<i>Francisella tularensis</i>
            Replicates within Alveolar Type II Epithelial Cells In Vitro and In Vivo following Inhalation

Hall, Joshua D.; Craven, Robin R.; Fuller, James R.; Pickles, Raymond J.; Kawula, Thomas H.

doi:10.1128/iai.01254-06

Cited by 122 publications

(135 citation statements)

References 19 publications

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“…This approach is a well established technique for exploring inflammasome activity (12, 13). 293T cells, like type II lung epithelial cells (42), can be infected with Francisella and support intracellular replication (Fig. 3A).…”

Section: Response Of Thp-1 Cells To Infection With Francisella-tlrmentioning

confidence: 99%

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

Atianand

Duffy

Shah

et al. 2011

Journal of Biological Chemistry

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Pathogen-triggered activation of the inflammasome complex leading to caspase-1 activation and IL-1␤ production involves similar sensor proteins between mouse and human. However, the specific sensors used may differ between infectious agents and host species. In mice, Francisella infection leads to seemingly exclusive activation of the Aim2 inflammasome with no apparent role for Nlrp3. Here we examine the IL-1␤ response of human cells to Francisella infection. Francisella strains exhibit differences in IL-1␤ production by influencing induction of IL-1␤ and ASC transcripts. Unexpectedly, our results demonstrate that Francisella activates the NLRP3 inflammasome in human cells. Innate immune responses to pathogens are initiated by recognition of pathogen-associated molecular patterns by both extracellular and intracellular sensors (1-3). Pathogen-associated molecular pattern recognition by members of the Toll-like receptor (TLR) 3 family result in the activation of the NF-B, MAPK, and/or interferon regulatory factor signaling pathways depending on the specific TLR engaged (1, 4 -8). Intracellular receptors of the MAVS/RIG-I family act similarly and are involved in recognition of viral nucleic acids (9, 10). Thus, production of inflammatory cytokines and chemokines such as TNF␣, IL-6, and MCP-1 in response to infection generally follows activation via these receptors. The inflammatory cytokines IL-1␤ and IL-18, however, require processing by caspase-1 to produce their active forms (11). Pathogen-associated molecular patterns and danger-associated molecular patterns activate various members of the nucleotide binding leucine-rich receptor (NLR) family in the cytoplasm, resulting in the assembly of an NLR containing, multiprotein complex (the inflammasome) that recruits and activates caspase-1 leading to IL-1␤ processing (12, 13). Although CARD domain-containing NLRs (e.g. Ipaf) can directly interact with caspase-1, most inflammasomes are assembled by Pyrin domain containing NLRs (NLRPs), which recruit caspase-1 indirectly through the adapter molecule ASC (14).Francisella tularensis is the causative agent of tularemia and a potential bioweapon (15). Pulmonary infection with even a single, virulent F. tularensis bacterium is potentially lethal if untreated (16,17). For humans, the type A strain, SchuS4 (F. tularensis sp. tularensis) results in the highest mortality, whereas neither the attenuated type B live vaccine strain LVS (F. tularensis sp. holarctica) or the U112 strain (Francisella tularensis sp. novicida) are virulent. In mice however, the SchuS4, LVS and U112 strains are lethal (18). Because of its importance in controlling bacterial infection and promoting adaptive immunity, the innate immune response to F. tularensis has been an area of recent interest. In mouse models of tularemia, the macrophage response to F. tularensis LVS is heavily reliant upon TLR2 as TLR2-deficient macrophages fail to produce TNF␣, IL-6, and other NF-B dependent proinflammatory cytokines (19,20). Mouse macrophages infected with U112 ...

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Section: Response Of Thp-1 Cells To Infection With Francisella-tlrmentioning

confidence: 99%

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

Atianand

Duffy

Shah

et al. 2011

Journal of Biological Chemistry

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“…Because IL-17Rs are expressed on a wide variety of cell types, including leukocytes and epithelial cells, and many of these cell types can support the growth of Francisella species (13,32,33), we investigated the direct impact of IL-17A on control of LVS growth in host cells. Interestingly, we found that IL-17A can cooperate with IFN-g to inhibit growth of LVS in alveolar epithelial cells and macrophages.…”

Section: Cd8mentioning

confidence: 99%

“…The in vitro culture and LVS infection of TC-1 cells has been previously described (13). One day prior to infection, RAWand TC-1 cells were plated at 2 3 10 5 viable cells per well in 24-well plates in cDMEM.…”

Section: Animals Infections and Determination Of Bacterial Organ Bumentioning

confidence: 99%

Lung CD4−CD8− Double-Negative T Cells Are Prominent Producers of IL-17A and IFN-γ during Primary Respiratory Murine Infection with Francisella tularensis Live Vaccine Strain

Cowley

Meierovics

Frelinger

et al. 2010

The Journal of Immunology

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For several intracellular infections, pulmonary vaccination provides measurably better protection against pulmonary challenge. The unique factors that contribute to pulmonary immune responses are not well characterized. In this study, we show that CD4−CD8− double negative (DN) T cells are a major responding T cell subset in the lungs of mice during pulmonary Francisella tularensis live vaccine strain (LVS) infection. DN T cells were a minor (<2%) subset in spleens and lungs of mice during sublethal intradermal infection with LVS. In contrast, they were a major responding T cell subset in lungs during pulmonary LVS infection, producing large quantities of IFN-γ and IL-17A. The numbers of IL-17A+ DN T cells in the lungs exceeded that of CD4+ and CD8+ T cells on day 7 postinfection; by day 14 postinfection, all three IL-17A–producing T cell subsets were present in equivalent numbers. CD4+, CD8+, and DN T cell production of IL-17A was not observed in the spleens of pulmonary-infected mice or the lungs and spleens of intradermally infected mice. Correspondingly, IL-17A knockout mice were more susceptible to respiratory than intradermal LVS infection, with delayed clearance 1–3 wk postinfection. Finally, in vitro treatment of LVS-infected macrophages and alveolar type II epithelial cells with IFN-γ and IL-17A affected significantly greater LVS growth control than treatment with either cytokine alone. The data presented in this study demonstrate that DN cells contribute to production of IL-17A and IFN-γ in the lungs during inhalational Francisella infection and that these cytokines additively activate host cells to control LVS intracellular growth.

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“…Francisella infects primarily monocytes and macrophages [2], and has the ability to escape from the host cell phagosome and replicate in the cytoplasm. The subspecies F. novicida is commonly used as an infection model because it is non-virulent in normal humans yet leads to fatal tularemia in mouse models [3].…”

Section: Introductionmentioning

confidence: 99%

IFNγ enhances IL‐23 production during Francisella infection of human monocytes

Butchar¹,

Parsa²,

Marsh³

et al. 2008

FEBS Letters

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We previously demonstrated that monocytes produce IL-23 during Francisella infection, and that IL-23 induces IFNc from NK cells. Here, we demonstrate that IFNc-priming of monocytes enhances IL-23 production during Francisella infection. This effect was seen on the IL12/23 p40 subunit. Induction of IL-12/23 p40 is reported to be enhanced by IRF-1 and IRF-8. Consistently, microarray analysis of IFNc-treated monocytes revealed a significant induction of the IRFs. Interestingly, IFNcprimed monocytes produced IL-12 p70, a more potent inducer of IFNc than IL-23. We propose that there exists an amplification loop between monocyte IL-23 and NK/T cell IFNc that leads to IL-12 p70 production.

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Francisella tularensis Replicates within Alveolar Type II Epithelial Cells In Vitro and In Vivo following Inhalation

Cited by 122 publications

References 19 publications

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

Lung CD4−CD8− Double-Negative T Cells Are Prominent Producers of IL-17A and IFN-γ during Primary Respiratory Murine Infection with Francisella tularensis Live Vaccine Strain

IFNγ enhances IL‐23 production during Francisella infection of human monocytes

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