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

TY - JOUR

T1 - Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans

AU - Hait, Alon Schneider

AU - Olagnier, David

AU - Sancho-Shimizu, Vanessa

AU - Skipper, Kristian Alsbjerg

AU - Helleberg, Marie

AU - Larsen, Simon Muller

AU - Bodda, Chiranjeevi

AU - Moldovan, Liviu Ionut

AU - Ren, Fanghui

AU - Brinck Andersen, Nanna-Sophie

AU - Thomsen, Michelle M

AU - Freytag, Mette Ratzer

AU - Darmalinggam, Sathya

AU - Parkes, Isobel

AU - Kadekar, Darshana D

AU - Rahbek, Stine Hess

AU - van der Horst, Demi

AU - Kristensen, Lasse Sommer

AU - Eriksson, Kristina

AU - Kjems, Jørgen

AU - Mostowy, Serge

AU - Christiansen, Mette

AU - Mikkelsen, Jacob Giehm

AU - Brandt, Christian Thomas

AU - Paludan, Søren R

AU - Mogensen, Trine H

N1 - Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85098235878&partnerID=8YFLogxK

U2 - 10.1126/sciimmunol.abc2691

DO - 10.1126/sciimmunol.abc2691

M3 - Journal article

C2 - 33310865

SN - 2470-9468

VL - 5

JO - Science Immunology

JF - Science Immunology

IS - 54

M1 - eabc2691

ER -