Herpes Simplex Virus 1 and 2 Infections during Differentiation of Human Cortical Neurons

• Published in: Viruses 2021-10, Vol.13 (10), p.2072
• Main Authors: Bergström, Petra, Trybala, Edward, Eriksson, Charlotta E, Johansson, Maria, Satir, Tugce Munise, Widéhn, Sibylle, Fruhwürth, Stefanie, Michno, Wojciech, Nazir, Faisal Hayat, Hanrieder, Jörg, Paludan, Soren Riis, Agholme, Lotta, Zetterberg, Henrik, Bergström, Tomas
• Format: Article
• Language: English
• Subjects: acyclovir; Brain; Cell differentiation; Cell Differentiation - genetics; Cell Survival; Central Nervous System; central nervous system infection; Clinical trials; cortical neurons; DNA-directed RNA polymerase; Encephalitis; Gene expression; Gene Expression Regulation; Herpes simplex; Herpes Simplex - pathology; Herpes Simplex - virology; herpes simplex virus; Herpes viruses; Herpesvirus 1, Human; Herpesvirus 2, Human; human; human induced pluripotent stem cells; human neuroprogenitors; Humans; Induced Pluripotent Stem Cells; Infections; Infectious Medicine; Infektionsmedicin; Inhibitory postsynaptic potentials; Meningitis; morbidity; Neonates; Neurodegeneration; Neurologi; Neurology; Neurons; Neurons - pathology; Neurons - virology; neuroprogenitors; plasticity; Pluripotency; pluripotent stem-cells; Replication; Stem cells; system; Tau protein; tissue; type-1 DNA; Viral infections; Virology; Virus Replication - physiology; Viruses
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v13102072

Herpes simplex virus 1 (HSV-1) and 2 (HSV-2) can infect the central nervous system (CNS) with dire consequences; in children and adults, HSV-1 may cause focal encephalitis, while HSV-2 causes meningitis. In neonates, both viruses can cause severe, disseminated CNS infections with high mortality rates. Here, we differentiated human induced pluripotent stem cells (iPSCs) towards cortical neurons for infection with clinical CNS strains of HSV-1 or HSV-2. Progenies from both viruses were produced at equal quantities in iPSCs, neuroprogenitors and cortical neurons. HSV-1 and HSV-2 decreased viability of neuroprogenitors by 36.0% and 57.6% ( < 0.0001), respectively, 48 h post-infection, while cortical neurons were resilient to infection by both viruses. However, in these functional neurons, both HSV-1 and HSV-2 decreased gene expression of two markers of synaptic activity, CAMK2B and ARC, and affected synaptic activity negatively in multielectrode array experiments. However, unaltered secretion levels of the neurodegeneration markers tau and NfL suggested intact axonal integrity. Viral replication of both viruses was found after six days, coinciding with 6-fold and 22-fold increase in gene expression of cellular RNA polymerase II by HSV-1 and HSV-2, respectively. Our results suggest a resilience of human cortical neurons relative to the replication of HSV-1 and HSV-2.