Article | Published:

Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system

Nature Microbiology volume 1, Article number: 16001 (2016) | Download Citation

Abstract

An important function of the blood–brain barrier is to exclude pathogens from the central nervous system, but some microorganisms benefit from the ability to enter this site. It has been proposed that Toxoplasma gondii can cross biological barriers as a motile extracellular form that uses transcellular or paracellular migration, or by infecting a host cell that then crosses the blood–brain barrier. Unexpectedly, analysis of acutely infected mice revealed significant numbers of free parasites in the blood and the presence of infected endothelial cells in the brain vasculature. The use of diverse transgenic parasites combined with reporter mice and intravital imaging demonstrated that replication in and lysis of endothelial cells precedes invasion of the central nervous system, and highlight a novel mechanism for parasite entry to the central nervous system.

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Acknowledgements

C.K. was supported by research grant KO 4609-1/1 from the German Research Foundation (DFG). This work was supported by grants from the National Institutes of Health (NIH AI 41158 to C.A.H., NIH NS065116 to A.A.K., NIH AI041930 to D.J.B.), the American Heart Association (14BGIA20380675 to M.B.L. and 15POST25550021 to N.U.) and the University of Arizona and the BIO5 Institute (A.A.K.). Imaging experiments were performed in the PennVet Imaging Core Facility on instrumentation supported by NIH S10RR027128, the School of Veterinary Medicine, the University of Pennsylvania, and the Commonwealth of Pennsylvania. sIgM-ko mice were provided by G. Debes (University of Pennsylvania). C.A.H is the Mindy Halikman Heyer President's Distinguished Chair.

Author information

Affiliations

  1. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    • Christoph Konradt
    • , David A. Christian
    • , Jonathan H. Delong
    • , Gretchen Harms Pritchard
    •  & Christopher A. Hunter
  2. Department of Molecular Biology and Biochemistry and Institute for Immunology, University of California, Irvine, California, 92697, USA

    • Norikiyo Ueno
    •  & Melissa B. Lodoen
  3. National Institute of Neurological Disorders and Stroke, The National Institutes of Health, Bethesda, Maryland, 20892, USA

    • Jasmin Herz
    •  & Dorian B. McGavern
  4. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, 03756, USA

    • David J. Bzik
  5. Department of Neurology, University of Arizona, Tucson, Arizona, 85724, USA

    • Anita A. Koshy

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Contributions

C.K. performed the majority of the experiments. N.U. and M.B.L. performed and analysed the microfluidic chamber experiments. J.D. and G.H.P. helped with sample collection. D.J.B. provided the CPS parasites. A.A.K. provided Cre-secreting parasites. D.A.C., J.H. and D.B.M were involved in study design. C.K. and C.A.H. wrote the paper. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Christopher A. Hunter.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Figures 1-6

Videos

  1. 1.

    Supplementary Video 1

    Intravital imaging of circulation kinetics of T. gondii after i.v. infection.

  2. 2.

    Supplementary Video 2

    Intravital imaging of the lysis of an infected Tie2-GFP+ endothelial cell in a large blood vessel in the brain.

  3. 3.

    Supplementary Video 3

    Intravital imaging of the lysis of an infected Tie2-GFP+ endothelial cell in a capillary in the brain and parasite entry into the parenchyma.

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DOI

https://doi.org/10.1038/nmicrobiol.2016.1

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