Patterns of Herpes Simplex Virus 1 Infection in Neural Progenitor Cells

Abstract

HSV-1 can induce damage in brain regions that include the hippocampus and associated limbic structures. These neurogenic niches are important because they are associated with memory formation and are highly enriched with neural progenitor cells (NPCs). The susceptibility and fate of HSV-1 infected NPCs is largely unexplored. We differentiated human induced pluripotent stem cells (iPSCs) into NPCs to generate two-dimensional (2D) and three-dimensional (3D) culture models to examine the interaction of HSV-1 with NPCs. Here, we show that: i) NPCs can be efficiently infected by HSV-1, but infection does not result in cell death of most NPCs, even at high multiplicity of infections (MOIs); ii) limited HSV-1 replication and gene expression can be detected in the infected NPCs; iii) a viral silencing mechanism is established in NPCs exposed to antivirals (E)-5-(2-bromovinyl)-2′-deoxyuridine (5BVdU) and interferon-α (IFN-α). When the antivirals are removed, spontaneous reactivation can occur at low frequency; iv) HSV-1 impairs the ability of NPCs to migrate in a dose-dependent fashion in the presence of 5BVdU + IFN-α; and v) 3D cultures of NPCs are less susceptible to HSV-1 infection than 2D cultures, yet still retain latent genomes. These results suggest that NPC pools could be sites of HSV-1 reactivation in the CNS. Finally, our results highlight the potential value of iPSC 3D cultures to model HSV-1-NPCs interaction. IMPORTANCE This study employed human induced pluripotent stem cells (hiPSCs) to model the interaction of HSV-1 with NPCs, which reside in the neurogenic niches of the CNS and play a fundamental role in adult neurogenesis. Herein, we provide evidence that in NPCs infected at an MOI as low as 0.001 HSV-1 can establish a latent state, suggesting that i) HSV-1 latency is not only restricted to mature neurons, but it can be established during earlier stages of neuronal differentiation; ii) neurogenic niches in the brain may constitute additional HSV-1 latent reservoirs. Lytic HSV-1 infections impaired NPCs migration, which represents a critical step in neurogenesis. Difference in susceptibility to HSV-1 infection between two-dimensional (2D) and three-dimensional (3D) NPC cultures was observed, highlighting the potential value of 3D cultures for modeling host-pathogen interactions. Together, our results are relevant in light of observations relating HSV-1 infection to post-encephalitic cognitive dysfunction.

Neural Stem Cells: What Happens When They Go Viral?

“…Whether a virus induces apoptosis or inhibits proliferation may be influenced, in part, by the choice of model system. HSV-1 infection of monolayer cultures results in cell death of the majority of the NSCs [ 45 ]. However, HSV-1 infection of NSCs in cerebral organoids or 3D cultures induced mild cell death despite increased expression of genes associated with apoptosis [ 46 ].…”

The Hippocampal Vulnerability to Herpes Simplex Virus Type I Infection: Relevance to Alzheimer’s Disease and Memory Impairment

“…Another study also showed that HSV-1 preferentially infects undifferentiated NSCs rather than mature hippocampal neurons, resulting in impaired hippocampal neurogenesis (Li Puma et al, 2019). More recent studies have shown that HSV-1 readily infects NSCs/NPCs and induces Aβ42 accumulation, neuroinflammation and neuronal impairments, which can be prevented with valacyclovir antiherpetic treatment (Abrahamson et al, 2020;Cairns et al, 2020;Zheng et al, 2020).…”

“…NPCs have also been found to be susceptible to HSV-1 infection and latency establishment in murine and neuronal 3D models (Menendez et al, 2016;Zheng et al, 2020). In cultured NPCs, HSV-1 infection decreased neuronal survival, which was prevented in co-cultures of NPCs with microglia (Chucair-Elliott et al, 2014).…”

Cerebral organoids and their potential for studies of brain diseases in domestic animals

“…A first study has indeed given some clues, revealing a preferential tropism for radial glia and astrocytes and a weaker antiviral response in the youngest organoids compared to older one [ 77 ]. Another example is given by the recent modeling of the herpes simplex virus 1 (HSV1) infection in brain organoids, allowing studies of the virus trafficking through the complex neural tissue structure, the processes of latency and reactivation that can be established in organoids [ 78 , 79 ] and the role of the virus as a facilitating agent of Alzheimer disease. Interestingly, HSV1 infection in both 2D and 3D in vitro models derived from iPSCs showed that infection led to the deposit of amyloid β42 aggregates, supporting the hypothesis that HSV1 may be involved in the occurrence of Alzheimer disease [ 78 – 80 ].…”