MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Zhoršení stavu

5-HT - 5-hydroxytryphan

  • Provides an accessory signal to T cells that enhances both their activation and proliferation
  • 5-HT pathways and its receptors with enhancement of viral infection, replication, and disease progression
    • JC polyomavirus, Hepatitis C virus, Ebola, and Marburg viruses utilize 5-HT receptors as
      • Viral entry receptor
      • Co-receptor
  • Can rescue IFN-g and IDO-mediated inhibition of Parainfluenza virus replication
  • Platelets and mast cells store large amounts of 5-HT
  • T cells, which are in part responsible for the immunopathogenesis associated with HSV infections of the eye
    • 5-HT functions as an accessory factor that enhances disease-promoting T cell activation and proliferation (Leon-Ponte et al., 2007).
  • Acute herpes keratitis
    • Strong, positive, and significant correlation between
      • 5-HT levels in AH and many inflammation-related clinical assessments of ocular disease severity
  • Excess 5-HT in tears has been associated with inflammatory dry eye
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8982329/

Beta2-adrenergic receptor

  • Expressed on sensory and sympathetic neurons
  • Activates adenylate cyclase
  • Results in increased levels of the second messenger cAMP
  • Gold et al., 1997, Vásquez and Lewis, 2003

Forskolin

  • Activates adenylate cyclase
  • Commonly used in cultured neurons to trigger HSV reactivation
  • Colgin et al., 2001, De Regge et al., 2010, Halford et al., 1996

cAMP-dependent signaling pathways

  • That ultimately promote HSV reactivation
  • Pseudorabies virus (PRV)
    • Repression of an axon-specific infection could be overcome by addition of forskolin in a JNK-dependent manner
  • Koyuncu et al., 2017


Epinephrine

  • Iontophoresis of epinephrine has been widely used to reactivate HSV-1 in different animal models
    • (Creech and Neumann, 2010, Rootman et al., 1990, Willey et al., 1984)

HDAC inhibitor

  • Potentially bypass up-stream cellular pathways
  • Act directly on the viral chromatin (Neumann et al., 2007b)
  • Stimuli result in efficient re-entry into lytic replication
    • Prove useful for assessing the role of host proteins in maintaining latency

HDAC inhibition

Depletion of a cellular protein


Lysine-specific demethylase 1 (LSD1) stimulace

  • HSV diverts a component of the repressive complex, lysine-specific demethylase 1 (LSD1), to demethylate suppressive epigenetic marks and thereby activate transcription (Roizman, 2011; Hill et al., 2014).

Adenovirus

  • Similarly inactivates REST/NRSF repressive functions through expression of E1A,
    • Thereby inducing normally suppressed neuron-associated gene expression (Guan et al., 2009).
  • Upregulation of TPH2 expression in Adenovirus infected epithelial cells
  • Viral induction of TPH enzymes and 5-HT synthesis may be a common theme among numerous viral pathogens to enable their efficient replication and consequently may also contribute to disease development.

Increased cyclooxygenase (COX)-2 expression

  • In the skin of UVB-exposed mice
  • Activation of a COX-2 gene
    • May well be a cellular mechanism important in the induction of herpetic recurrences
    • Stimulate the virus to reproduce
  • Mice heat stress
    • Increase in COX-2 gene transcription occurs
    • Within an hour after the application of heat stress alone, only COX-2 and heat shock protein genes were activated
  • Heat-stressed animals that are prone to herpes recurrences
    • Require the induction of the COX-2 gene to induce the recurrences
    • Perhaps agents that inhibit this process would also be effective in preventing the recurrences
  • iovs.arvojournals.org/article.aspx?articleid=2123004


Atopic dermatitis

  • Associated with atopic dermatitis is disseminated infection with herpes simplex virus resulting in eczema herpeticum
    • Diffuse vesicular rash, fever, and lymphadenopathy
  • Approximately 3% of patients with atopic dermatitis
    • Mortality rate of up to 10% when left untreated

Immunocompromised individuals


Dexamethasone

  • A synthetic corticosteroid
  • Stimulates reactivation of HSV-1
    • Both ex vivo and in primary neuronal cultures
  • Cliffe et al., 2015, Du et al., 2012
  • Closely related bovine herpesvirus 1 (BHV-1)
    • Can also be reactivated in latently infected calves by intravenous injection of dexamethasone
  • Workman et al., 2012
  • Dexamethasone can also trigger JNK activity ( Lee et al., 2014; Zhang et al., 2000)
  • Dexamethasone-induced HSV reactivation in primary sympathetic neurons has been found to be JNK dependent (Cliffe et al., 2015).
  • Contribution of adenylate cyclase and JNK activity to stress-hormone induced reactivation
  • CAMP and JNK may be key regulators of the HSV quiescence/lytic switch in response to stress.

Heat shock

  • Of cultured neurons can trigger reactivation (Halford and Schaffer, 2001)
  • In non-neuronal systems viral lytic promoters can be activated in response to heat shock (Kushnir et al., 2009)
  • Cellular heat shock response involves
    • Increased synthesis of the heat shock proteins (HSPs),
    • Activation of the mitogen-activated protein kinase family,
      • Including JNK,
        • Linked to HSV reactivation
  • Non-neuronal cells heat-stress activation of lytic-promoters
    • Linked to the cellular protein NF-Y (Kushnir et al., 2009).
  • www.sciencedirect.com/science/article/pii/S0042682218302137

IDO expression

  • Can also enhance viral replication and disease manifestations
    • Associated with many viral pathogens
  • By suppressing cell-intrinsic type I IFN antiviral responses (Hoshi et al., 2012; Kim et al., 2016).
  • IDO-initiated production of antiviral kynurenine metabolites
    • Shown to reduce viral transcription and translation (Mehraj and Routy, 2015; Rabbani and Barik, 2017; Raniga and Liang, 2018).

Inhibition of mTORC1 activity

Transient inhibition of protein synthesis

  • Can result in HSV reactivation in rat primary neurons (Kobayashi et al., 2012)
  • MTOR as a key mediator of the HSV lytic/latent switch in neurons
    • Directly by sustaining the synthesis of proteins required for the maintenance of latency
    • Indirectly by activating pathways following protein synthesis inhibition

JAK inhibitors

  • Associated with an increased risk of herpesvirus infection
  • JAK inhibitors may potentially increase the risk of all herpesviruses
  • Rheumatoid arthritis and ulcerative colitis treated with JAK inhibitors
    • Increased risk of herpes zoster during JAK inhibitor therapy

Tofacitinib

  • Higher than with anti-tumor necrosis factor monoclonal antibodies
  • Tofacitinib had crude incidences of
    • 3.87/100 patient-years for herpes zoster
    • 3.74/100 patient-years for herpes simplex virus
    • Celkem 7.61/100 patient-years
  • Greater than the combined incidence rates for
    • Abatacept, rituximab, etanercept, and tocilizumab
      • Which ranged from 4.96-6.27/100 patient-years
  • Emerging as a treatment for
    • Atopic dermatitis,
    • Chronic inflammatory condition of the skin

Baricitinib


Nerve-growth factor (NGF) deprivation

  • One pathway that has been found to stimulate HSV reactivation in multiple systems
  • May occur during the developmental period
    • Through adolescence
  • Damage to innervated tissues that results in loss of the neurotrophin-producing cells or changes in neurotrophin synthesis
    • May occur following periods of chronic stress (Eckart et al., 2013)
    • Changes in hormone levels (Kaur et al., 2007)
    • UV irradiation (Stefanato et al., 2003)
  • NGF-deprivation
    • Trigger HSV reactivation in primary neuronal models of HSV latency using rat sympathetic neurons (Wilcox and Johnson, 1987)
  • In vivo injection of anti-NGF serum into latently infected rabbits
    • Has also been shown to enhance reactivation of HSV (Hill et al., 1997).
  • Interruption of signals downstream of the NGF receptor
    • Triggered reactivation in a variety of in vitro models of HSV latency (Camarena et al., 2010, Cliffe et al., 2015, Kobayashi et al., 2012, Linderman et al., 2017),
  • Enhance explant mediated reactivation ex vivo (Du et al., 2011, Messer et al., 2015).
  • www.sciencedirect.com/science/article/pii/S0042682218302137

Serotonin

  • HSV infection induced expression of the critical serotonin synthesis enzymes
    • TPH-1,
    • TPH-2,
    • DOPA decarboxylase (DDC)
  • And serotonin transporter, SERT
  • HSV-infected cells upregulated
  • Increased serotonin synthesis and uptake was shown to influence HSV replication.
  • Exogenous addition of serotonin
    • Increased HSV-1 yield
  • TPH-1/2 and SERT pharmacological inhibition
    • Reduced viral yield
  • Rabbits intraocularly infected with HSV-1
    • Exhibited significantly higher aqueous humor serotonin concentrations
      • Positively and strongly correlated with viral load and ocular disease severity
  • HSV-1 promotes serotonin synthesis and cellular uptake
    • To facilitate viral replication
  • Serotonin’s proinflammatory effects
    • May enhance the development of ocular disease
  • Enteric viral infections, including
    • Rotavirus, reovirus, and adenovirus
    • Stimulate the release of serotonin stores from enterochromaffin cells in the gut
      • Resulting in enhanced viral titers, as well as serotonin-associated pathophysiological responses
        • Diarrhea and vomiting
  • Upregulation of serotonin synthesis pathway genes in HSV infection
  • HSV-induced upregulation of 5-HT synthesis and intracellular uptake enhances HSV replication
  • Pharmacological inhibition of these processes reduces HSV yields
  • HSV-infected eyes exhibit a marked increase in aqueous humor 5-HT levels that significantly and positively correlate with severity of HSV-mediated ocular disease.
  • serotonin potentially facilitating host-mediated viral disease
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8982329/
  • Supplementation with serotonin
    • Can enhance viral replication independent of L-Trp availability.

L-Tryptophan (L-Trp)

  • Tryptophan hydroxylase (TPH)
    • TPH-1 being predominantly expressed in the periphery
    • TPH-2 expression confined almost exclusively to the CNS
  • Seven different receptor families comprised of 14 distinct subtypes
  • Crucial for pathogen replication
  • Tryptophan hydroxylase 2 (TPH2)
    • Neuronal specific rate-limiting enzyme for serotonin synthesis
    • Most significantly upregulated gene by HSV in an amino acid metabolism PCR array
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC8982329/

O úroveň výše

Poslední aktualizace: 18. 12. 2022 3:38:23