pathophysiology of herpes simplex virus 2

However, HSV reactivation can result in recurrent infection of the corneal stroma and HSK, characterized by a chronic inflammatory response that can cause neovascularization, corneal scarring, thinning and vision loss [300,301]. Genital herpes is an STD caused by two types of viruses - herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). Both organisms are enveloped DNA viruses that are sensitive to disinfectants and environmental factors 1. Schiffer JT, Abu-Raddad L, Mark KE, et al. Here we review the HSV life cycle, the interaction of HSV with the immune system and three of the best-studied pathologies: Herpes stromal keratitis, herpes simplex encephalitis and genital herpes. A. Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections, PML contributes to a cellular mechanism of repression of herpes simplex virus type 1 infection that is inactivated by ICP0, Replication of ICP0-null mutant herpes simplex virus type 1 is restricted by both PML and Sp100, Regulation of ICP0-null mutant herpes simplex virus type 1 infection by ND10 components ATRX and hDaxx, MORC3, a component of PML nuclear bodies, has a role in restricting herpes simplex virus 1 and human cytomegalovirus. The use of iPSC-derived neurons with characteristic of CNS or PNS from patients with inborn errors in the TLR3 pathway suggests that the relevance of this PRR against HSV-1 infection differs between these two types of neurons [400]. Toll-like receptors (TLRs) are PRRs that detect PAMPs in nucleic acids and proteins. IFN-s mediate antiviral protection through a distinct class II cytokine receptor complex, The virus battles: IFN induction of the antiviral state and mechanisms of viral evasion. HSV-2. HSV-2-specific CD4 T cells have a Trm phenotype and persist in previously infected human skin and genital mucosa and, together with NK cells, express IFN- [273]. Schoenborn JR, Dorschner MO, Sekimata M, et al. Hence, it is plausible that HSV-1 initially afflicts the limbic system, then travels to basal forebrain areas, resulting in retrograde and anterograde amnesias [422]. Distinct factors control histone variant H3.3 localization at specific genomic regions, Histone chaperone HIRA deposits histone H3.3 onto foreign viral DNA and contributes to anti-viral intrinsic immunity, ATRX promotes maintenance of herpes simplex virus heterochromatin during chromatin stress, The histone variant H3.3 regulates gene expression during lytic infection with herpes simplex virus type 1, The two functions of herpes simplex virus 1 ICP0, inhibition of silencing by the CoREST/REST/HDAC complex and degradation of PML, are executed in tandem, During latency, herpes simplex virus type 1 DNA is associated with nucleosomes in a chromatin structure, Strength in diversity: understanding the pathways to herpes simplex virus reactivation. However, other reports suggest that neutrophils are not essential for virus clearance [312,316]. Neuronal hyperexcitability is a DLK-dependent trigger of herpes simplex virus reactivation that can be induced by IL-1, Neuronal stress pathway mediating a histone methyl/phospho switch is required for herpes simplex virus reactivation, Transient reversal of episome silencing precedes VP16-dependent transcription during reactivation of latent HSV-1 in neurons, HSV-1 gene expression from reactivated ganglia is disordered and concurrent with suppression of latency-associated transcript and miRNAs, Virologic characteristics of subclinical and symptomatic genital herpes infections, Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons, Asymptomatic shedding of herpes simplex virus (HSV) in the oral cavity, Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Two of the most prevalent human viruses worldwide, herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2, respectively), cause a variety of diseases, including cold sores, genital herpes, herpes . To achieve antibody-mediated protection in the vaginal mucosa plasma cells must migrate into the tissue since circulating antibodies do not normally enter. Everett RD, Earnshaw WC, Findlay J, et al. Lafaille FG, Pessach IM, Zhang SY, et al. The hypotheses are that HSV-1 either directly infects these brain areas through the olfactory bulb during acute infection phase, or after reactivation in the TG. Miranda-Saksena M, Boadle RA, Armati P, et al. Introduction of the HSV-2 VP16 promoter sequence in the HSV-1 background led to a more virulent virus that reactivated more efficiently and caused higher mortality in mice upon corneal infection [96]. Identification and characterization of herpes simplex virus-specific CD4+ T cells in corneas of herpetic stromal keratitis patients, Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition, An effector phenotype of CD8+ T cells at the junction epithelium during clinical quiescence of herpes simplex virus 2 infection, Persistence of skin-resident memory T cells within an epidermal niche, T cell memory. These observations indicate the existence of a chronic inflammatory response that could be pathogenic [418]. pUL36 and pUL37 direct the movement of capsids on microtubules toward the site of secondary envelopment [5257]. Moreover, the genital ulcers caused by HSV-2 disrupt the mucosa, facilitating HIV acquisition [371]. Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden. Most of the signaling cascades activated by PRRs upon recognition of HSV lead to the expression of IFNs, one of the main cytokine families inhibiting HSV. Dohner K, Ramos-Nascimento A, Bialy D, et al. Experiments in vitro suggest that A binds HSV-1 gB, gC, gD, gE, gH and gG and that A fibrillar structures capture and neutralize HSV-1 and HHV-6 particles [435]. Several proteins inhibit the activation of IRF3. Since HSV-1 recurrences are less aggressive than those caused by HSV-2, it is important to determine with a laboratory assay such as polymerase chain reaction (PCR) whether HSV-1 or HSV-2 is the causative agent, in order to tailor the patient counseling [355]. [1] Most commonly, viral replication occurs in epithelial tissue and establishes dormancy in sensory neurons, reactivating periodically as localized recurrent lesions. The answer to this question could be in the connection between the neuronal stress response and the c-Jun N-terminal kinase (JNK) pathway. However, HSV can establish latency and reactivate in human brain organoids [65]. The very first outbreak of genital herpes often causes more severe symptoms than later outbreaks. These cells, together with resident cells secrete cytokines to control virus spread in the CNS, and some of them are highly concentrated in the CSF during acute HSE. However, HSV DNA has been found in human CNS and HSV-1 can establish latency in human brain organoids [65,66], suggesting that a similar process could occur in vivo. The anus is also affected, especially in men who have sex with men. In the U.S.HSV-1 is more prevalent than HSV-2,. Letter in response to: making the case: married versus separate models of alphaherpes virus anterograde transport in axons, Microtubule-dependent trafficking of alphaherpesviruses in the nervous system: the ins and outs, Modeling herpes simplex virus 1 infections in human central nervous system neuronal cells using two- and three-dimensional cultures derived from induced pluripotent stem cells, Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction, Polarized cell migration during cell-to-cell transmission of herpes simplex virus in human skin keratinocytes, Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. sharing sensitive information, make sure youre on a federal Sensory neurons regulate the effector functions of CD8+ T cells in controlling HSV-1 latency ex vivo. There is no cure for herpes , but treatment can help manage symptoms and reduce the likelihood of . Further outbreaks are usually milder. The tegument protein VP22 interacts with cGAS, inhibiting the formation of cGAMP and thereby type I IFN production [202]. Secreted herpes simplex virus-2 glycoprotein G modifies NGF-TrkA signaling to attract free nerve endings to the site of infection. In humans, HSV-1-specific CD8 and CD4 T cells are also present in infected TG [110,111]. Herpes simplex is caused by one of two types of herpes simplex virus (HSV), members of the Herpesvirales family of double-stranded DNA viruses. The VP16/HCF-1/Oct-1 complex also binds to REST/CoREST/HDAC nuclear repressor complex, leading to the removal of heterochromatin and facilitating the addition of euchromatin marks on histones associated with IE genes. There are two types of this virus. In humans, exposure to UV light, changes in hormone levels and fever can trigger HSV reactivation [145]. Jambunathan N, Charles AS, Subramanian R, et al. A mechanism employed by HSV to inhibit NFB signaling is to block the nuclear translocation of the p50/p65 complex to the nucleus. Without treatment, most infants die, in particular those suffering from encephalitis or disseminated disease [359,363]. Both bind to HSV DNA and promote its heterochromatinization, silencing the viral genome [129131]. Genital herpes is caused by two types of herpes simplex virus. The risk of transmission to the newborn is higher when infection of a seronegative mother occurs in the third trimester of pregnancy [6,358]. It has been suggested that the existence of a pro-inflammatory immune response and an angiogenic milieu is due to HSV latency in the cornea or the presence of HSV DNA or proteins after resolution of an active infection [303]. Pro-inflammatory cytokines and immune cells are present in these lesions, including T cells, monocytes and macrophages [280,351]. herpes simplex virus type 2 typically causes genital herpes, usually sexually transmitted. Herpes simplex encephalitis. Like all herpesviruses, HSV has two replication cycles: lytic and latent. HSV-1 pUS3 inhibits TLR2 signaling pathway by reducing TRAF6 ubiquitination and thereby the NFB pathway [200]. pUL36 and pUL37 are required for HSV transport from the nucleus toward the periphery through interaction with kinesin [27,52,54,60,61]. The disease is more common in women than men, at least in certain geographical locations [344]. HSV inhibits antigen presentation through several mechanisms. Electron microscope cannot distinguish different [] Sequelae related to brain inflammation include changes in behavior, lower consciousness and altered cognitive functions. Children with SCID are not at higher risk of HSE than others, but have more severe epithelial infection, suggesting that the adaptive immune response is not the main defense against childhood HSE but is required for protection at the periphery [414]. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC, Innate immune mechanisms and herpes simplex virus infection and disease. Herpes simplex virus type 1 encephalitis. During the lytic cycle, histones 3 (H3) containing repressive marks decorate the incoming HSV-1 genomes from one hour post-infection [120,121] and inhibit the transition from IE to E gene expression [122]. The different levels of LAT expression in different neurons might also influence establishment and maintenance of latency. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. This increases the innate immune response against HSV-1 by inducing the expression of antiviral genes, including cytokines and ISG [192]. Practice parameter for the diagnosis and management of primary immunodeficiency, Herpes simplex encephalitis. Most commonly, viral replication occurs in epithelial tissue and establishes dormancy in sensory neurons, reactivating periodically as localized recurrent lesions. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells, Homing in on the cellular immune response to HSV-2 in humans. ICP34.5 inhibits STING activation [208]. pUL36 also deubiquitinates TRAF3, required for the induction of IFN through TLR3 [206]. The herpes simplex viruses comprise 2 distinct types of DNA viruses: herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). Type 1 HSV is mainly associated with oral and facial infections Type 2 HSV is mainly associated with genital and rectal infections ( anogenital herpes) The virus may also travel to the CNS where it could cause encephalitis or meningitis. Sawtell NM, Thompson RL, Stanberry LR, et al. The interaction between HSV and the host, in particular with the immune system, determines the outcome of infection. HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression, Herpes simplex virus 1 gamma134.5 protein inhibits STING activation that restricts viral replication, Evasion of the STING DNA-sensing pathway by VP11/12 of herpes simplex virus 1, Herpes simplex virus 1 tegument protein UL46 inhibits TANK-binding kinase 1-mediated signaling, Herpes simplex virus 1 VP22 inhibits AIM2-dependent inflammasome activation to enable efficient viral replication, Relative contributions of herpes simplex virus 1 ICP0 and vhs to loss of cellular IFI16 vary in different human cell types, Herpes simplex virus 1 abrogates the cGAS/STING-mediated cytosolic DNA-sensing pathway via its virion host shutoff protein, UL41, Herpes simplex virus 1 protein kinase US3 hyperphosphorylates p65/RelA and dampens NF-B activation, Herpes simplex virus 1 Ubiquitin-specific protease UL36 abrogates NF-B activation in DNA sensing signal pathway, Herpes simplex virus 1 E3 Ubiquitin Ligase ICP0 protein inhibits tumor necrosis factor alpha-induced NF-B activation by interacting with p65/RelA and p50/NF-B1, HSV-1 ICP27 suppresses NF-B activity by stabilizing IB, Herpes simplex virus 1 UL24 abrogates the DNA sensing signal pathway by inhibiting NF-B activation, Herpes simplex virus 1-encoded tegument protein VP16 abrogates the production of beta interferon (IFN) by inhibiting NF-kappaB activation and blocking IFN regulatory factor 3 to recruit its coactivator CBP, Herpes simplex virus virion host shutoff attenuates establishment of the antiviral state, Inhibition of PKR activation by the proline-rich RNA binding domain of the herpes simplex virus type 1 Us11 protein, The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase, Herpes simplex virus 1 serine protease VP24 blocks the DNA-sensing signal pathway by abrogating activation of interferon regulatory factor 3, Control of TANK-binding kinase 1-mediated signaling by the gamma(1)34.5 protein of herpes simplex virus 1, Role of herpes simplex virus 1 gamma34.5 in the regulation of IRF3 signaling, Herpes simplex virus 1 serine/threonine kinase US3 hyperphosphorylates IRF3 and inhibits beta interferon production, Cellular localization of the herpes simplex virus ICP0 protein dictates its ability to block IRF3-mediated innate immune responses, The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes, Expression of gamma interferon-dependent genes is blocked independently by virion host shutoff RNase and by US3 protein kinase, Herpes simplex virus 1 UL36USP antagonizes type I interferon-mediated antiviral innate immunity, Herpes simplex virus 1 gene products occlude the interferon signaling pathway at multiple sites, Herpes simplex virus 1 counteracts viperin via its virion host shutoff protein UL41, Herpes simplex virus 1 counteracts tetherin restriction via its virion host shutoff activity, Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation, Immune surveillance by CD8alphaalpha+ skin-resident T cells in human herpes virus infection, Enrichment of herpes simplex virus type 2 (HSV-2) reactive mucosal T cells in the human female genital tract, Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine, Peripheral blood CD4 T-cell and plasmacytoid dendritic cell (pDC) reactivity to herpes simplex virus 2 and pDC number do not correlate with the clinical or virologic severity of recurrent genital herpes, Diversity in CD8(+) T cell function and epitope breadth among persons with genital herpes, CD4 T-cell memory responses to viral infections of humans show pronounced immunodominance independent of duration or viral persistence. We also discuss the potential association between HSV-1 infection and Alzheimers disease. It is not clear how CD4 and CD8 T cells recognize the latently infected neurons since viral proteins are not normally expressed during latency and neurons are not efficient antigen presenting cells. Other HSV proteins such as pUL20 and gK also participate in secondary envelopment [58,59]. Cunningham A, Miranda-Saksena M, Diefenbach R, et al. The deubiquitinase (DUB) activity of pUL36 is required to reduce type I IFN production in mice [205]. Kropp KA, Lopez-Munoz AD, Ritter B, et al. Suryawanshi A, Veiga-Parga T, Rajasagi NK, et al. The neurotrophic factors like nerve growth factor (NGF) and the cytokine IL-17C induce neurite outgrowth. Causes Symptoms Transmission Diagnosis Treatment Herpes meningitis is a form of meningitis caused by the herpes virus. Trm cells contact several cells with their dendrite-like projections and stay activated in the absence of antigen stimulation [275]. Melchjorsen J, Rintahaka J, Soby S, et al. The presence of HSV-specific CD8 T cells that could control HSV reactivation in mouse and human sensory ganglia does not match with the frequent reactivation observed in humans [151,269]. In vitro experiments with primary human genital epithelial cells showed that Fc receptors facilitate transcytosis of anti-HSV-2 IgG antibodies. For instance, the expression of several proteins involved in the intrinsic response can be enhanced by IFN. natalizumab) increases the risk of HSE. Herpes is a viral infection that comes in two types. HSV cell cycle. Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation, Herpes simplex virus type 1 DNA is located within Alzheimers disease amyloid plaques. Stefanidou M, Ramos I, Mas Casullo V, et al. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells, NEMO is a key component of NF-kappaB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus. Immediate early (IE) genes infected cell protein (ICP) 0, ICP4, ICP22, ICP27, ICP47 and unique short (US) 1.5 are expressed in the absence of de novo viral protein synthesis. T cell density inversely correlates with symptomatic recurrences [277,279]. Sensing of HSV leads to the expression of cytokines resulting in HIRA interaction with PML-NBs in a JAK, cyclin-dependent kinase and Sp100-dependent manner. The inner tegument protein pUL36 deubiquitinates IB and thereby inhibits its degradation [215]. Viral replication is required for induction of ocular immunopathology by herpes simplex virus, Characterization of herpes simplex virus type-1 infection and herpetic stromal keratitis development in IFN-gamma knockout mice. Epigenetic modifications regulate establishment and maintenance of latency and reactivation at the molecular level [118]. Epidemiological and clinical studies showed that genital herpes is positively linked to the risk of acquiring and transmitting HIV [368370]. Herpes simplex viruses (human herpesviruses types 1 and 2) commonly cause recurrent infection affecting the skin, mouth, lips, eyes, and genitals. Some HSE patients suffer relapses after the first episode [388], normally due to HSV replication or to HSE-induced autoimmune encephalitis, a disease that impairs cognitive performance. Both non-hematopoietic and hematopoietic resident cells of the CNS play relevant roles in protection. The mature, DNA containing capsids (C capsids) leave the nucleus through an envelopment-deenvelopment process and acquire tegument and envelope (not shown) prior to cellular egress (14). Data from animal models and in vitro suggest that the view of latent and lytic cycles as mutually exclusive is perhaps not completely correct, and that there are intermediate stages with different levels of viral gene expression [103]. In developed countries, 20% of the general population is HSV2 seropositive. The fusion of the HSV envelope with a cellular membrane is also sensed by PRR, triggering calcium signaling, activation of the stimulator of IFN genes (STING), IRF3 and IFN response [169]. The action of the immune system clears primary HSV infection in about 714days. The RE1-silencing transcription factor (REST)/CoREST/histone deacetylases (HDAC) nuclear repressor complex contributes to silence the HSV-1 genome and to regulate latency and reactivation [122]. These particles travel in an anterograde manner to the skin or mucosa causing the typical herpes lesions. Interestingly, HSV-2 also induces IL-17C expression in keratinocytes of the human genital tract during reactivation, leading to neurite outgrowth [72].

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