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

Pascalis, Roberto De; Rossi, Amy; Mittereder, Lara; Takeda, Kazuyo; Akue, Adovi; Kurtz, Sherry L.; Elkins, Karen L.

doi:10.1371/journal.pone.0237034

Cited by 5 publications

(4 citation statements)

References 58 publications

(68 reference statements)

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“…In contrast, not only did the MYD88 −/− mice succumb to infection faster with the WT LVS, but also the virulence of the ∆ tolC mutant was fully restored. Our data agree with previous reports that MYD88 serves a broader role than TLR2 in mediating host protection against Francisella ( 26 , 38 - 64 - 64 ). MYD88 is required for the secretion of IFN-γ in response to F. tularensis infection, and IFN-γ is capable of restricting the growth of virulent F. tularensis both in vitro and in vivo ( 65 - 67 ).…”

Section: Discussionsupporting

confidence: 93%

Francisella tularensis disrupts TLR2-MYD88-p38 signaling early during infection to delay apoptosis of macrophages and promote virulence in the host

Benziger

Kopping

McLaughlin

et al. 2023

mBio

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Francisella tularensis is a zoonotic pathogen and the causative agent of tularemia. F. tularensis replicates to high levels within the cytosol of macrophages and other host cells while subverting the host response to infection. Critical to the success of F. tularensis is its ability to delay macrophage apoptosis to maintain its intracellular replicative niche. However, the host-signaling pathway(s) modulated by F. tularensis to delay apoptosis are poorly characterized. The outer membrane channel protein TolC is required for F. tularensis virulence and its ability to suppress apoptosis and cytokine expression during infection of macrophages. We took advantage of the F. tularensis ∆ tolC mutant phenotype to identify host pathways that are important for activating macrophage apoptosis and that are disrupted by the bacteria. Comparison of macrophages infected with wild-type or ∆ tolC F. tularensis revealed that the bacteria interfere with TLR2-MYD88-p38 signaling at early times post infection to delay apoptosis, dampen innate host responses, and preserve the intracellular replicative niche. Experiments using the mouse pneumonic tularemia model confirmed the in vivo relevance of these findings, revealing contributions of TLR2 and MYD88 signaling to the protective host response to F. tularensis , which is modulated by the bacteria to promote virulence . IMPORTANCE Francisella tularensis is a Gram-negative intracellular bacterial pathogen and the causative agent of the zoonotic disease tularemia. F. tularensis , like other intracellular pathogens, modulates host-programmed cell death pathways to ensure its replication and survival. We previously identified the outer membrane channel protein TolC as required for the ability of F. tularensis to delay host cell death. However, the mechanism by which F. tularensis delays cell death pathways during intracellular replication is unclear despite being critical to pathogenesis. In the present study, we address this gap in knowledge by taking advantage of ∆ tolC mutants of F. tularensis to uncover signaling pathways governing host apoptotic responses to F. tularensis and which are modulated by the bacteria during infection to promote virulence. These findings reveal mechanisms by which intracellular pathogens subvert host responses and enhance our understanding of the pathogenesis of tularemia.

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Section: Discussionsupporting

confidence: 93%

Francisella tularensis disrupts TLR2-MYD88-p38 signaling early during infection to delay apoptosis of macrophages and promote virulence in the host

Benziger

Kopping

McLaughlin

et al. 2023

mBio

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“…It is not excluded that cDC1 and cDC2, especially in resistant C57BL/6 mice, are substantial sources of IFN-γ and CCL3 not only during the early stages of mousepox, but also during recovery, since at 14 dpi most cDC1 cells produced this cytokine. This observation aligns with prior research showing that both murine and human cDC1 and cDC2 cells are key producers of IFN-γ in response to viruses [ 26 , 45 , 46 ] and various other intracellular pathogens or their components [ 47 , 48 , 49 , 50 ]. It is possible that the heightened production of Th1-polarizing cytokines by cDC subpopulations, particularly cDC1, in C57BL/6 mice during the early stages of mousepox could positively influence the timing, kinetics, and intensity of the protective Th1 immune response in resistant strains.…”

Section: Discussionsupporting

confidence: 90%

Differential Activation of Splenic cDC1 and cDC2 Cell Subsets following Poxvirus Infection of BALB/c and C57BL/6 Mice

Szulc-Dąbrowska,

Biernacka,

Koper

et al. 2023

Cells

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Conventional dendritic cells (cDCs) are innate immune cells that play a pivotal role in inducing antiviral adaptive immune responses due to their extraordinary ability to prime and polarize naïve T cells into different effector T helper (Th) subsets. The two major subpopulations of cDCs, cDC1 (CD8α+ in mice and CD141+ in human) and cDC2 (CD11b+ in mice and CD1c+ in human), can preferentially polarize T cells toward a Th1 and Th2 phenotype, respectively. During infection with ectromelia virus (ECTV), an orthopoxvirus from the Poxviridae family, the timing and activation of an appropriate Th immune response contributes to the resistance (Th1) or susceptibility (Th2) of inbred mouse strains to the lethal form of mousepox. Due to the high plasticity and diverse properties of cDC subpopulations in regulating the quality of a specific immune response, in the present study we compared the ability of splenic cDC1 and cDC2 originating from different ECTV-infected mouse strains to mature, activate, and polarize the Th immune response during mousepox. Our results demonstrated that during early stages of mousepox, both cDC subsets from resistant C57BL/6 and susceptible BALB/c mice were activated upon in vivo ECTV infection. These cells exhibited elevated levels of surface MHC class I and II, and co-stimulatory molecules and showed enhanced potential to produce cytokines. However, both cDC subsets from BALB/c mice displayed a higher maturation status than that of their counterparts from C57BL/6 mice. Despite their higher activation status, cDC1 and cDC2 from susceptible mice produced low amounts of Th1-polarizing cytokines, including IL-12 and IFN-γ, and the ability of these cells to stimulate the proliferation and Th1 polarization of allogeneic CD4+ T cells was severely compromised. In contrast, both cDC subsets from resistant mice produced significant amounts of Th1-polarizing cytokines and demonstrated greater capability in differentiating allogeneic T cells into Th1 cells compared to cDCs from BALB/c mice. Collectively, our results indicate that in the early stages of mousepox, splenic cDC subpopulations from the resistant mouse strain can better elicit a Th1 cell-mediated response than the susceptible strain can, probably contributing to the induction of the protective immune responses necessary for the control of virus dissemination and for survival from ECTV challenge.

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“…IL-15 expression in DCs is upregulated immediately after Listeria infection (59). Following Francisella tularensis infection, DCs accounted for 15-50% of innate IFNg producing cells (60). As depletion of IFNg in infected Il15ra-/-mice rendered them susceptible to low-dose Listeria infection (Figure 7B), it is possible that the DCs are a potential source of early IFNg in the spleens of Il15ra-/-mice.…”

Section: Discussionmentioning

confidence: 99%

IL-15Rα-Independent IL-15 Signaling in Non-NK Cell-Derived IFNγ Driven Control of Listeria monocytogenes

et al. 2021

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Interleukin-15, produced by hematopoietic and parenchymal cells, maintains immune cell homeostasis and facilitates activation of lymphoid and myeloid cell subsets. IL-15 interacts with the ligand-binding receptor chain IL-15Rα during biosynthesis, and the IL-15:IL-15Rα complex is trans-presented to responder cells that express the IL-2/15Rβγc complex to initiate signaling. IL-15-deficient and IL-15Rα-deficient mice display similar alterations in immune cell subsets. Thus, the trimeric IL-15Rαβγc complex is considered the functional IL-15 receptor. However, studies on the pathogenic role of IL-15 in inflammatory and autoimmune diseases indicate that IL-15 can signal independently of IL-15Rα via the IL-15Rβγc dimer. Here, we compared the ability of mice lacking IL-15 (no signaling) or IL-15Rα (partial/distinct signaling) to control Listeria monocytogenes infection. We show that IL-15-deficient mice succumb to infection whereas IL-15Rα-deficient mice clear the pathogen as efficiently as wildtype mice. IL-15-deficient macrophages did not show any defect in bacterial uptake or iNOS expression in vitro. In vivo, IL-15 deficiency impaired the accumulation of inflammatory monocytes in infected spleens without affecting chemokine and pro-inflammatory cytokine production. The inability of IL-15-deficient mice to clear L. monocytogenes results from impaired early IFNγ production, which was not affected in IL-15Rα-deficient mice. Administration of IFNγ partially enabled IL-15-deficient mice to control the infection. Bone marrow chimeras revealed that IL-15 needed for early bacterial control can originate from both hematopoietic and non-hematopoietic cells. Overall, our findings indicate that IL-15-dependent IL-15Rα-independent signaling via the IL-15Rβγc dimeric complex is necessary and sufficient for the induction of IFNγ from sources other than NK/NKT cells to control bacterial pathogens.

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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

Cited by 5 publications

References 58 publications

Francisella tularensis disrupts TLR2-MYD88-p38 signaling early during infection to delay apoptosis of macrophages and promote virulence in the host

Francisella tularensis disrupts TLR2-MYD88-p38 signaling early during infection to delay apoptosis of macrophages and promote virulence in the host

Differential Activation of Splenic cDC1 and cDC2 Cell Subsets following Poxvirus Infection of BALB/c and C57BL/6 Mice

IL-15Rα-Independent IL-15 Signaling in Non-NK Cell-Derived IFNγ Driven Control of Listeria monocytogenes

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