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

Trends in Microbiology, Год журнала: 2020, Номер 28(10), С. 808 - 820

Опубликована: Май 5, 2020

After primary infection, HSV-1 can reach the central nervous system where, in rare cases, it replicates and triggers an acute inflammatory response resulting herpes simplex encephalitis (HSE).The presence of genome has been revealed tissues peripheral individuals with no clinical signs HSE.In humans, levels circulating anti-HSV immunoglobulins, considered as markers reactivation, have positively correlated increased risk Alzheimer's disease (AD).Experimental data show that infection neurons activates neurotoxic pathways typical AD, repeated reactivations brain infected mice produce AD-like phenotype.Further studies are required to get greater mechanistic understanding causal links between recurrent infections AD well validate experimental findings humans. Herpes virus-1 (HSV-1) establishes latency preferentially sensory ganglia. A variety stresses induce virus, which spreads then actively site (usually lips or eyes). Viral particles produced following reactivation also brain, causing a but severe form diffuse namely encephalitis. Most time, this is clinically asymptomatic. However, was recently production accumulation neuropathological biomarkers disease. In review we discuss different cellular molecular mechanisms underlying long-term damage caused by brain. widely distributed neurotropic human pathogen transmitted mainly intimate contact susceptible individuals, causes labial, ocular, genital [1.Roizman B. et al.Herpes viruses.in: Knipe D.M. Fields Virology. 6th edn. Wolters Kluwer/Lippincott Williams & Wilkins, 2013: 1823-1897Google Scholar]. Primary usually occurs during childhood: over 60% under 50 years age worldwide [2.Looker K.J. al.Global regional estimates prevalent incident virus type 1 2012.PLoS One. 2015; 10e0140765Crossref PubMed Scopus (203) Google epithelial cells, becomes latent (PNS) be periodically reactivated subclinical episodes throughout life Although sympathetic affected, infects close [3.Bastian F.O. al.Herpesvirushominis: isolation from trigeminal ganglion.Science. 1972; 178: 306-307Crossref Scholar,4.Warren K.G. al.Isolation superior cervical vagus ganglions beings.N. Engl. J. Med. 1978; 298: 1068-1069Crossref Scholar], subsequently traveling retrogradely along axon cell body Studies animal models shown (CNS) [5.Kastrukoff L. al.Central immune inoculated into lip 1.J. Neuroimmunol. 1982; 2: 295-305Abstract Full Text PDF Scholar, 6.Rock D.L. Fraser N.W. Detection latently mice.Nature. 1983; 302: 523Crossref (226) 7.Shimeld C. al.Spread distribution after intraocular mouse.Arch. Virol. 1985; 85: 175-187Crossref (0) 8.Dyson H. within ocular nerves mouse: demonstration viral antigen whole mounts eye tissue.J. Gen. 1987; 68: 2989-2995Crossref 9.Mori I. al.The vomeronasal chemosensory route neuroinvasion virus.Virology. 2005; 334: 51-58Crossref 10.Chen S.H. al.Efficient mouse tissues.J. 2006; 80: 12387-12392Crossref (26) 11.Yao H.W. al.In vivo occur before occurring ganglion.J. 2014; 88: 11264-11270Crossref (28) 12.Jennische E. anterior commissure pathway for contralateral spread olfactory tract infection.J. Neurovirol. 21: 129-147Crossref (13) 13.Doll J.R. al.Infectious brainstem ganglia.J. 2019; 93: e02209-e02218Crossref (3) 14.De Chiara G. al.Recurrent induces hallmarks neurodegeneration cognitive deficits mice.PLoS Pathog. 15e1007617Crossref (12) Scholar] (Figures 2A ). replication may result (HSE) (reviewed [15.Gnann Jr., J.W. Whitley R.J. encephalitis: update.Curr. Infect. Dis. Rep. 2017; 19: 13Crossref (42) Scholar]) milder/asymptomatic eventually followed [16.Olsson al.HSV brains without dementia: TASTY series.Dis. Model. Mech. 2016; 9: 1349-1355Crossref growing evidence indicates cumulative effects 'mild' neuronal similar found neurodegenerative disorders such (AD), most common dementia elderly (Box 1) [17.De agents neurodegeneration.Mol. Neurobiol. 2012; 46: 614-638Crossref (69) Here, recent knowledge on pathogenic reactivations.Figure 2Schematic Representation Simplex Virus-1 Human Murine Brain Areas.Show full caption(A) Sagittal representation murine showing areas detected oral, nasal, inoculation (indicated colored dots) models; related studies, detection methods, listed below. (B) (left) external (right) DNA postmortem brains; methods Colored HSV-1-positive. (See Scholar,36.Fraser tissue.Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 6461-6465Crossref Scholar,37.Baringer Pisani P. genomes tissue analyzed polymerase chain reaction.Ann. Neurol. 1994; 36: 823-829Crossref Scholar,68.Jamieson G.A. al.Latent normal brains.J. 1991; 33: 224-227Crossref Scholar,69.Ithzaki R.F. disease.Lancet. 1997; 349: 241-244Abstract (384) Scholar,105.Wozniak M.A. located amyloid plaques.J. Pathol. 2009; 217: 131-138Crossref (186) Scholar,115.Gordon al.Detection (types 2) herpesvirus 6 reaction.Clin. Diagn. 1996; 6: 33-40Abstract 116.Itabashi 1102Abstract 117.Cheon M.S. al.Evidence relation Down syndrome disease.Electrophoresis. 2001; 22: 445-448Crossref Scholar].)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Box 1Alzheimer's DiseaseAlzheimer's (AD) estimated 40–50 million currently affected worldwide, number expected double next 20 [63.Scheltens al.Alzheimer's 388: 505-517Abstract (1214) characterized progressive impairment functions, particularly memory. While genetic mutations precursor protein (APP) presenilin proteins account small percentage cases [familial (FAD)], majority sporadic (SAD), thought involve as-yet-unidentified environmental factors. There effective therapy available pharmacological treatments primarily aimed at enhancing cholinergic activity, reduced patients, delaying formation plaques (see Box 3). Several mechanisms, including beta (Aβ) phospho Tau (pTau) oligomers, oxidative stress, mitochondrial dysfunction, neuroinflammation proposed contribute onset progression. Recent epidemiological strongly support hypothesis microbial factors AD. Specifically, type-1 gaining attention because its ability cause recurrent, life-long infection. (A) Scholar].) consists linear double-stranded icosapentahedral capsid. The capsid surrounded amorphous proteinaceous coating (the tegument) envelope, multiple glycoprotein spikes embedded. Virus binding entry host cells mediated specific association glycoproteins (gB, gC, gD, gH/gL complex) receptors target mediator (HVEM), heparan sulfate moieties, cell-adhesion nectin-1 nectin-2 [18.Hilterbrand A.T. Heldwein E.E. Go gadget glycoprotein! draws sizeable tool kit customize diverse routes.PLoS 15e1007660Crossref (1) Scholar]). enters fusion membranes, process interaction gD [19.Richart S.M. al.Entry vitro Nectin-1/HveC.J. 2003; 77: 3307-3311Crossref (63) This termini ganglia (TG) innervate orofacial corneal layer. capsids travel retrograde axonal transport, enter ganglion neurons, release nucleus establish favored inefficient transport tegument transactivator VP16, efficiently activate lytic program, described below [20.Sawtell N.M. Thompson R.L. De novo VP16 expression gates dynamic programmatic transition sets latent/lytic balance ganglia.PLoS 12e1005877Crossref [21.Wilson A.C. Mohr cultured affair: HSV neurons.Trends Microbiol. 20: 604-611Abstract (76) Latent persist episomal forms nucleus, where they interact promyelocytic leukemia (PML) nuclear bodies (NBs) involved establishment [22.Catez F. al.HSV-1 subnuclear positioning associations host-cell PML-NBs centromeres regulate LAT locus transcription neurons.PLoS 8e1002852Crossref 23.Maroui al.Latency determined environment.PLoS 12e1005834Crossref (18) 24.Cohen al.Promyelocytic latent/quiescent chromatinization through PML NB/histone H3.3/H3.3 chaperone axis.PLoS 2018; 14e1007313Crossref (7) During latency, chromatinized heterochromatic histone marks, whereby only subset genes expressed [25.Knipe Cliffe Chromatin control infection.Nat. Rev. 2008; 211-221Google Scholar,26.Bloom D.C. al.Epigenetic regulation gene expression.Biochim. Biophys. Acta. 2010; 1799: 246-256Crossref (130) abundant products latency-associated transcripts (LATs), 8.3/9 kb transcript two stable introns (2.0 1.5 kb) derived rapid splicing Scholar,25.Knipe addition LATs, produces several microRNAs (miRNA) Glossary) [27.Krause P.R. preliminary characterization 1988; 62: 4819-4823Crossref Scholar,28.Umbach J.L. al.MicroRNAs mRNAs.Nature. 454: 780-783Crossref (460) act synergistically LATs repress inhibition apoptosis stimulation [29.Cokarić Brdovčak M. deregulation micrornas.Noncoding RNA. 4: 36Google range stimuli, fever, emotional hormone imbalance, UV exposure, trauma, immunosuppression, reactivate These directly affect HSV-1-infected level surrounding, non-neuronal (e.g., satellite glia CD8+ T cells), promoting Newly synthesized sustain [30.Thompson al.De synthesis coordinates exit vivo.PLoS 5e1000352Crossref Reactivation results productive although abortive Scholar,31.Ma J.Z. al.Lytic frequent correlates engagement cell-intrinsic transcriptional response.PLoS 10e1004237Crossref begins sequential three subsets [immediate early (IE), (E), late (L) genes] RNA II. initial IE genes, E expression, turn L genes. Structural new assembled capsids, translocate cytoplasm, probably budding inner membrane (envelopment phase) fusing outer (de-envelopment phase). Naked acquire their definitive envelope (re-envelopment vesicles trans-Golgi network, mature virion exits near [32.Miranda-Saksena al.Infection neurons: role cytoskeleton.Viruses. 10: 92Crossref Alternatively, naked glycoproteins, complete virions, anterogradely inside separate anchored microtubule scaffolding, reaching shaft tip periphery, released Usually, gives rise blisters, sores, ulcers asymptomatic, despite shedding newly infectious [33.Ramchandani tears, nasal oral mucosa healthy adults.Sex. Transm. 43: 756Crossref Because pseudounipolar, CNS via anterograde transport. one branches TG projects nuclei brainstem, projections thalamus and, there, cortex. therefore direct [34.Bearer E.L. HSV, disease: relationships.Fut. 7: 885-899Crossref HSE, (estimated incidence: 2.5–12 cases/million/year [35.Modi al.Burden United States.J. 264: 1204-1208Crossref (17) 70% mortality untreated patients up 30% combined high incidence neurological sequelae treated antivirals. one-third two-thirds all HSE respectively suggesting [36.Fraser Postmortem must interpreted caution, confounding taken fixation/storage lateralization, handling, contamination, protein/nucleic acid degradation, impact antemortem drug duration agonal status (discussed [37.Baringer Scholar,38.Ferrer al.Effects formalin fixation, paraffin embedding, time storage preservation tissue: BrainNet Europe study.Brain 2007; 17: 297-303Crossref these unlikely influenc

Язык: Английский

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Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

Frontiers in Neuroscience, Год журнала: 2018, Номер 12

Опубликована: Июнь 8, 2018

Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in elderly population worldwide. A growing body epidemiological studies suggest that people with T2DM at a higher risk developing AD. Likewise, AD brains less capable glucose uptake from surroundings resembling condition brain insulin resistance. Pathologically is characterized by extracellular plaques A intracellular neurofibrillary tangles hyperphosphorylated tau. T2DM, on other hand metabolic disorder hyperglycemia In this review we have discussed how Insulin resistance directly exacerbates tau pathologies elucidated pathophysiological traits synaptic dysfunction, inflammation autophagic impairments common to both indirectly impact functions neurons. Elucidation underlying pathways connect these will be immensely valuable for designing novel drug targets disease.

Язык: Английский

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Dendritic Tau in Alzheimer’s Disease

Neuron, Год журнала: 2018, Номер 99(1), С. 13 - 27

Опубликована: Июль 1, 2018

The microtubule-associated protein tau and amyloid-β (Aβ) are key players in Alzheimer's disease (AD). Aβ linked a molecular pathway at the post-synapse with tau-dependent synaptic dysfunction being major pathomechanism AD. Recent work on site-specific modification of dendritic more specifically post-synaptic has revealed new endogenous functions that limits toxicity. Thus, studies opened perspective tau, placing it center neurotoxic neuroprotective signaling post-synapse. Here, we review recent advances compartments, implications for understanding treatment AD related neurological conditions.

Язык: Английский

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Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice

PLoS Pathogens, Год журнала: 2019, Номер 15(3), С. e1007617 - e1007617

Опубликована: Март 14, 2019

Herpes simplex virus type 1 (HSV-1) is a DNA neurotropic virus, usually establishing latent infections in the trigeminal ganglia followed by periodic reactivations. Although numerous findings suggested potential links between HSV-1 and Alzheimer's disease (AD), causal relation has not been demonstrated yet. Hence, we set up model of recurrent infection mice undergoing repeated cycles viral reactivation. By virological molecular analyses found: i) spreading replication different brain regions after thermal stress-induced reactivations; ii) accumulation AD hallmarks including amyloid-β protein, tau hyperphosphorylation, neuroinflammation markers (astrogliosis, IL-1β IL-6). Remarkably, progressive biomarkers neocortex hippocampus infected mice, triggered reactivations, correlated with increasing cognitive deficits becoming irreversible seven Collectively, our provide evidence that mild central nervous system produce an AD-like phenotype suggest they are risk factor for AD.

Язык: Английский

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Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade

Journal of Alzheimer s Disease, Год журнала: 2018, Номер 64(s1), С. S611 - S631

Опубликована: Май 29, 2018

The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in last 25 years. It posits that increase of amyloid-β (Aβ) is key event AD triggers tau pathology followed by neuronal death and eventually, disease. However, therapeutic approaches aimed at d ecreasing Aβ levels have so far failed, tau-based clinical trials not yet produced positive findings. This begs question whether hypothesis correct. Here we examined literature on role synaptic dysfunction, memory loss, seeding spreading AD, highlighting important parallelisms between two proteins all these phenomena. We discuss novel findings showing binding both oligomers to protein precursor (AβPP), requirement for presence this enter neurons induce abnormal function memory. Most importantly, propose a view pathogenesis which extracellular act parallel upstream AβPP. Such will call reconsideration directed against tau, paving way an increased interest toward AβPP, understanding elaborating new strategies.

Язык: Английский

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Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases

Progress in Neurobiology, Год журнала: 2022, Номер 214, С. 102270 - 102270

Опубликована: Апрель 18, 2022

Aggregation of specific proteins are histopathological hallmarks several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer's disease (AD); morphologically different inclusions ratiometric 3 repeat (3 R) 4 (4 isoforms progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) dystrophic neurites (LNs) Parkinson's (PD) dementia with (DLB). However, mixed brain protein pathologies have been frequently observed many these diseases normal aging brains, among which Aβ/tau tau/α-Syn crosstalks received increased attention. Interestingly, studies also shown synergistic interplay Aβ, tau, α-Syn suggesting a triumvirate. In this review, we summarize the emerging evidence aggregation pathophysiology, their overlap spectrum including AD, PSP, PiD, CBD, PD DLB. We discuss prognostic advancements made biomarker imaging techniques triumvirate proteinopathies. Finally, combined therapeutic modality involving biomarkers for future combinatorial immunotherapeutic targeting more than one aggregates. hope that multitarget approach will or additive effects to manage two might uncover promising strategy personalized combination therapies. Managing by optimizing diagnostic criteria correct immunotherapies be key factor success treatment.

Язык: Английский

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Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects

Frontiers in Neuroscience, Год журнала: 2018, Номер 12

Опубликована: Фев. 6, 2018

Alzheimer's disease (AD), the most common form of dementia in late life, will become even more prevalent by midcentury, constituting a major global health concern with huge implications for individuals and society. Despite scientific breakthroughs during past decades that have expanded our knowledge on cellular molecular bases AD, therapies effectively halt progression are still lacking, focused efforts needed to address this public challenge. Because AD is classically recognized as memory, studies mainly investigating memory-associated brain defects. However, compelling evidence has indicated additional regions, not linked also affected course disease. In review, we outline current understanding key pathophysiological mechanisms their clinical manifestation. We highlight how considering complex nature pathogenesis, exploring repurposed drug approaches can pave road toward development novel therapeutics AD.

Язык: Английский

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The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases

Translational Neurodegeneration, Год журнала: 2021, Номер 10(1)

Опубликована: Ноя. 10, 2021

Abstract Alzheimer’s disease (AD) is a neurodegenerative characterized by progressive cognitive decline, accompanied amyloid-β (Aβ) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark AD, recognized as main cause of impairments. Accumulating evidence suggests that synaptic dysfunction could be early event AD. Pathological tau, which detached from axonal microtubules mislocalized into pre- postsynaptic neuronal compartments, suggested to induce several ways, including reducing mobility release presynaptic vesicles, decreasing glutamatergic receptors, impairing maturation dendritic spines at terminals, disrupting mitochondrial transport function synapses, promoting phagocytosis synapses microglia. Here, we review current understanding how mediates contributes decline We propose elucidating mechanism impairs essential for exploring novel therapeutic strategies

Язык: Английский

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Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease

Neuron, Год журнала: 2022, Номер 110(18), С. 2929 - 2948.e8

Опубликована: Июль 25, 2022

Язык: Английский

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Synaptic oligomeric tau in Alzheimer’s disease — A potential culprit in the spread of tau pathology through the brain

Neuron, Год журнала: 2023, Номер 111(14), С. 2170 - 2183.e6

Опубликована: Май 15, 2023

In Alzheimer's disease, fibrillar tau pathology accumulates and spreads through the brain synapses are lost. Evidence from mouse models indicates that trans-synaptically pre- to postsynapses oligomeric is synaptotoxic, but data on synaptic in human scarce. Here we used sub-diffraction-limit microscopy study accumulation postmortem temporal occipital cortices of control donors. Oligomeric present postsynaptic terminals, even areas without abundant deposition. Furthermore, there a higher proportion compared with phosphorylated or misfolded found at terminals. These suggest an early event pathogenesis may progress via trans-synaptic spread disease. Thus, specifically reducing be promising therapeutic strategy for

Язык: Английский

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