title: An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity.
abstract: Type I IFNs were discovered as the primary antiviral cytokines and are now known to serve critical functions in host defense against bacterial pathogens. Accordingly, established mediators of IFN antiviral activity may mediate previously unrecognized antibacterial functions. RNase-L is the terminal component of an RNA decay pathway that is an important mediator of IFN-induced antiviral activity. Here, we identify a role for RNase-L in the host antibacterial response. RNase-L(-/-) mice exhibited a dramatic increase in mortality after challenge with Bacillus anthracis and Escherichia coli; this increased susceptibility was due to a compromised immune response resulting in increased bacterial load. Investigation of the mechanisms of RNase-L antibacterial activity indicated that RNase-L is required for the optimal induction of proinflammatory cytokines that play essential roles in host defense from bacterial pathogens. RNase-L also regulated the expression of the endolysosomal protease, cathepsin-E, and endosome-associated activities, that function to eliminate internalized bacteria and may contribute to RNase-L antimicrobial action. Our results reveal a unique role for RNase-L in the antibacterial response that is mediated through multiple mechanisms. As a regulator of fundamental components of the innate immune response, RNase-L represents a viable therapeutic target to augment host defense against diverse microbial pathogens.
authors.affiliation: Graduate Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Li
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Ezelle
authors.forename: Tae-Jin
authors.initials: TJ
authors.lastname: Kang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.forename: Janette
authors.initials: J
authors.lastname: Harro
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Hasday
authors.forename: Saroj K
authors.initials: SK
authors.lastname: Mohapatra
authors.forename: Oswald R
authors.initials: OR
authors.lastname: Crasta
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.forename: Alan S
authors.initials: AS
authors.lastname: Cross
authors.forename: Bret A
authors.initials: BA
authors.lastname: Hassel
mesh_terms: D000818:Animals; D000881:Anthrax / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D001408:Bacillus anthracis / Q000276:immunology; D020059:Cathepsin E / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004722:Endoribonucleases / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D011992:Endosomes / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020871:RNA Stability / Q000235:genetics / Q000276:immunology
chemical_list: D007370:Interferon Type I; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D020059:Cathepsin E; C533926:Ctse protein, mouse