Control of Francisella tularensis intracellular growth by pulmonary epithelial cells

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Journal titlePLoS ONE
Article numbere0138565
Subjectgamma interferon; inducible nitric oxide synthase; interleukin 17; organonitrogen derivative; reactive nitrogen intermediate; tumor necrosis factor alpha; animal cell; animal experiment; animal model; animal tissue; bacterial growth; bacterial growth control; bacterial strain; bacterial virulence; correlational study; epithelium cell; Francisella tularensis; gene expression regulation; growth inhibition; immune response; macrophage; male; mouse; nonhuman; NOS2 gene; pulmonary epithelial cell; respiratory tract infection; tularemia
AbstractThe virulence of F. tularensis is often associated with its ability to grow in macrophages, although recent studies show that Francisella proliferates in multiple host cell types, including pulmonary epithelial cells. Thus far little is known about the requirements for killing of F. tularensis in the non-macrophage host cell types that support replication of this organism. Here we sought to address this question through the use of a murine lung epithelial cell line (TC-1 cells). Our data show that combinations of the cytokines IFN-γ, TNF, and IL-17A activated murine pulmonary epithelial cells to inhibit the intracellular growth of the F. tularensis Live Vaccine Strain (LVS) and the highly virulent F. tularensis Schu S4 strain. Although paired combinations of IFN-γ, TNF, and IL-17A all significantly controlled LVS growth, simultaneous treatment with all three cytokines had the greatest effect on LVS growth inhibition. In contrast, Schu S4 was more resistant to cytokine-induced growth effects, exhibiting significant growth inhibition only in response to all three cytokines. Since one of the main antimicrobial mechanisms of activated macrophages is the release of reactive nitrogen intermediates (RNI) via the activity of iNOS, we investigated the role of RNI and iNOS in Francisella growth control by pulmonary epithelial cells. NOS2 gene expression was significantly up-regulated in infected, cytokine-treated pulmonary epithelial cells in a manner that correlated with LVS and Schu S4 growth control. Treatment of LVS-infected cells with an iNOS inhibitor significantly reversed LVS killing in cytokine-treated cultures. Further, we found that mouse pulmonary epithelial cells produced iNOS during in vivo respiratory LVS infection. Overall, these data demonstrate that lung epithelial cells produce iNOS both in vitro and in vivo, and can inhibit Francisella intracellular growth via reactive nitrogen intermediates.
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AffiliationNational Research Council Canada (NRC-CNRC); Human Health Therapeutics
Peer reviewedYes
NPARC number21277324
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Record identifier05d42fa9-085b-4694-9427-b06be84c7cb6
Record created2016-03-09
Record modified2016-05-09
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