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

Lauren C Kinkead; Laura C Whitmore; Jenna M McCracken; Joshua R Fletcher; Brandi B Ketelsen; Justin W Kaufman; Bradley D Jones; David S Weiss; Jason H Barker; Lee‐Ann H Allen

doi:10.1111/cmi.12795

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

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

Lauren C Kinkead, Laura C Whitmore, Jenna M McCracken, Joshua R Fletcher, Brandi B Ketelsen, Justin W Kaufman, Bradley D Jones, David S Weiss, Jason H Barker and Lee‐Ann H Allen

Cellular microbiology, Vol.20(2), e12795

02/2018

DOI: 10.1111/cmi.12795

PMCID: PMC5764820

PMID: 29063667

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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 [14C] 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.

Apoptosis

Lipoproteins

SNP

neutrophils

tularaemia

TLR2

Details

Title: Subtitle: Bacterial lipoproteins and other factors released by Francisella tularensis modulate human neutrophil lifespan: Effects of a TLR1 SNP on apoptosis inhibition
Creators: 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 - Iowa City VA Health Care System
Justin W Kaufman - University of Iowa
Bradley D Jones - University of Iowa
David S Weiss - Emory University
Jason H Barker - University of Iowa
Lee‐Ann H Allen - Iowa City VA Health Care System
Resource Type: Journal article
Publication Details: Cellular microbiology, Vol.20(2), e12795
DOI: 10.1111/cmi.12795
PMID: 29063667
PMCID: PMC5764820
NLM abbreviation: Cell Microbiol
ISSN: 1462-5814
eISSN: 1462-5822
Number of pages: 1
Grant note: U.S. Department of Veterans Affairs (1I01BX002108) National Institute of Allergy and Infectious Diseases (R01 AI04728; T32 AI007511; U54 AI057160)
Language: English
Date published: 02/2018
Academic Unit: Microbiology and Immunology; Infectious Diseases; Stead Family Department of Pediatrics; Internal Medicine
Record Identifier: 9984083299902771

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