PMID- 26980837
OWN - NLM
STAT- MEDLINE
DCOM- 20170110
LR  - 20191227
IS  - 2150-7511 (Electronic)
VI  - 7
IP  - 2
DP  - 2016 Mar 15
TI  - Early Interactions of Murine Macrophages with Francisella tularensis Map to Mouse 
      Chromosome 19.
PG  - e02243
LID - 10.1128/mBio.02243-15 [doi]
LID - e02243-15
AB  - Differences among individuals in susceptibility to infectious diseases can be 
      modulated by host genetics. Much of the research in this field has aimed to 
      identify loci within the host genome that are associated with these differences. 
      In mice, A/J (AJ) and C57BL/6J (B6) mice show differential susceptibilities to 
      various pathogens, including the intracellular pathogen Francisella tularensis. 
      Because macrophages are the main initial target during F. tularensis infection, 
      we explored early interactions of macrophages from these two mouse strains with 
      F. tularensis as well as the genetic factors underlying these interactions. Our 
      results indicate that bacterial interactions with bone marrow-derived macrophages 
      (BMDMs) during early stages of infection are different in the AJ and B6 strains. 
      During these early stages, bacteria are more numerous in B6 than in AJ 
      macrophages and display differences in trafficking and early transcriptional 
      response within these macrophages. To determine the genetic basis for these 
      differences, we infected BMDMs isolated from recombinant inbred (RI) mice derived 
      from reciprocal crosses between AJ and B6, and we followed early bacterial counts 
      within these macrophages. Quantitative trait locus (QTL) analysis revealed a 
      locus on chromosome 19 that is associated with early differences in bacterial 
      counts in AJ versus B6 macrophages. QTL analysis of published data that measured 
      the differential susceptibilities of the same RI mice to an in vivo challenge 
      with F. tularensis confirmed the F. tularensis susceptibility QTL on chromosome 
      19. Overall, our results show that early interactions of macrophages with F. 
      tularensis are dependent on the macrophage genetic background. IMPORTANCE: 
      Francisella tularensis is a highly pathogenic bacterium with a very low 
      infectious dose in humans. Some mechanisms of bacterial virulence have been 
      elucidated, but the host genetic factors that contribute to host resistance or 
      susceptibility are largely unknown. In this work, we have undertaken a genetic 
      approach to assess what these factors are in mice. Analyzing early interactions 
      of macrophages with the bacteria as well as data on overall susceptibility to 
      infection revealed a locus on chromosome 19 that is associated with both 
      phenotypes. In addition, our work revealed differences in the early macrophage 
      response between macrophages with different genetic backgrounds. Overall, this 
      work suggests some intriguing links between in vitro and in vivo infection models 
      and should aid in further elucidating the genetic circuits behind the host 
      response to Francisella tularensis infection.
CI  - Copyright (c) 2016 Fink et al.
FAU - Fink, Avner
AU  - Fink A
AD  - Department of Microbiology and Immunobiology, Harvard Medical School, Boston, 
      Massachusetts, USA.
FAU - Hassan, Musa A
AU  - Hassan MA
AD  - Department of Biology, Massachusetts Institute of Technology, Cambridge, 
      Massachusetts, USA Wellcome Trust Centre for Molecular Parasitology, University 
      of Glasgow, Glasgow, United Kingdom.
FAU - Okan, Nihal A
AU  - Okan NA
AD  - Department of Microbiology and Immunobiology, Harvard Medical School, Boston, 
      Massachusetts, USA.
FAU - Sheffer, Michal
AU  - Sheffer M
AD  - Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
FAU - Camejo, Ana
AU  - Camejo A
AD  - Department of Biology, Massachusetts Institute of Technology, Cambridge, 
      Massachusetts, USA.
FAU - Saeij, Jeroen P J
AU  - Saeij JP
AD  - Department of Biology, Massachusetts Institute of Technology, Cambridge, 
      Massachusetts, USA Department of Pathology, Microbiology & Immunology, University 
      of California, Davis, Davis, California, USA.
FAU - Kasper, Dennis L
AU  - Kasper DL
AD  - Department of Microbiology and Immunobiology, Harvard Medical School, Boston, 
      Massachusetts, USA dennis_kasper@hms.harvard.edu.
LA  - eng
GR  - T32 AI007061/AI/NIAID NIH HHS/United States
GR  - R01 AI080621/AI/NIAID NIH HHS/United States
GR  - U54 AI057159/AI/NIAID NIH HHS/United States
GR  - AI057159/AI/NIAID NIH HHS/United States
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160315
PL  - United States
TA  - mBio
JT  - mBio
JID - 101519231
SB  - IM
MH  - Animals
MH  - Bacterial Load
MH  - *Chromosome Mapping
MH  - Crosses, Genetic
MH  - Francisella tularensis/*immunology/isolation & purification
MH  - Macrophages/*immunology/microbiology
MH  - Mice
MH  - *Quantitative Trait Loci
PMC - PMC4807373
EDAT- 2016/03/17 06:00
MHDA- 2017/01/11 06:00
PMCR- 2016/03/15
CRDT- 2016/03/17 06:00
PHST- 2016/03/17 06:00 [entrez]
PHST- 2016/03/17 06:00 [pubmed]
PHST- 2017/01/11 06:00 [medline]
PHST- 2016/03/15 00:00 [pmc-release]
AID - mBio.02243-15 [pii]
AID - mBio02243-15 [pii]
AID - 10.1128/mBio.02243-15 [doi]
PST - epublish
SO  - mBio. 2016 Mar 15;7(2):e02243. doi: 10.1128/mBio.02243-15.