Herpes Simplex Virus Type 1 Neuronal Infection Triggers the Disassembly of Key Structural Components of Dendritic Spines

Abstract

Herpes simplex virus type 1 (HSV-1) is a widespread neurotropic virus. Primary infection of HSV-1 in facial epithelium leads to retrograde axonal transport to the central nervous system (CNS) where it establishes latency. Under stressful conditions, the virus reactivates, and new progeny are transported anterogradely to the primary site of infection. During the late stages of neuronal infection, axonal damage can occur, however, the impact of HSV-1 infection on the morphology and functional integrity of neuronal dendrites during the early stages of infection is unknown. We previously demonstrated that acute HSV-1 infection in neuronal cell lines selectively enhances Arc protein expression - a major regulator of long-term synaptic plasticity and memory consolidation, known for being a protein-interaction hub in the postsynaptic dendritic compartment. Thus, HSV-1 induced Arc expression may alter the functionality of infected neurons and negatively impact dendritic spine dynamics. In this study we demonstrated that HSV-1 infection induces structural disassembly and functional deregulation in cultured cortical neurons, an altered glutamate response, Arc accumulation within the somata, and decreased expression of spine scaffolding-like proteins such as PSD-95, Drebrin and CaMKIIβ. However, whether these alterations are specific to the HSV-1 infection mechanism or reflect a secondary neurodegenerative process remains to be determined.

Modelling viral encephalitis caused by herpes simplex virus 1 infection in cerebral organoids

“…Previous reports showed that lytic HSV-1 neuronal infection caused synaptic dysfunction and disassembly of dendritic spines and upregulation of activity-regulated cytoskeleton-associated protein 25,26 . In our system, we observed massive downregulation of synaptic transmission genes (Extended Data Fig.…”

The Causes and Long-Term Consequences of Viral Encephalitis

“…The primary infection of HSVs occurs through direct contact of the host mucosal membranes or damaged skin with infected fluids. This virus can then reach and infect sensory neurons, leading to secondary encephalitis ( Bradshaw and Venkatesan, 2016 ; Marcocci et al, 2020 ; Acuña-Hinrichsen et al, 2021 ). The clinical signs described in patients with HSV encephalitis (HSE) are fever, headache, seizure, focal neurological deficits, and general encephalopathy ( Table 1 ; Bradshaw and Venkatesan, 2016 ).…”

“…Interestingly, HSV not only infects neurons but can also establish latency on these cells as well as in astrocytes ( Marcocci et al, 2020 ; Słońska et al, 2021 ). HSV-1-infected cortical neurons exhibit an altered expression of dendritic spine proteins as well as their distribution and changes in response to a glutamate stimulation altering the normal function of these cells ( Acuña-Hinrichsen et al, 2021 ). Importantly, HSV-1-infected NCSs present impairment in their growth, proliferation, and neuronal differentiation, which can cause neurodevelopment disorder observed in neonatal HSV-1 infections ( Qiao et al, 2020 ).…”

Disrupting Neurons and Glial Cells Oneness in the Brain—The Possible Causal Role of Herpes Simplex Virus Type 1 (HSV-1) in Alzheimer’s Disease

“…Recently, it was shown that the HSV-1 infection of mice causes hippocampal damage and neuronal apoptosis, which is related to the downregulation of the suppressor of cytokine signaling 2 (SOCS2) and SOCS3, and to increased hippocampal expression of inflammatory cytokines, such as TNFα, IL-1β, IL-6, and IFN-α/β [ 230 ]. In the cultured neurons, HSV-1 infection decreased the expression of the dendritic postsynaptic density scaffolding proteins, such as postsynaptic density protein 95 (PSD-95), Drebrin, and CaMKIIb, and induced extensive loss of dendritic spines and retraction of secondary dendrites, as well as entailed unresponsiveness to glutamate stimulation, culminating in the functional deregulation of neurons [ 231 ]. Latterly, Doll et al provided evidence that sensory neurons undergo apoptosis as a result of HSV reactivation in mice [ 232 ].…”

“…Oligodendrocytes produce exosomes with regulatory RNA and can send functional molecules to neurons, affecting their properties [ 296 ]. HSV-1 influences neuronal physiology, and induces structural disassembly and functional deregulation, as shown in the blue box [ 231 ]. Infected neurons largely secrete IFN-α, IFN-β, IL-1β, CXCL10, and Aβ peptides [ 49 , 84 , 85 , 297 ].…”