Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans
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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.
Originalsprog | Engelsk |
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Artikelnummer | eabc2691 |
Tidsskrift | Science immunology |
Vol/bind | 5 |
Udgave nummer | 54 |
ISSN | 0065-2776 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
We wish to thank the patients participating in this study. In addition, we wish to thank technician K. S. Pedersen for excellent technical assistance and B. D. Andersen for performing skin biopsies on the two patients. The PhD scholarship to A.S.H. was funded by the European Union under the Horizon 2020 research and innovation program (H2020) and Marie Sk?odowska-Curie Actions?Innovative Training Networks Programme MSCA-ITN GA 675278 EDGE (Training Network providing cutting-EDGE knowlEDGE on Herpes Virology and Immunology). D.O. salary was supported by a Weiman fond Associate Professor Fellowship. J.G.M. received funding from the Novo Nordisk Foundation (NNF17OC0029042). S.R.P. was supported by grants from the European Research Council (786602), the Lundbeck Foundation (R198-2015-171 and R268-2016-3927), and the Novo Nordisk Foundation (NNF18OC0030274). T.H.M. was funded by the Independent Research Fund Denmark (4004-00047B), Aarhus University Research Fund (AUFF-E-2015-FLS-66), and the Lundbeck Foundation (R268-2016-3927).
Publisher Copyright:
Copyright © 2020 The Authors,
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