The Potential Influence Of Herpes Simplex Virus Type 1 On Foetal Neurodevelopment

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Herpes & the Brain

You’re probably thinking of its popular presentation, the common cold sore. However, herpes simplex virus type 1 (HSV-1), can have dangerous consequences, such as loss of cognitive function, which may result in learning disabilities and dementia. Currently, the majority of HSV-1 research is centred around its effect on adults and less research is based on its effect on foetal brain development, due to appropriate restrictions on testing foetal brain tissue. As the prevalence of herpes simplex virus (HSV) increases within our population, there is a subsequent increase in the risk of transmitting this virus to a foetus during pregnancy.  Additionally, in recent years there has been a rise in the number of publications that have presented connections between HSV infected foetuses during pregnancy and neurodevelopmental disorders, potentially leading to learning disabilities and dementia.

Previous research to study this link has been conducted using animal models, which gives rise to concerns about the application of these results to the human brain, as the human brain has 100 billion neurons and 10 times the number of glial cells (non-neuronal cells that play an important role in maintaining homeostasis within the central nervous system (CNS)). Therefore, to study the effect of HSV-1 on foetal brain development using human tissue, researchers at Wuhan University generated in vitro neurodevelopmental disorder models, including human pluripotent stem cells (undifferentiated cells which can develop into any cell type) to produce a 3-D neuroepithelial bud and 3-D cerebral organoid (a brain-like structure and a mono layer of cells respectively). These models allowed the pathology of neurodevelopmental disorders in the human neonatal brain to be displayed.

A schematic showing the effect of HSV-1 on the neuroepithelial bud and cerebral organoid which act as models of developing foetal neuropathological features.
Source: Herpes simplex virus type 1 infection leads to neurodevelopmental disorder-associated neuropathological changes: Qiao H, Guo M, Shang J, Zhao W, Wang Z, Liu N et al.

Results

Nerve stem cells (NSCs) were targets of the HSV-1 infection and under this attack, these cells displayed cell growth inhibition partly due to cell death. The HSV-1 infection impaired neurogenesis within the NSCs due to the reduced expression of SOX2 (a transcription factor which plays an important role in maintaining the pluripotency of stem cells) and Nestin (an NSC marker). The researchers also discovered higher levels of cell death in HSV-1-infected NSCs in comparison to uninfected NSCs.  Additionally, the formation of multicellular structures were also observed, these structures have been shown to be a feature of  Alzheimer’s disease, a common type of dementia. This suggests that these structures are involved in neurological diseases. This study showed an increased risk of dysregulated neural differentiation (neural differentiation is important in the maturation of neurons and it allows them to produce subpopulations which are important for different parts of the nervous system) in HSV-1 infected NSCs. HSV-1 infected NSCs were also found to inhibit neuronal differentiation – this may be of help in understanding the effect of an HSV infection in postnatal cognitive dysfunctions.

Additionally, HSV-1 enhanced the proliferation and activation of the microglia (microglial cells act as macrophages mediating immune responses within the CNS). Microglia plays an important role in regulating inflammatory responses (an inflammatory response may contribute towards neurodevelopmental disorders). The increase in the rate of activation within these cells causes an increase in the expression of major contributors to the inflammatory response – pro-inflammatory mediators such as TNF-α and IL-6 and the expression of anti-inflammatory cytokines such as IL-10 and IL-14. These findings provide novel evidence of the role, an HSV-1 infection plays in inhibiting the foetal human brain development, which may give rise to postnatal neurodevelopmental disorders. They also provide a gateway in the discovery of new therapeutics in regards to neurodevelopmental disorders caused by viral infections such as HSV-1.

Notes

1.) There were inconsistent results about the role HSV-1 plays on NSC neurogenesis, as Nestin decreased in expression in the neuroepithelial bud but was expressed at the same amount in the monolayer of infected NSCs. This questions the result that HSV-1 infection within NSCs impairs neurogenesis. However, as explained by the researchers of this study, this is may be a trend as this has been shown to be true in other studies that have utilised similar models. More research is required to determine the role HSV-1 plays in neurogenesis of NSCs.

2.) This research was not carried out on the actual human foetal brain – for obvious reasons. Therefore, concluding thoughts cannot be: HSV-1 does impair brain development in the human foetal brain, but rather: HSV-1 may impair brain development within the human foetal brain.

Original Source:  Qiao H, Guo M, Shang J, Zhao W, Wang Z, Liu N et al. Herpes simplex virus type 1 infection leads to neurodevelopmental disorder-associated neuropathological changes. PLOS Pathogens. 2020;16(10):e1008899.

Link: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008899

Feature Image Source: GettyImages

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