Francisella tularensis Schu S4 O-Antigen and Capsule Biosynthesis Gene Mutants Induce Early Cell Death in Human Macrophages

Stephen R Lindemann; Kaitian Peng; Matthew E Long; Jason R Hunt; Michael A Apicella; Denise M Monack; Lee-Ann H Allen; Bradley D Jones

doi:10.1128/IAI.00863-10

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Francisella tularensis Schu S4 O-Antigen and Capsule Biosynthesis Gene Mutants Induce Early Cell Death in Human Macrophages

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Francisella tularensis Schu S4 O-Antigen and Capsule Biosynthesis Gene Mutants Induce Early Cell Death in Human Macrophages

Stephen R Lindemann, Kaitian Peng, Matthew E Long, Jason R Hunt, Michael A Apicella, Denise M Monack, Lee-Ann H Allen and Bradley D Jones

Infection and immunity, Vol.79(2), pp.581-594

02/2011

DOI: 10.1128/IAI.00863-10

PMCID: PMC3028865

PMID: 21078861

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Abstract

Francisella tularensis is capable of rampant intracellular growth and causes a potentially fatal disease in humans. Whereas many mutational studies have been performed with avirulent strains of Francisella , relatively little has been done with strains that cause human disease. We generated a near-saturating transposon library in the virulent strain Schu S4, which was subjected to high-throughput screening by transposon site hybridization through primary human macrophages, negatively selecting 202 genes. Of special note were genes in a locus of the Francisella chromosome, FTT1236 , FTT1237 , and FTT1238 . Mutants with mutations in these genes demonstrated significant sensitivity to complement-mediated lysis compared with wild-type Schu S4 and exhibited marked defects in O-antigen and capsular polysaccharide biosynthesis. In the absence of complement, these mutants were phagocytosed more efficiently by macrophages than wild-type Schu S4 and were capable of phagosomal escape but exhibited reduced intracellular growth. Microscopic and quantitative analyses of macrophages infected with mutant bacteria revealed that these macrophages exhibited signs of cell death much earlier than those infected with Schu S4. These data suggest that FTT1236 , FTT1237 , and FTT1238 are important for polysaccharide biosynthesis and that the Francisella O antigen, capsule, or both are important for avoiding the early induction of macrophage death and the destruction of the replicative niche.

Molecular Pathogenesis

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Title: Subtitle: Francisella tularensis Schu S4 O-Antigen and Capsule Biosynthesis Gene Mutants Induce Early Cell Death in Human Macrophages
Creators: Stephen R Lindemann - Department of Microbiology, The University of Iowa, Iowa City, Iowa
Kaitian Peng - Department of Microbiology, The University of Iowa, Iowa City, Iowa
Matthew E Long - Department of Microbiology, The University of Iowa, Iowa City, Iowa
Jason R Hunt - Department of Microbiology, The University of Iowa, Iowa City, Iowa
Michael A Apicella - Department of Microbiology, The University of Iowa, Iowa City, Iowa
Denise M Monack - Department of Microbiology, The University of Iowa, Iowa City, Iowa
Lee-Ann H Allen - Department of Microbiology, The University of Iowa, Iowa City, Iowa
Bradley D Jones - Department of Microbiology, The University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: Infection and immunity, Vol.79(2), pp.581-594
DOI: 10.1128/IAI.00863-10
PMID: 21078861
PMCID: PMC3028865
NLM abbreviation: Infect Immun
ISSN: 0019-9567
eISSN: 1098-5522
Publisher: American Society for Microbiology (ASM)
Language: English
Date published: 02/2011
Academic Unit: Microbiology and Immunology; Infectious Diseases; Internal Medicine
Record Identifier: 9984083269602771

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