Herpes Simplex Virus-1 in the Brain: The Dark Side of a Sneaky Infection

Marcocci, Maria Elena; Napoletani, Giorgia; Protto, Virginia; Kolesova, Olga; Piacentini, Roberto; Puma, Domenica Donatella Li; Lomonte, Patrick; Grassi, Claudio; Palamara, Anna Teresa; Chiara, Giovanna De

doi:10.1016/j.tim.2020.03.003

Cited by 164 publications

(150 citation statements)

References 115 publications

(131 reference statements)

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“…A growing body of evidence supports the role of HSV-1 in AD pathogenesis and progression [ 44 ]. We previously demonstrated that recurrent HSV-1 infection in mice triggers the accumulation of the main AD pathognomic hallmarks, including cognitive dysfunction [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Multiple Herpes Simplex Virus-1 (HSV-1) Reactivations Induce Protein Oxidative Damage in Mouse Brain: Novel Mechanisms for Alzheimer’s Disease Progression

et al. 2020

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Compelling evidence supports the role of oxidative stress in Alzheimer’s disease (AD) pathophysiology. Interestingly, Herpes simplex virus-1 (HSV-1), a neurotropic virus that establishes a lifelong latent infection in the trigeminal ganglion followed by periodic reactivations, has been reportedly linked both to AD and to oxidative stress conditions. Herein, we analyzed, through biochemical and redox proteomic approaches, the mouse model of recurrent HSV-1 infection we previously set up, to investigate whether multiple virus reactivations induced oxidative stress in the mouse brain and affected protein function and related intracellular pathways. Following multiple HSV-1 reactivations, we found in mouse brains increased levels of oxidative stress hallmarks, including 4-hydroxynonenal (HNE), and 13 HNE-modified proteins whose levels were found significantly altered in the cortex of HSV-1-infected mice compared to controls. We focused on two proteins previously linked to AD pathogenesis, i.e., glucose-regulated protein 78 (GRP78) and collapsin response-mediated protein 2 (CRMP2), which are involved in the unfolded protein response (UPR) and in microtubule stabilization, respectively. We found that recurrent HSV-1 infection disables GRP78 function and activates the UPR, whereas it prevents CRMP2 function in mouse brains. Overall, these data suggest that repeated HSV-1 reactivation into the brain may contribute to neurodegeneration also through oxidative damage.

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Section: Discussionmentioning

confidence: 99%

Multiple Herpes Simplex Virus-1 (HSV-1) Reactivations Induce Protein Oxidative Damage in Mouse Brain: Novel Mechanisms for Alzheimer’s Disease Progression

et al. 2020

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“…In female microglia, distinct up‐regulated genes were mainly associated with pathways to neurodegenerative diseases, such as Huntington disease (mmu05016), Parkinson disease (mmu05012), and Alzheimer disease (mmu05010). Female‐specific down‐regulated genes were enriched in the pathways of Herpes Simplex Virus 1 Infection (mmu05168) and ECM‐receptor Interaction (mmu04512) which are responsible for acute and inflammatory response and neuronal damage (Maguire, 2018; Marcocci et al, 2020), suggesting that females might suffer a higher risk of developing neurodegenerative disease after brain injury. To further investigate the mechanism of sex differences in microglial transcriptome after stab wound injury, we analyzed the gene set that had opposite changes in expression between males and females (Figure 3d), and found that genes that were up‐regulated in males but were down‐regulated in females were significantly enriched in ECM‐receptor Interaction (mmu04512) and Focal Adhesion (mmu04510).…”

Section: Resultsmentioning

confidence: 99%

“…showed that male-specific up-regulated genes were involved in T Cell Receptor Signaling Pathway (mmu04660), TNF Signaling Pathway (mmu04668), and Primary Immunodeficiency (mmu05340), while male-specific down-regulated genes were related to Axon Guidance (Maguire, 2018;Marcocci et al, 2020), suggesting that females might suffer a higher risk of developing neurodegenerative disease after brain injury. To further investigate the mechanism of sex differences in microglial F I G U R E 3 Sex difference in microglial transcriptome following cortical stab wound injury.…”

Section: Kegg Pathway Analysis (Figures 3c) and S4) Kegg Pathway Anamentioning

confidence: 99%

Transcriptional profiling of microglia in the injured brain reveals distinct molecular features underlying neurodegeneration

Cong

Dai

Shi

et al. 2021

Glia

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Neurotrauma has been recognized as a risk factor for neurodegenerative diseases, and sex difference of the incidence and outcome of neurodegenerative diseases has long been recognized. Past studies suggest that microglia could play a versatile role in both health and disease. So far, the microglial mechanisms underlying neurodegeneration and potentially lead to sex‐specific therapies are still very open. Here we applied whole transcriptome analysis of microglia acutely isolated at different timepoints after a cortical stab wound injury to gain insight into genes that might be dysregulated and transcriptionally different between males and females after cortical injury. We found that microglia displayed distinct temporal and sexual molecular signatures of transcriptome after cortical injury. Hypotheses and gene candidates that we presented in the present study could be worthy to be examined to explore the roles of microglia in neurotrauma and in sex‐biased neurodegenerative diseases.

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“…HSV-1 has been found in the trigeminal, facial and vestibular nerve ganglia [68]. HSV-1 infection of corneal epithelial cells is thought to result in travel along the branches of the trigeminal nerves and into the trigeminal ganglion [69]. In mouse studies, HSV-1 infection was detected in the olfactory bulbs, following ocular infection [70].…”

Section: Herpes Simplex Virus-1: General Virology and Route Of Infectionmentioning

confidence: 99%

Bioinformatics Review of the Role of HSV-1 in Alzheimer’s Disease

Reiss¹,

Eggleston²,

Godbole³

et al. 2020

AAD

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Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive loss of cognitive functions in affected individuals. Brain tissue pathology is associated with the formation of senile plaques which result from the overproduction of amyloid β (Aβ), due to the cleavage of a membrane bound glycoprotein. It is unclear what causes AD and its associated pathologies, but age and genetic predisposition play an import role in the likelihood of disease development. Studies have shown that the reactivation of latent herpes simplex virus 1 (HSV-1) infection can lead to the neuropathy of acute herpes simplex encephalitis (HSE), which causes similar symptoms to AD. HSV-1 infection is a known risk factor for the development of AD, but no study has determined a definitive causal relationship. Using the Qiagen Ingenuity Pathway Analysis (IPA) tool, the inhibitory relationship between therapeutics for AD and HSV-1 were explored. Thirteen drugs developed to decrease Aβ buildup in AD and 32 drugs that act as HSV antivirals were retrieved from the data in the Qiagen Knowledge Base. These drugs were analyzed displayed as two separate networks. While many promising Aβ aggregation-targeting drugs have been discontinued due to lack of efficacy, HSV drugs could serve as potential therapeutics for those with AD. This review aims to describe new insights on how HSV-1 relates to the development of AD and highlight the mechanism of action of Aβ-related drugs and HSV drugs in the context of AD. With HSV-1 being a likely candidate for the causation of AD, there is a need to study the effects of HSV antiviral drugs on those who have AD.

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Herpes Simplex Virus-1 in the Brain: The Dark Side of a Sneaky Infection

Cited by 164 publications

References 115 publications

Multiple Herpes Simplex Virus-1 (HSV-1) Reactivations Induce Protein Oxidative Damage in Mouse Brain: Novel Mechanisms for Alzheimer’s Disease Progression

Multiple Herpes Simplex Virus-1 (HSV-1) Reactivations Induce Protein Oxidative Damage in Mouse Brain: Novel Mechanisms for Alzheimer’s Disease Progression

Transcriptional profiling of microglia in the injured brain reveals distinct molecular features underlying neurodegeneration

Bioinformatics Review of the Role of HSV-1 in Alzheimer’s Disease

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