Virus-nucleus interactions in late herpesvirus infection

Herpes simplex virus 1 (HSV-1) on alfaherpesviruksiin kuuluva vaipallinen, kaksijuosteista DNA:ta sisältävä virus. Kosketus- ja pisaratartuntana herkästi leviävä HSV-1 on maailmanlaajuisesti huomattava taudinaiheuttaja, sillä virusta kantaa arviolta 67 % väestöstä. Tartunta on elinikäinen. Latentiss...

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Main Author: Hakanen, Satu
Other Authors: Matemaattis-luonnontieteellinen tiedekunta, Faculty of Sciences, Bio- ja ympäristötieteiden laitos, Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylän yliopisto
Format: Master's thesis
Language:eng
Published: 2017
Subjects:
Online Access: https://jyx.jyu.fi/handle/123456789/56574
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author Hakanen, Satu
author2 Matemaattis-luonnontieteellinen tiedekunta Faculty of Sciences Bio- ja ympäristötieteiden laitos Department of Biological and Environmental Science University of Jyväskylä Jyväskylän yliopisto
author_facet Hakanen, Satu Matemaattis-luonnontieteellinen tiedekunta Faculty of Sciences Bio- ja ympäristötieteiden laitos Department of Biological and Environmental Science University of Jyväskylä Jyväskylän yliopisto Hakanen, Satu Matemaattis-luonnontieteellinen tiedekunta Faculty of Sciences Bio- ja ympäristötieteiden laitos Department of Biological and Environmental Science University of Jyväskylä Jyväskylän yliopisto
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description Herpes simplex virus 1 (HSV-1) on alfaherpesviruksiin kuuluva vaipallinen, kaksijuosteista DNA:ta sisältävä virus. Kosketus- ja pisaratartuntana herkästi leviävä HSV-1 on maailmanlaajuisesti huomattava taudinaiheuttaja, sillä virusta kantaa arviolta 67 % väestöstä. Tartunta on elinikäinen. Latentissa vaiheessa HSV-1:n genomi säilyy aistihermojen hermosolmukkeissa. Viruksen aktivoituminen lyyttiseen lisääntymiskiertoon oireilee tyypillisesti rakkuloina kasvojen iholla ja limakalvoilla. HSV-1:n genomin replikoituminen ja uusien viruskapsidien muodostuminen tapahtuvat isäntäsolun tumassa, jossa viruksen rakentumisalue laajenee infektion edetessä. Samalla isäntäsolun kromatiini tiivistyy ja pakkautuu tuman reunamille. Uudet viruskapsidit poistuvat tumasta kuroutumalla tumakalvon läpi mekanismilla, joka tunnetaan jo varsin hyvin. Sen sijaan on vielä epäselvää, kuinka kapsidit saavuttavat sisemmän tumakalvon liikkuessaan kromatiinin seassa. Tässä tutkimuksessa määritettiin isäntäsolun kromatiinin ominaisuuksia ja vuorovaikutuksia viruksen kanssa lyyttisen HSV-1-infektion myöhäisessä vaiheessa. Löyhästi pakkautuneen aktiivisen eukromatiinin ja tiiviimmin pakkautuneen hiljaisen heterokromatiinin erottamiseen käytettiin vasta-ainemarkkereita, jotka sitoutuvat kromatiinin eri muodoille ominaisiin histonimodifikaatioihin. Konfokaali- ja elektronimikrokooppikuvauksen perusteella infektoituneen solun kromatiini oli tiivistynyt tuman reunoille epäsäännöllisen muotoiseksi renkaaksi. Tiivistynyttä kromatiinirengasta katkoivat paikoitellen sisemmälle tumakalvolle ulottuvat aukkokohdat, joiden kautta viruskapsidien nähtiin päätyvän tumakalvon läheisyyteen. Tiheämmän kromatiinin sekaan sijoittuneiden viruskapsidien ympärillä nähtiin elektronimikroskooppikuvauksessa usein sädekehän kaltainen tyhjä tila, joka voisi selittyä kapsidin ja kromatiinin välisillä vuorovaikutuksilla. Kromatiinin eri muotojen sijoittuminen muuttui infektiossa siten, että eukromatiinia havaittiin tumakalvon vieressä ns. periferaalisella alueella. Periferaalinen eukromatiini saattaa viitata viruksen aikaansaamiin muutoksiin geenitoiminnassa. Lyyttisellä HSV-1-infektiolla on merkittävä vaikutus isäntäsolun tumaan ja kromatiinin rakenteeseen. Kromatiinin ja viruksen välisten vuorovaikutusten tarkempi määrittäminen voi tuoda lisätietoa kapsidien tumansisäisistä vaiheista ja tarjota samalla potentiaalisia kohteita lääkemolekyyleille, joilla infektion eteneminen pyritään pysäyttämään tumaan. Herpes simplex virus 1 (HSV-1) is an enveloped icosahedral dsDNA virus, and a common human pathogen with an estimated incidence of 67% in the global population. Infected individuals permanently carry the latent HSV-1 in neuronal cells. Sporadic virus reactivation into the lytic life cycle typically manifests as facial lesions known as cold sores. HSV-1 utilizes the host cell nucleus for genome replication and nucleocapsid assembly. Nuclear interior is occupied by viral replication compartments, whereas the host chromatin becomes compressed and marginalized to the nuclear periphery. Progeny nucleocapsids exit the intact nucleus by budding through the nuclear envelope. While the mechanism of nuclear egress has been well-characterized, less is known about progeny nucleocapsid movement among the host chromatin to the inner nuclear membrane. The aim of this study was to observe the properties of host chromatin in relation to viral replication compartments and progeny nucleocapsids during the late phase of lytic HSV-1 infection. In order to gain a more detailed look into the host chromatin as a structural element, we studied the redistribution of the loosely packed active euchromatin and the compacted silent heterochromatin by labeling their respective histone post-translational modifications. Confocal and transmission electron microscopy (TEM) imaging of HSV-1 infected nuclei showed that the marginalized host chromatin forms an uneven ring, which contains gaps that allow progeny nucleocapsids to access the inner nuclear membrane for egress. Nanometer-scale visualization of nucleocapsids in TEM images revealed that nucleocapsids are frequently surrounded by an electron-lucent, halo-like space, which might be related to nucleocapsid movement through the host chromatin. Notably, active euchromatin appears in the nuclear periphery adjacent to the inner nuclear membrane upon infection, although it is yet unclear if this finding represents virally activated euchromatin. Chromatin remodeling is a prominent feature of lytic HSV-1 infection. Further characterization of the key interactions between host chromatin and viral components could expose critical steps in HSV-1 nuclear egress, which might have additional value as therapeutic targets of this widespread human virus.
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Kosketus- ja pisaratartuntana herk\u00e4sti levi\u00e4v\u00e4 HSV-1 on maailmanlaajuisesti huomattava taudinaiheuttaja, sill\u00e4 virusta kantaa arviolta 67 % v\u00e4est\u00f6st\u00e4. Tartunta on elinik\u00e4inen. Latentissa vaiheessa HSV-1:n genomi s\u00e4ilyy aistihermojen hermosolmukkeissa. Viruksen aktivoituminen lyyttiseen lis\u00e4\u00e4ntymiskiertoon oireilee tyypillisesti rakkuloina kasvojen iholla ja limakalvoilla. HSV-1:n genomin replikoituminen ja uusien viruskapsidien muodostuminen tapahtuvat is\u00e4nt\u00e4solun tumassa, jossa viruksen rakentumisalue laajenee infektion edetess\u00e4. Samalla is\u00e4nt\u00e4solun kromatiini tiivistyy ja pakkautuu tuman reunamille. Uudet viruskapsidit poistuvat tumasta kuroutumalla tumakalvon l\u00e4pi mekanismilla, joka tunnetaan jo varsin hyvin. Sen sijaan on viel\u00e4 ep\u00e4selv\u00e4\u00e4, kuinka kapsidit saavuttavat sisemm\u00e4n tumakalvon liikkuessaan kromatiinin seassa. 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spellingShingle Hakanen, Satu Virus-nucleus interactions in late herpesvirus infection HSV-1 herpesvirukset tuma kromatiini virus-tuma-vuorovaikutukset Solu- ja molekyylibiologia Cell and molecular biology 4013 herpes simplex -virus
title Virus-nucleus interactions in late herpesvirus infection
title_full Virus-nucleus interactions in late herpesvirus infection
title_fullStr Virus-nucleus interactions in late herpesvirus infection Virus-nucleus interactions in late herpesvirus infection
title_full_unstemmed Virus-nucleus interactions in late herpesvirus infection Virus-nucleus interactions in late herpesvirus infection
title_short Virus-nucleus interactions in late herpesvirus infection
title_sort virus nucleus interactions in late herpesvirus infection
title_txtP Virus-nucleus interactions in late herpesvirus infection
topic HSV-1 herpesvirukset tuma kromatiini virus-tuma-vuorovaikutukset Solu- ja molekyylibiologia Cell and molecular biology 4013 herpes simplex -virus
topic_facet 4013 Cell and molecular biology HSV-1 Solu- ja molekyylibiologia herpes simplex -virus herpesvirukset kromatiini tuma virus-tuma-vuorovaikutukset
url https://jyx.jyu.fi/handle/123456789/56574 http://www.urn.fi/URN:NBN:fi:jyu-201801031024
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