11138
2013
eng
article
1
2015-03-20
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Reactivation of Chromosomally Integrated Human Herpesvirus-6 by Telomeric Circle Formation
More than 95% of the human population is infected with human herpesvirus-6 (HHV-6) during early childhood and maintains latent HHV-6 genomes either in an extra-chromosomal form or as a chromosomally integrated HHV-6 (ciHHV-6). In addition, approximately 1% of humans are born with an inheritable form of ciHHV-6 integrated into the telomeres of chromosomes. Immunosuppression and stress conditions can reactivate latent HHV-6 replication, which is associated with clinical complications and even death. We have previously shown that Chlamydia trachomatis infection reactivates ciHHV-6 and induces the formation of extra-chromosomal viral DNA in ciHHV-6 cells. Here, we propose a model and provide experimental evidence for the mechanism of ciHHV-6 reactivation. Infection with Chlamydia induced a transient shortening of telomeric ends, which subsequently led to increased telomeric circle (t-circle) formation and incomplete reconstitution of circular viral genomes containing single viral direct repeat (DR). Correspondingly, short t-circles containing parts of the HHV-6 DR were detected in cells from individuals with genetically inherited ciHHV-6. Furthermore, telomere shortening induced in the absence of Chlamydia infection also caused circularization of ciHHV-6, supporting a t-circle based mechanism for ciHHV-6 reactivation.
Author Summary:
Human herpesviruses (HHVs) can reside in a lifelong non-infectious state displaying limited activity in their host and protected from immune responses. One possible way by which HHV-6 achieves this state is by integrating into the telomeric ends of human chromosomes, which are highly repetitive sequences that protect the ends of chromosomes from damage. Various stress conditions can reactivate latent HHV-6 thus increasing the severity of multiple human disorders. Recently, we have identified Chlamydia infection as a natural cause of latent HHV-6 reactivation. Here, we have sought to elucidate the molecular mechanism of HHV-6 reactivation. HHV-6 efficiently utilizes the well-organized telomere maintenance machinery of the host cell to exit from its inactive state and initiate replication to form new viral DNA. We provide experimental evidence that the shortening of telomeres, as a consequence of interference with telomere maintenance, triggers the release of the integrated virus from the chromosome. Our data provide a mechanistic basis to understand HHV-6 reactivation scenarios, which in light of the high prevalence of HHV-6 infection and the possibility of chromosomal integration of other common viruses like HHV-7 have important medical consequences for several million people worldwide.
10.1371/journal.pgen.1004033
urn:nbn:de:bvb:20-opus-111380
PLoS Genetics 9(12): e1004033. doi:10.1371/journal.pgen.1004033
Thomas Rudel
George Krohne
Bhupesh K. Prusty
eng
uncontrolled
chlamydia infection
eng
uncontrolled
circular DNA
eng
uncontrolled
telomeres
eng
uncontrolled
polymerase chain reaction
eng
uncontrolled
DNA electrophoresis
eng
uncontrolled
chromosomes
eng
uncontrolled
southern hybridization
eng
uncontrolled
DNA hybridization
Genetik und Evolution
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2014
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11138/042_Rudel_PLoSGenetics.pdf
12556
2015
eng
e1004846
4
11
article
1
2016-01-26
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EphrinA2 Receptor (EphA2) Is an Invasion and Intracellular Signaling Receptor for Chlamydia trachomatis
The obligate intracellular bacterium Chlamydia trachomatis invades into host cells to replicate inside a membrane-bound vacuole called inclusion. Multiple different host proteins are recruited to the inclusion and are functionally modulated to support chlamydial development. Invaded and replicating Chlamydia induces a long-lasting activation of the PI3 kinase signaling pathway that is required for efficient replication. We identified the cell surface tyrosine kinase EphrinA2 receptor (EphA2) as a chlamydial adherence and invasion receptor that induces PI3 kinase (PI3K) activation, promoting chlamydial replication. Interfering with binding of C. trachomatis serovar L2 (Ctr) to EphA2, downregulation of EphA2 expression or inhibition of EphA2 activity significantly reduced Ctr infection. Ctr interacts with and activates EphA2 on the cell surface resulting in Ctr and receptor internalization. During chlamydial replication, EphA2 remains active accumulating around the inclusion and interacts with the p85 regulatory subunit of PI3K to support the activation of the PI3K/Akt signaling pathway that is required for normal chlamydial development. Overexpression of full length EphA2, but not the mutant form lacking the intracellular cytoplasmic domain, enhanced PI3K activation and Ctr infection. Despite the depletion of EphA2 from the cell surface, Ctr infection induces upregulation of EphA2 through the activation of the ERK pathway, which keeps the infected cell in an apoptosis-resistant state. The significance of EphA2 as an entry and intracellular signaling receptor was also observed with the urogenital C. trachomatis-serovar D. Our findings provide the first evidence for a host cell surface receptor that is exploited for invasion as well as for receptor-mediated intracellular signaling to facilitate chlamydial replication. In addition, the engagement of a cell surface receptor at the inclusion membrane is a new mechanism by which Chlamydia subverts the host cell and induces apoptosis resistance.
PLoS Pathogens
10.1371/journal.ppat.1004846
urn:nbn:de:bvb:20-opus-125566
PLoS Pathogens 11(4): e1004846. doi:10.1371/journal.ppat.1004846
Prema Subbarayal
Karthika Karunakaran
Ann-Cathrin Winkler
Marion Rother
Erik Gonzalez
Thomas F. Meyer
Thomas Rudel
eng
uncontrolled
membrane proteins
eng
uncontrolled
chlamydia infection
eng
uncontrolled
chlamydia trachomatis
eng
uncontrolled
chlamydia
eng
uncontrolled
HeLa cells
eng
uncontrolled
apoptosis
eng
uncontrolled
host cells
eng
uncontrolled
membrane receptor signaling
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2015
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12556/Rudel_journal.ppat.1004846.pdf
9673
2013
eng
article
1
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Chlamydia trachomatis Infection Induces Replication of Latent HHV-6
Human herpesvirus-6 (HHV-6) exists in latent form either as a nuclear episome or integrated into human chromosomes in more than 90% of healthy individuals without causing clinical symptoms. Immunosuppression and stress conditions can reactivate HHV-6 replication, associated with clinical complications and even death. We have previously shown that co-infection of Chlamydia trachomatis and HHV-6 promotes chlamydial persistence and increases viral uptake in an in vitro cell culture model. Here we investigated C. trachomatis-induced HHV-6 activation in cell lines and fresh blood samples from patients having Chromosomally integrated HHV-6 (CiHHV-6). We observed activation of latent HHV-6 DNA replication in CiHHV-6 cell lines and fresh blood cells without formation of viral particles. Interestingly, we detected HHV-6 DNA in blood as well as cervical swabs from C. trachomatis-infected women. Low virus titers correlated with high C. trachomatis load and vice versa, demonstrating a potentially significant interaction of these pathogens in blood cells and in the cervix of infected patients. Our data suggest a thus far underestimated interference of HHV-6 and C. trachomatis with a likely impact on the disease outcome as consequence of co-infection.
PLoS ONE
10.1371/journal.pone.0061400
urn:nbn:de:bvb:20-opus-96731
In: PLoS ONE (2013) 8: 4, doi:10.1371/journal.pone.0061400
Thomas Rudel
Bhupesh K. Prusty
Christine Siegl
Petra Hauck
Johannes Hain
Suvi J. Korhonen
Eija Hiltunen-Back
Mirja Poulakkainen
eng
uncontrolled
blood
eng
uncontrolled
chlamydia
eng
uncontrolled
chlamydia infection
eng
uncontrolled
chlamydia trachomatis
eng
uncontrolled
DNA replication
eng
uncontrolled
macrophages
eng
uncontrolled
polymerase chain reaction
eng
uncontrolled
viral load
Medizin und Gesundheit
open_access
Institut für Mathematik
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2013
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/9673/Rudel_journal.pone.0061400.pdf