PMID- 29119662
OWN - NLM
STAT- MEDLINE
DCOM- 20190107
LR  - 20190107
IS  - 1462-5822 (Electronic)
IS  - 1462-5814 (Linking)
VI  - 20
IP  - 3
DP  - 2018 Mar
TI  - Toxoplasma gondii infection shifts dendritic cells into an amoeboid rapid 
      migration mode encompassing podosome dissolution, secretion of TIMP-1, and 
      reduced proteolysis of extracellular matrix.
LID - 10.1111/cmi.12808 [doi]
AB  - Dendritic cells (DCs) infected by Toxoplasma gondii rapidly acquire a 
      hypermigratory phenotype that promotes systemic parasite dissemination by a 
      "Trojan horse" mechanism in mice. Recent paradigms of leukocyte migration have 
      identified the amoeboid migration mode of DCs as particularly suited for rapid 
      locomotion in extracellular matrix and tissues. Here, we have developed a 
      microscopy-based high-throughput approach to assess motility and matrix 
      degradation by Toxoplasma-challenged murine and human DCs. DCs challenged with 
      T. gondii exhibited dependency on metalloproteinase activity for hypermotility 
      and transmigration but, strikingly, also dramatically reduced pericellular 
      proteolysis. Toxoplasma-challenged DCs up-regulated expression and secretion of 
      tissue inhibitor of metalloproteinases-1 (TIMP-1) and their supernatants impaired 
      matrix degradation by naive DCs and by-stander DCs dose dependently. Gene 
      silencing of TIMP-1 by short hairpin RNA restored matrix degradation activity in 
      Toxoplasma-infected DCs. Additionally, dissolution of podosome structures in 
      parasitised DCs coincided with abrogated matrix degradation. Toxoplasma lysates 
      inhibited pericellular proteolysis in a MyD88-dependent fashion whereas abrogated 
      proteolysis persevered in Toxoplasma-infected MyD88-deficient DCs. This indicated 
      that both TLR/MyD88-dependent and TLR/MyD88-independent signalling pathways 
      mediated podosome dissolution and the abrogated matrix degradation. We report 
      that increased TIMP-1 secretion and cytoskeletal rearrangements encompassing 
      podosome dissolution are features of Toxoplasma-induced hypermigration of DCs 
      with an impact on matrix degradation. Jointly, the data highlight how an obligate 
      intracellular parasite orchestrates key regulatory cellular processes consistent 
      with non-proteolytic amoeboid migration of the vehicle cells that facilitate its 
      dissemination.
CI  - (c) 2017 John Wiley & Sons Ltd.
FAU - Olafsson, Einar B
AU  - Olafsson EB
AD  - Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm 
      University, Stockholm, Sweden.
FAU - Varas-Godoy, Manuel
AU  - Varas-Godoy M
AD  - Centro de Investigacion Biomedica, Faculty of Medicine, Universidad de los Andes, 
      Santiago, Chile.
FAU - Barragan, Antonio
AU  - Barragan A
AUID- ORCID: 0000-0001-7746-9964
AD  - Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm 
      University, Stockholm, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171218
PL  - India
TA  - Cell Microbiol
JT  - Cellular microbiology
JID - 100883691
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
SB  - IM
MH  - Animals
MH  - Dendritic Cells/cytology/*immunology
MH  - Extracellular Matrix/*metabolism
MH  - Humans
MH  - Mice
MH  - Myeloid Differentiation Factor 88/metabolism
MH  - Tissue Inhibitor of Metalloproteinase-1/*metabolism
MH  - Toxoplasma/immunology/*pathogenicity
MH  - Toxoplasmosis/immunology/metabolism
OTO - NOTNLM
OT  - apicomplexa
OT  - coccidia
OT  - host-pathogen
OT  - leukocyte migration
OT  - matrix metalloproteinase
OT  - tissue inhibitor of metalloproteinases
EDAT- 2017/11/10 06:00
MHDA- 2019/01/08 06:00
CRDT- 2017/11/10 06:00
PHST- 2017/06/30 00:00 [received]
PHST- 2017/10/10 00:00 [revised]
PHST- 2017/11/03 00:00 [accepted]
PHST- 2017/11/10 06:00 [pubmed]
PHST- 2019/01/08 06:00 [medline]
PHST- 2017/11/10 06:00 [entrez]
AID - 10.1111/cmi.12808 [doi]
PST - ppublish
SO  - Cell Microbiol. 2018 Mar;20(3). doi: 10.1111/cmi.12808. Epub 2017 Dec 18.