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

Bastian Zimmer, Osefame Ewaleifoh, Oliver Harschnitz, Yoon Seung Lee, Camille Peneau, Jessica L. McAlpine, Becky Liu, Jason Tchieu, Julius A. Steinbeck, Fabien Lafaille, Stefano Volpi, Luigi D. Notarangelo, Jean Laurent Casanova*, Shen Ying Zhang, Gregory A. Smith, Lorenz Studer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E8775-E8782
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 11 2018


  • Antiviral immunity
  • HSE
  • HSV-1
  • TG neurons
  • TLR3

ASJC Scopus subject areas

  • General


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