Evasion of IFN-γ Signaling by Francisella novicida Is Dependent upon Francisella Outer Membrane Protein C

dc.contributor.authorNallaparaju, Kalyan C.
dc.contributor.authorYu, Jieh-Juen
dc.contributor.authorRodriguez, Stephen A.
dc.contributor.authorZogaj, Xhavit
dc.contributor.authorManam, Srikanth
dc.contributor.authorGuentzel, M. Neal
dc.contributor.authorSeshu, Janakiram
dc.contributor.authorMurthy, Ashlesh K.
dc.contributor.authorChambers, James P.
dc.contributor.authorKlose, Karl E.
dc.contributor.authorArulanandam, Bernard P.
dc.date.accessioned2023-06-16T16:25:03Z
dc.date.available2023-06-16T16:25:03Z
dc.date.issued2011-03-31
dc.description.abstractBackground: Francisella tularensis is a Gram-negative facultative intracellular bacterium and the causative agent of the lethal disease tularemia. An outer membrane protein (FTT0918) of F. tularensis subsp. tularensis has been identified as a virulence factor. We generated a F. novicida (F. tularensis subsp. novicida) FTN_0444 (homolog of FTT0918) fopC mutant to study the virulence-associated mechanism(s) of FTT0918. Methods and Findings: The ΔfopC strain phenotype was characterized using immunological and biochemical assays. Attenuated virulence via the pulmonary route in wildtype C57BL/6 and BALB/c mice, as well as in knockout (KO) mice, including MHC I, MHC II, and µmT (B cell deficient), but not in IFN-γ or IFN-γR KO mice was observed. Primary bone marrow derived macrophages (BMDM) prepared from C57BL/6 mice treated with rIFN-γ exhibited greater inhibition of intracellular ΔfopC than wildtype U112 strain replication; whereas, IFN-γR KO macrophages showed no IFN-γ-dependent inhibition of ΔfopC replication. Moreover, phosphorylation of STAT1 was downregulated by the wildtype strain, but not the fopC mutant, in rIFN-γ treated macrophages. Addition of NG-monomethyl-L-arginine, an NOS inhibitor, led to an increase of ΔfopC replication to that seen in the BMDM unstimulated with rIFN-γ. Enzymatic screening of ΔfopC revealed aberrant acid phosphatase activity and localization. Furthermore, a greater abundance of different proteins in the culture supernatants of ΔfopC than that in the wildtype U112 strain was observed. Conclusions: F. novicida FopC protein facilitates evasion of IFN-γ-mediated immune defense(s) by down-regulation of STAT1 phosphorylation and nitric oxide production, thereby promoting virulence. Additionally, the FopC protein also may play a role in maintaining outer membrane stability (integrity) facilitating the activity and localization of acid phosphatases and other F. novicida cell components.en_US
dc.description.departmentMolecular Microbiology and Immunologyen_US
dc.description.departmentNeuroscience, Developmental and Regenerative Biology
dc.identifier.citationNallaparaju, K. C., Yu, J.-J., Rodriguez, S. A., Zogaj, X., Manam, S., Guentzel, M. N., . . . Arulanandam, B. P. (2011). Evasion of IFN-γ Signaling by Francisella novicida Is Dependent upon Francisella Outer Membrane Protein C. PLOS ONE, 6(3), e18201. doi:10.1371/journal.pone.0018201en_US
dc.identifier.issn1932-6203
dc.identifier.otherhttps://doi.org/10.1371/journal.pone.0018201
dc.identifier.urihttps://hdl.handle.net/20.500.12588/1896
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.titleEvasion of IFN-γ Signaling by Francisella novicida Is Dependent upon Francisella Outer Membrane Protein Cen_US
dc.typeArticleen_US

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