Defects in
| Autor: | Alon Schneider, Hait, David, Olagnier, Vanessa, Sancho-Shimizu, Kristian Alsbjerg, Skipper, Marie, Helleberg, Simon Muller, Larsen, Chiranjeevi, Bodda, Liviu Ionut, Moldovan, Fanghui, Ren, Nanna-Sophie, Brinck Andersen, Michelle M, Thomsen, Mette Ratzer, Freytag, Sathya, Darmalinggam, Isobel, Parkes, Darshana D, Kadekar, Stine Hess, Rahbek, Demi, van der Horst, Lasse Sommer, Kristensen, Kristina, Eriksson, Jørgen, Kjems, Serge, Mostowy, Mette, Christiansen, Jacob Giehm, Mikkelsen, Christian Thomas, Brandt, Søren R, Paludan, Trine H, Mogensen |
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| Rok vydání: | 2020 |
| Předmět: |
Herpesvirus 2
Human Autophagy-Related Proteins Membrane Proteins Fibroblasts Middle Aged Viral Load Virus Replication Meningitis Viral Article Cysteine Endopeptidases Recurrence Host-Pathogen Interactions Mutation Autophagy Humans Female Genetic Predisposition to Disease Disease Susceptibility Microtubule-Associated Proteins Cells Cultured Aged Disease Resistance Signal Transduction |
| Zdroj: | Sci Immunol |
| ISSN: | 2470-9468 |
| Popis: | Recurrent herpesvirus infections can lead to numerous forms of diseases ranging from cold sore and genital herpes to encephalitis. Currently, there is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent HSV2 infections in the central nervous system (CNS). Here we describe two adult patients with recurrent HSV2 lymphocytic Mollaret’s meningitis each carrying a rare monoallelic variant in one of the autophagy proteins ATG4A and LC3B2. Importantly, HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication together with 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 UV irradiation of the virus and inhibited in the presence of acyclovir, highlighting the need for a functional viral DNA genome and viral replication. However, HSV2-induced autophagy was independent of the DNA-activated STING pathway. Finally, reconstitution of wildtype 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 represents the first autophagy defect causing a primary immunodeficiency with increased susceptibility to viral infection described in humans which altogether suggests an important role for autophagy in anti-HSV2 immunity in the CNS. |
| Databáze: | OpenAIRE |
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