Repression of bacterial lipoprotein production by Francisella novicida facilitates evasion of innate immune recognition

• Type of Material: Article
• Authors: Crystal L. Jones, Emory University; Timothy R. Sampson, Emory University; Helder Imoto Nakaya, Emory University; Bali Pulendran, Emory University; David S Weiss, Emory University
• Language: English
• Date: 2012-10
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Blackwell Publishing Ltd
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2012.01816.x/abstract
• Title of Journal or Parent Work: Cellular Microbiology
• ISSN: 1462-5814
• Volume: 14
• Issue: 10
• Start Page: 1531
• End Page: 1543
• Grant/Funding Information: We are grateful to the Vanderbilt Genome Sciences Resource which is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Digestive Disease Center (P30 DK58404), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956), for microarray processing. The Resource collaborates with the Computational Genomics Core of the Center Human Genetic Research and the Center for Quantitative Sciences.; The project described was supported by NIH grant #U54 AI057157 from the Southeastern Regional Center of Excellence for Emerging Infections and Biodefense.; This research was also supported by the National Science Foundation Graduate Research Fellowship (C.L.J. and T.R.S.), as well as the ARCS Foundation (T.R.S.).; We thank the Emory Proteomics Core, which is supported in part by the Proteomics Core of the Emory Neuroscience NINDS Core Facilities grant, P30NS055077.
• Research Categories: Biology, Microbiology; Health Sciences, Pathology; Health Sciences, Immunology

Abstract

Innate recognition systems, including the Toll-like receptors (TLRs), play a critical role in activating host defenses and proinflammatory pathways in response to infection. Pathogens have developed strategies to subvert TLRs in order to survive and replicate within the host. The model intracellular pathogen, Francisella novicida, modulates host defenses to promote survival and replication in macrophages. TLR2, which recognizes bacterial lipoproteins (BLPs), is critical for activating host defenses and proinflammatory cytokine production in response to Francisella infection. Here we show that the F. novicida protein FTN_0757 acts to repress BLP production, dampening TLR2 activation. The ΔFTN_0757 mutant strain induced robust TLR2-dependent cytokine production in macrophages compared to wild-type bacteria, and produced increased amounts of BLPs. The deletion of one BLP (FTN_1103) from ΔFTN_0757 decreased the total BLP concentration to near wild-type levels and correlated with a decrease in the induction of TLR2 signaling. The overproduction of BLPs also contributed to the in vivo attenuation of the ΔFTN_0757 mutant, which was significantly rescued when FTN_1103 was deleted. Taken together, these data reveal a novel mechanism of immune evasion by the downregulation of BLP expression to subvert TLR2 activation, which is likely used by numerous other intracellular bacterial pathogens.