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  • Hait, A. S. (author)

Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • American Association for the Advancement of Science (AAAS),2020

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/302525
  • https://gup.ub.gu.se/publication/302525URI
  • https://doi.org/10.1126/sciimmunol.abc2691DOI

Supplementary language notes

  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.

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Added entries (persons, corporate bodies, meetings, titles ...)

  • Olagnier, D. (author)
  • Sancho-Shimizu, V. (author)
  • Skipper, K. A. (author)
  • Helleberg, M. (author)
  • Larsen, S. M. (author)
  • Bodda, C. (author)
  • Moldovan, L. I. (author)
  • Ren, F. H. (author)
  • Andersen, N. S. B. (author)
  • Thomsen, M. M. (author)
  • Freytag, M. R. (author)
  • Darmalinggam, S. (author)
  • Parkes, I. (author)
  • Kadekar, D. D. (author)
  • Rahbek, S. H. (author)
  • van der Horst, D. (author)
  • Kristensen, L. S. (author)
  • Eriksson, Kristina,1962Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research(Swepub:gu)xerikr (author)
  • Kjems, J. (author)
  • Mostowy, S. (author)
  • Christiansen, M. (author)
  • Mikkelsen, J. G. (author)
  • Brandt, C. T. (author)
  • Paludan, Sören R,1972Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research(Swepub:gu)xriiso (author)
  • Mogensen, T. H. (author)
  • Göteborgs universitetInstitutionen för medicin, avdelningen för reumatologi och inflammationsforskning (creator_code:org_t)

Related titles

  • In:Science Immunology: American Association for the Advancement of Science (AAAS)5:542470-9468

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