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Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8775-E8782. doi: 10.1073/pnas.1809853115. Epub 2018 Aug 28.

Human iPSC-derived trigeminal neurons lack constitutive TLR3-dependent immunity that protects cortical neurons from HSV-1 infection.

Author information

1
Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY 10065.
2
Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065.
3
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
4
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
5
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, 75015 Paris, France.
6
Imagine Institute, Paris Descartes University, 75015 Paris, France.
7
Pediatric and Rheumatology Unit, Center for Autoinflammatory Diseases and Immunodeficiencies, Istituto Giannina Gaslini and University of Genoa, 16147 Genoa, Italy.
8
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
9
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065; casanova@rockefeller.edu g-smith3@northwestern.edu studerl@mskcc.org.
10
Howard Hughes Medical Institute, The Rockefeller University, New York, NY.
11
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France.
12
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; casanova@rockefeller.edu g-smith3@northwestern.edu studerl@mskcc.org.
13
Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY 10065; casanova@rockefeller.edu g-smith3@northwestern.edu studerl@mskcc.org.

Abstract

Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Some HSE children carry inborn errors of the Toll-like receptor 3 (TLR3)-dependent IFN-α/β- and -λ-inducing pathway. Induced pluripotent stem cell (iPSC)-derived cortical neurons with TLR3 pathway mutations are highly susceptible to HSV-1, due to impairment of cell-intrinsic TLR3-IFN immunity. In contrast, the contribution of cell-intrinsic immunity of human trigeminal ganglion (TG) neurons remains unclear. Here, we describe efficient in vitro derivation and purification of TG neurons from human iPSCs via a cranial placode intermediate. The resulting TG neurons are of sensory identity and exhibit robust responses to heat (capsaicin), cold (icilin), and inflammatory pain (ATP). Unlike control cortical neurons, both control and TLR3-deficient TG neurons were highly susceptible to HSV-1. However, pretreatment of control TG neurons with poly(I:C) induced the cells into an anti-HSV-1 state. Moreover, both control and TLR3-deficient TG neurons developed resistance to HSV-1 following pretreatment with IFN-β but not IFN-λ. These data indicate that TG neurons are vulnerable to HSV-1 because they require preemptive stimulation of the TLR3 or IFN-α/β receptors to induce antiviral immunity, whereas cortical neurons possess a TLR3-dependent constitutive resistance that is sufficient to block incoming HSV-1 in the absence of prior antiviral signals. The lack of constitutive resistance in TG neurons in vitro is consistent with their exploitation as a latent virus reservoir in vivo. Our results incriminate deficiencies in the constitutive TLR3-dependent response of cortical neurons in the pathogenesis of HSE.

KEYWORDS:

HSE; HSV-1; TG neurons; TLR3; antiviral immunity

PMID:
30154162
PMCID:
PMC6140487
DOI:
10.1073/pnas.1809853115
[Indexed for MEDLINE]
Free PMC Article

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