Defects in LC3B2 and ATG4A 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 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 KjemsSerge Mostowy, Mette Christiansen, Jacob Giehm Mikkelsen, Christian Thomas Brandt, Søren R Paludan, Trine H Mogensen


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.

TidsskriftScience immunology
Udgave nummer54
StatusUdgivet - 11 dec. 2020


Dyk ned i forskningsemnerne om 'Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans'. Sammen danner de et unikt fingeraftryk.