Herpes simplex virus type 1 infection leads to neurodevelopmental disorder-associated neuropathological changes

Abstract

Neonatal herpes simplex virus type 1 (HSV-1) infections contribute to various neurodevelopmental disabilities and the subsequent long-term neurological sequelae into the adulthood. However, further understanding of fetal brain development and the potential neuropathological effects of the HSV-1 infection are hampered by the limitations of existing neurodevelopmental models due to the dramatic differences between humans and other mammalians. Here we generated in vitro neurodevelopmental disorder models including human induced pluripotent stem cell (hiPSC)-based monolayer neuronal differentiation, three-dimensional (3D) neuroepithelial bud, and 3D cerebral organoid to study fetal brain development and the potential neuropathological effects induced by the HSV-1 infections. Our results revealed that the HSV-1-infected neural stem cells (NSCs) exhibited impaired neural differentiation. HSV-1 infection led to dysregulated neurogenesis in the fetal neurodevelopment. The HSV-1-infected brain organoids modelled the pathological features of the neurodevelopmental disorders in the human fetal brain, including the impaired neuronal differentiation, and the dysregulated cortical layer and brain regionalization. Furthermore, the 3D cerebral organoid model showed that HSV-1 infection promoted the abnormal microglial activation, accompanied by the induction of inflammatory factors, such as TNF-α, IL-6, IL-10, and IL-4. Overall, our in vitro neurodevelopmental disorder models reconstituted the neuropathological features associated with HSV-1 infection in human fetal brain development, providing the causal relationships that link HSV biology with the neurodevelopmental disorder pathogen hypothesis.

Viral infection of human neurons triggers strain-specific differences in host neuronal and viral transcriptomes

“…However, at the highest infectious dose, all neuronal cell bodies for each strain had detectable viral protein consistent with productive replication ( S2 Fig ). This finding is in accordance with prior studies demonstrating that high multiplicities of infection are necessary to uniformly infect neurons with alphaherpesviruses [ 58 – 61 ]. For samples used in the RNA-sequencing analysis, differentiated SH-SY5Y human neuronal cells were infected with purified virions of HSV-1 strain KOS, F, or McKrae at 1.6e 7 PFU/dish to ensure synchronous infection.…”

“…Additionally, we observed the activation of host immune responses, including genes involved in pathways such as death receptor signaling and retinoic acid-mediated apoptosis signaling ( Fig 1B ). Broadly, these findings are in agreement with previous findings indicating the induction of host immune pathways with neuronal HSV-1 infection and latency, and the altered activation of neuronal cell adhesion and migration pathways [ 17 , 19 – 21 , 23 , 24 , 61 ].…”

“Non-Essential” Proteins of HSV-1 with Essential Roles In Vivo: A Comprehensive Review

“…They exhibit neuronal heterogeneity and lamina-like structure [ 839 ]. Brain organoids can be infected with HSV-1 and exhibit inflammation, HSV-1 can establish hallmarks of latency in such cultures in the presence of antivirals like interferon (IFN), and HSV-1 can infect the outer laminar structure of these organoids moving further inside after infection [ 840 , 841 ]. All these elements make the use of brain organoids in HSV-1 research attractive.…”

Modeling SARS-CoV-2 infection in individuals with opioid use disorder with brain organoids

“… 213 , 214 HSV-1-infected cerebral organoids confirmed that the virus impairs neuronal differentiation and cortical layering, as well as revealed the abnormal increase in microglial proliferation and specific inflammatory factors. 148 …”

“…213,214 HSV-1-infected cerebral organoids confirmed that the virus impairs neuronal differentiation and cortical layering, as well as revealed the abnormal increase in microglial proliferation and specific inflammatory factors. 148 Brain organoids have even been exploited to investigate non-virus pathogens. Sporadic Creutzfeldt-Jakob Disease (sCJD), a transmissible neurodegenerative disease targeting several brain regions and caused by infectious prions, was shown with cerebral organoids to increase metabolism, LDH release, and cytokine release.…”