Inherited IRAK-4 Deficiency in Acute Human Herpesvirus-6 Encephalitis

J Clin Immunol. 2023 Jan;43(1):192-205. doi: 10.1007/s10875-022-01369-4. Epub 2022 Oct 7.


Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4, encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient's cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient's leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency.

Keywords: Encephalitis; HHV-6; IRAK-4 deficiency; Primary immunodeficiency diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Encephalitis, Viral* / diagnosis
  • Encephalitis, Viral* / genetics
  • Herpesvirus 6, Human* / genetics
  • Humans
  • Infant
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Primary Immunodeficiency Diseases* / genetics
  • Roseolovirus Infections* / diagnosis
  • Roseolovirus Infections* / genetics
  • Toll-Like Receptors / metabolism


  • Interleukin-1 Receptor-Associated Kinases
  • Toll-Like Receptors

Supplementary concepts

  • IRAK4 Deficiency