated Kinases (ERKs) and p38 In the Later Stage

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Putzová

et al. 2018

Molecular & Cellular Proteomics

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Dendritic cells (DCs) infected by are poorly activated and do not undergo classical maturation process. Although reasons of such unresponsiveness are not fully understood, their impact on the priming of immunity is well appreciated. Previous attempts to explain the behavior of-infected DCs were hypothesis-driven and focused on events at later stages of infection. Here, we took an alternative unbiased approach by applying methods of global phosphoproteomics to analyze the dynamics of cell signaling in primary DCs during the first hour of infection by Presented results show that the early response of DCs to occurs in phases and that ERK and p38 signaling modules induced at the later stage are differentially regulated by virulent and attenuated Δ strain. These findings imply that the temporal orchestration of host proinflammatory pathways represents the integral part of life-cycle inside hijacked DCs.

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Section: Discussionmentioning

confidence: 90%

The Early Dendritic Cell Signaling Induced by Virulent Francisella tularensis Strain Occurs in Phases and Involves the Activation of Extracellular Signal-Regulated Kinases (ERKs) and p38 In the Later Stage

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Putzová

et al. 2018

Molecular & Cellular Proteomics

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“…Following inhalation of bacteria, lung DC and alveolar macrophages are targeted by Ft for invasion and replication. Ft deploys several effective evasion strategies to counteract host immune defenses in both the extracellular space and in intracellular compartments [15][16][17]. In addition, virulent Ft can actively suppress pro-inflammatory cytokine responses by human monocytes [18].…”

Section: Introductionmentioning

confidence: 99%

Production of IFN-γ by splenic dendritic cells during innate immune responses against Francisella tularensis LVS depends on MyD88, but not TLR2, TLR4, or TLR9

et al. 2020

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Production of IFN-γ is a key innate immune mechanism that limits replication of intracellular bacteria such as Francisella tularensis (Ft) until adaptive immune responses develop. Previously, we demonstrated that the host cell types responsible for IFN-γ production in response to murine Francisella infection include not only natural killer (NK) and T cells, but also a variety of myeloid cells. However, production of IFN-γ by mouse dendritic cells (DC) is controversial. Here, we directly demonstrated substantial production of IFN-γ by DC, as well as hybrid NK-DC, from LVS-infected wild type C57BL/6 or Rag1 knockout mice. We demonstrated that the numbers of conventional DC producing IFN-γ increased progressively over the course of 8 days of LVS infection. In contrast, the numbers of conventional NK cells producing IFN-γ, which represented about 40% of non-B/T IFN-γ-producing cells, peaked at day 4 after LVS infection and declined thereafter. This pattern was similar to that of hybrid NK-DC. To further confirm IFN-γ production by infected cells, DC and neutrophils were sorted from naïve and LVS-infected mice and analyzed for gene expression. Quantification of LVS by PCR revealed the presence of Ft DNA not only in macrophages, but also in highly purified, IFN-γ producing DC and neutrophils. Finally, production of IFN-γ by infected DC was confirmed by immunohistochemistry and confocal microscopy. Notably, IFN-γ production patterns similar to those in wild type mice were observed in cells derived from LVSinfected TLR2, TLR4, and TLR2xTLR9 knockout (KO) mice, but not from MyD88 KO mice. Taken together, these studies demonstrate the pivotal roles of DC and MyD88 in IFN-γ production and in initiating innate immune responses to this intracellular bacterium.

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“…Once in the cytosol, F. tularensis replicates robustly, eventually triggering host cell death, which contributes to bacterial release, dissemination, and infection of additional host cells (9). Early during infection, F. tularensis actively downmodulates the host's proinflammatory responses (12)(13)(14)(15)(16)(17). In addition, F. tularensis actively dampens host programmed cell death responses during infection, presumably to preserve intracellular replicative niches (18)(19)(20)(21)(22)(23)(24).…”

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Contributions of TolC Orthologs to Francisella tularensis Schu S4 Multidrug Resistance, Modulation of Host Cell Responses, and Virulence

et al. 2019

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Francisella tularensis is a Gram-negative, facultative intracellular pathogen and the causative agent of tularemia. Previous studies with the attenuated live vaccine strain (LVS) identified a role for the outer membrane protein TolC in modulation of host cell responses during infection and virulence in the mouse model of tularemia. TolC is an integral part of efflux pumps that export small molecules and type I secretion systems that export a range of bacterial virulence factors. In this study, we analyzed TolC and its two orthologs, FtlC and SilC, present in the fully virulent F. tularensis Schu S4 strain for their contributions to multidrug efflux, suppression of innate immune responses, and virulence. We found that each TolC ortholog participated in multidrug efflux, with overlapping substrate specificities for TolC and FtlC and a distinct substrate profile for SilC. In contrast to their shared roles in drug efflux, only TolC functioned in the modulation of macrophage apoptotic and proinflammatory responses to Schu S4 infection, consistent with a role in virulence factor delivery to host cells. In agreement with previous results with the LVS, the Schu S4 ΔtolC mutant was highly attenuated for virulence in mice by both the intranasal and intradermal routes of infection. Unexpectedly, FtlC was also critical for Schu S4 virulence, but only by the intradermal route. Our data demonstrate a conserved and critical role for TolC in modulation of host immune responses and Francisella virulence and also highlight strain-and route-dependent differences in the pathogenesis of tularemia.

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Subversion of innate immune responses byFrancisellainvolves the disruption of TRAF3 and TRAF6 signalling complexes

Cited by 12 publications

References 55 publications

The Early Dendritic Cell Signaling Induced by Virulent Francisella tularensis Strain Occurs in Phases and Involves the Activation of Extracellular Signal-Regulated Kinases (ERKs) and p38 In the Later Stage

The Early Dendritic Cell Signaling Induced by Virulent Francisella tularensis Strain Occurs in Phases and Involves the Activation of Extracellular Signal-Regulated Kinases (ERKs) and p38 In the Later Stage

Production of IFN-γ by splenic dendritic cells during innate immune responses against Francisella tularensis LVS depends on MyD88, but not TLR2, TLR4, or TLR9

Contributions of TolC Orthologs to Francisella tularensis Schu S4 Multidrug Resistance, Modulation of Host Cell Responses, and Virulence

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