Bacterial lipoproteins and other factors released by Francisella tularensis modulate human neutrophil lifespan: Effects of a TLR1 SNP on apoptosis inhibition

• Type of Material: Article
• Authors: Lauren C. Kinkead, University of Iowa; Laura C. Whitmore, University of Iowa; Jenna M. McCracken, University of Iowa; Joshua R. Fletcher, University of Iowa; Brandi B. Ketelsen, University of Iowa; Justin W. Kaufman, University of Iowa; Bradley D. Jones, University of Iowa; David Weiss, Emory University; Jason H. Barker, University of Iowa; Lee-Ann H. Allen, University of Iowa
• Language: English
• Date: 2018-02-01
• Publisher: Wiley: 12 months
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Authors Cellular Microbiology Published by John Wiley & Sons Ltd
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/cmi.12795
• Title of Journal or Parent Work: Cellular Microbiology
• ISSN: 1462-5814
• Volume: 20
• Issue: 2
• Start Page: e12795
• End Page: e12795
• Grant/Funding Information: This study was supported by a U.S. Department of Veterans Affairs Merit Review Grant 1I01BX002108 (awarded to L.A.H.A.), National Institutes of Health/National Institute of Allergy and Infectious Diseases U54 AI057160 funds (awarded to L.A.H.A. and B.D.J.) and R01 AI04728 (awarded to J.H.B.).; L.C.K. was supported in part by a predoctoral fellowship via National Institutes of Health/National Institute of Allergy and Infectious Diseases T32 AI007511.
• Keywords: PULMONARY INFECTION; INTRAMACROPHAGE GROWTH; apoptosis; CUTTING EDGE; SNP; NADPH OXIDASE; neutrophils; PROTEIN-KINASE; TOLL-LIKE RECEPTORS; Cell Biology; RESPIRATORY BURST; Microbiology; NOVICIDA; LIVE VACCINE STRAIN; tularaemia; TLR2; ACTIVATION; Science & Technology; lipoproteins; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery; Biology, Microbiology

Abstract

Francisella tularensis infects several cell types including neutrophils, and aberrant neutrophil accumulation contributes to tissue destruction during tularaemia. We demonstrated previously that F. tularensis strains Schu S4 and live vaccine strain markedly delay human neutrophil apoptosis and thereby prolong cell lifespan, but the bacterial factors that mediate this aspect of virulence are undefined. Herein, we demonstrate that bacterial conditioned medium (CM) can delay apoptosis in the absence of direct infection. Biochemical analyses show that CM contained F. tularensis surface factors as well as outer membrane components. Our previous studies excluded roles for lipopolysaccharide and capsule in apoptosis inhibition, and current studies of [ 14 C] acetate-labelled bacteria argue against a role for other bacterial lipids in this process. At the same time, studies of isogenic mutants indicate that TolC and virulence factors whose expression requires FevR or MglA were also dispensable, demonstrating that apoptosis inhibition does not require Type I or Type VI secretion. Instead, we identified bacterial lipoproteins (BLPs) as active factors in CM. Additional studies of isolated BLPs demonstrated dose-dependent neutrophil apoptosis inhibition via a TLR2-dependent mechanism that is significantly influenced by a common polymorphism, rs5743618, in human TLR1. These data provide fundamental new insight into pathogen manipulation of neutrophil lifespan and BLP function.