Anna Reichel

Suche


B3 Interference of the viral effector proteins pp71 and IE1 with ND10-mediated intrinsic immunity against human cytomegalovirus infections

Principal investigator
Thomas Stamminger

Mentor
Heinrich Sticht

Role of the subnuclear structure ND10 for interferon-induced gene expression during viral infections

The nuclear domain 10 (ND10) is a subnuclear structure, which modulates gene expression. The major ND10 components PML, hDaxx, and Sp100 were shown to function as cellular restriction factors that mediate an intrinsic immune response against herpesviruses by repressing the initiation of viral gene expression. Human cytomegalovirus (HCMV), however, has evolved viral effector proteins like pp71 and IE1, which are able to counteract the antiviral activity instituted by ND10. Moreover, ND10 structures are considered as part of the innate immune response, since certain ND10 proteins (PML, Sp100) are induced by interferons (IFN type I and II). Interestingly, recent findings indicate that ND10 components themselves act as regulators of the interferon response by inducing the expression of a certain subset of ISGs (interferon-stimulated genes). For instance, Ulbricht et al. (2012) demonstrated that a knockdown of PML leads to an impairment of IFN-g-induced MHC II transcription. Furthermore, it was discovered that the ND10-associated factor PLZF (the promyelocytic leukemia zinc finger protein) plays a key role in the IFN-a mediated immune response by activating the expression of a subset of specific ISGs (IFN-stimulated genes), which are involved in antiviral defense. Thus, we hypothesize that viral effector proteins targeting ND10 may not only inhibit the direct ND10-mediated repression of viral replication, but may also counteract specific aspects of the interferon response.
This project aims at a detailed analysis of the role of ND10 structures for the interferon-mediated immune response against viral infections. With the help of knockdown cell lines we would like to address the relevance of individual ND10 proteins for the IFN-based induction of ISG expression which will be systematically investigated by cDNA array and RNAseq analyses. Furthermore, we would like to identify the respective ISGs which are induced in an ND10-dependent manner and investigate how they contribute to the control of herpesvirus infections. Finally, we want to clarify whether and how viral effector proteins (e.g. IE1) antagonize the interferon response by disturbing ND10 integrity. Overall, a detailed understanding of interferon-antagonistic mechanisms will contribute substantially to the development of novel antiviral therapies.

 

Figure: Stimulation of control and PML-knockdown (kd) HFF (human foreskin fibroblasts) cells with type I  Detection of HLA-DRA, HLA-DRB3, CCL8 and IFIT3 gene expression by quantitative RT-PCR in control and PML-kd fibroblasts in the presence or absence of IFN treatment.

 

Publications

Viruses. 2014 Feb 10;6(2):661-82. doi: 10.3390/v6020661.
Intracellular trafficking of the human cytomegalovirus-encoded 7-trans-membrane protein homologs pUS27 and pUL78 during viral infection: a comparative analysis.
Niemann I1, Reichel A2, Stamminger T3.

Viruses. 2015 Jun 5;7(6):2884-907. doi: 10.3390/v7062751.
Contribution of the Major ND10 Proteins PML, hDaxx and Sp100 to the Regulation of Human Cytomegalovirus Latency and Lytic Replication in the Monocytic Cell Line THP-1.
Wagenknecht N1, Reuter N2, Scherer M3, Reichel A4, Müller R5, Stamminger T6

 

Presentations

October 2016 8th Annual Retreat, Erlangen School of Molecular Communication, Schloss Schney, Lichtenfels, Germany
”The chromatin remodeling factor SPOC1 as a novel player in the intrinsic defense against HCMV”
Talk
     
October 2015 2nd International SFB 796 Conference: Mechanisms of microbial host cell manipulation: From plants to humans, Erlangen, Germany
”The chromatin remodeling factor SPOC1: A novel player in the cellular defense against HCMV?”
Poster
     
July 2015 7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany
”SPOC1: A novel restriction factor for HCMV replication?”
Poster
     
July 2014

6th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
”Role of the ND10 protein PLZF for restriction of HCMV replication”

Poster
     

 

Awards

Best Talk Award

First place

8th Annual Retreat, Erlangen School of Molecular Communication, Schloss Schney, Lichtenfels, Germany, October 2016
“The chromatin remodeling factor SPOC1 as a novel player in the intrinsic defense against HCMV“

Best Poster Award

Second place

7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany, July 2015
“SPOC1: A novel restriction factor for HCMV replication?“