Role of Primary Human Alveolar Epithelial Cells in Host Defense against
            <i>Francisella tularensis</i>
            Infection

Gentry, Megan S.; Taormina, Joanna; Pyles, Richard B.; Yeager, Linsey A.; Kirtley, Michelle L.; Popov, Vsevolod L.; Klimpel, Gary R.; Eaves-Pyles, Tonyia

doi:10.1128/iai.00157-07

Cited by 45 publications

(48 citation statements)

References 58 publications

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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%

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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Section: Cd8mentioning

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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“…However, both of these subspecies are attenuated in humans. Due to this attenuation, it is unsurprising that following infection with these strains, human DCs and monocytes are activated to produce proinflammatory cytokines and upregulate receptors associated with antigen presentation and that DCs can easily control bacterial replication when exposed to the appropriate stimulus following infection (22,26,27,31). However, this does not necessarily reflect how human cells, in particular DCs, might behave when infected with a more formidable and virulent strain of F. tularensis.…”

mentioning

confidence: 99%

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

2009

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The gram-negative, facultative intracellular bacterium Francisella tularensis causes acute, lethal pneumonic disease following infection with only 10 CFU. The mechanisms used by the bacterium to accomplish this in humans are unknown. Here, we demonstrate that virulent, type A F. tularensis strain Schu S4 efficiently infects and replicates in human myeloid dendritic cells (DCs). Despite exponential replication over time, Schu S4 failed to stimulate transforming growth factor ␤, interleukin-10 (IL-10), IL-6, IL-1␤, IL-12, tumor necrosis factor alpha, alpha interferon (IFN-␣), and IFN-␤ throughout the course of infection. Schu S4 also suppressed the ability of directly infected DCs to respond to different Toll-like receptor agonists. Furthermore, we also observed functional inhibition of uninfected bystander cells. This inhibition was mediated, in part, by a heat-stable bacterial component. Lipopolysaccharide (LPS) from Schu S4 was present in Schu S4-conditioned medium. However, Schu S4 LPS was weakly inflammatory and failed to induce suppression of DCs at concentrations below 10 g/ml, and depletion of Schu S4 LPS did not significantly alleviate the inhibitory effect of Schu S4-conditioned medium in uninfected human DCs. Together, these data show that type A F. tularensis interferes with the ability of a central cell type of the immune system, DCs, to alert the host of infection both intra-and extracellularly. This suggests that immune dysregulation by F. tularensis operates on a broader and more comprehensive scale than previously appreciated.Francisella tularensis is a gram-negative, facultative intracellular bacterium and the causative agent of tularemia. Although the bacteria was identified nearly 100 years ago, the nature of its interaction with host cells and tissues has remained largely undefined until recent times. The unfortunate realization of the potential of F. tularensis as a biological weapon has resulted in a resurgence of research on tularemia. Much of our recent understanding of tularemia pathogenesis has come from manipulation of the mouse model of Francisella infections. While these murine studies have yielded many important advances in our understanding of tularemia pathogenesis, very little is understood about how Francisella, especially the most virulent type A strains such as Schu S4, interacts with human cells.Dendritic cells (DCs) serve as a central cell type in the immune system, bridging the innate and adaptive immune response to effectively eradicate invading pathogens.

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“…ATI cells reside in the alveoli of the lung where they are separated from inspired air from the blood in the capillaries [24]. ATII cells cover approximately 5% of the alveolar surface but constitute 15% of total lung cells [25].…”

Section: Discussionmentioning

confidence: 99%

“…HPAEpiCs have been reported to contain > 96% ATII cells [25] and are known to respond to foreign RNA stimuli (Figure 1). In this present study, we introduced poly(I:C) into cells to test for a role of RLR signaling.…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

Chiba

Matsumiya

Satoh

et al. 2015

Biochemical and Biophysical Research Communications

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Upon viral infection, the cytoplasmic viral sensor retinoic acid-inducible gene-I (RIG-I) recognizes viral RNA to activate antiviral signaling to induce type I interferon (IFN).RIG-I-like receptors (RLRs) activate antiviral signaling in a tissue-specific manner. The molecular mechanism underlying antiviral signaling in the respiratory system remains unclear.We studied antiviral signaling in the lower respiratory tract (LRT), which is the site of many harmful viral infections. Epithelial cells of the LRT can be roughly divided into two groups: bronchial epithelial cells (BECs) and pulmonary alveolar epithelial cells (AECs). These two cell types exhibit different phenotypes; therefore, we hypothesized that these cells may play different roles in antiviral innate immunity. We found that BECs exhibited higher antiviral activity than AECs. TNF receptor-associated factor 3 (TRAF3) has been shown to be a crucial molecule in RLR signaling. The expression levels of TRAF3 and TRAF5, which have conserved domains that are nearly identical, in the LRT were examined. We found that the bronchus exhibited the highest expression levels of TRAF3 and TRAF5 in the LRT. These findings suggest the importance of the bronchus in antiviral innate immunity in the LRT and indicate that TRAF3 and TRAF5 may contribute to RLR signaling.

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Role of Primary Human Alveolar Epithelial Cells in Host Defense against Francisella tularensis Infection

Cited by 45 publications

References 58 publications

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

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

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

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