Defects in <i>LC3B2</i> and <i>ATG4A</i> underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans
Alon Schneider Hait, David Olagnier, Vanessa Sancho‐Shimizu, Kristian Alsbjerg Skipper, Marie Helleberg, Simon Müller Larsen, Chiranjeevi Bodda, Liviu Ionut Moldovan, Fanghui Ren, Nanna-Sophie Brinck Andersen, Michelle M. Thomsen, Mette Ratzer Freytag, Sathya Darmalinggam, Isobel Parkes, Darshana Kadekar, Stine H. Rahbek, Demi van der Horst, Lasse S. Kristensen, Kristina Eriksson, Jørgen Kjems, Serge Mostowy, Mette Christiansen, Jacob Giehm Mikkelsen, Christian Brandt, Søren R. Paludan, Trine H. Mogensen
Abstract
, 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.