TY  - JOUR
AB  - The tetraspanin CD81 is one of the main entry receptors for Hepatitis C virus, which is a major causative agent to develop liver cirrhosis and hepatocellular carcinoma (HCC). Here, we identify CD81 as one of few surface proteins that are downregulated in HCV expressing hepatoma cells, discovering a functional role of CD81 beyond mediating HCV entry. CD81 was downregulated at the mRNA level in hepatoma cells that replicate HCV. Kinetics of HCV expression were increased in CD81-knockout cells and accompanied by enhanced cellular growth. Furthermore, loss of CD81 compensated for inhibition of pro-survival TBK1-signaling in HCV expressing cells. Analysis of functional phenotypes that could be associated with pro-survival signaling revealed that CD81 is a negative regulator of NF-κB. Interaction of the NF-κB subunits p50 and p65 was increased in cells lacking CD81. Similarly, we witnessed an overall increase in the total levels of phosphorylated and cellular p65 upon CD81-knockout in hepatoma cells. Finally, translocation of p65 in CD81-negative hepatoma cells was markedly induced upon stimulation with TNFα or PMA. Altogether, CD81 emerges as a regulator of pro-survival NF-κB signaling. Considering the important and established role of NF-κB for HCV replication and tumorigenesis, the downregulation of CD81 by HCV and the associated increase in NF-κB signaling might be relevant for viral persistence and chronic infection.
AU  - Bunz, M.*
AU  - Eisele, M.*
AU  - Hu, D.*
AU  - Ritter, M.*
AU  - Kammerloher, J.
AU  - Lampl, S.
AU  - Schindler, M.*
C1  - 69982
C2  - 55443
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - CD81 suppresses NF-κB signaling and is downregulated in hepatitis C virus expressing cells.
JO  - Front. Cell. Infect. Microbiol.
VL  - 14
PB  - Frontiers Media Sa
PY  - 2024
SN  - 2235-2988
ER  - 

TY  - JOUR
AB  - INTRODUCTION: Oxysterol-binding protein (OSBP) is known for its crucial role in lipid transport, facilitating cholesterol exchange between the Golgi apparatus and endoplasmic reticulum membranes. Despite its established function in cellular processes, its involvement in coronavirus replication remains unclear. METHODS: In this study, we investigated the role of OSBP in coronavirus replication and explored the potential of a novel OSBP-binding compound, ZJ-1, as an antiviral agent against coronaviruses, including SARS-CoV-2. We utilized a combination of biochemical and cellular assays to elucidate the interactions between OSBP and SARS-CoV-2 non-structural proteins (Nsps) and other viral proteins. RESULTS: Our findings demonstrate that OSBP positively regulates coronavirus replication. Moreover, treatment with ZJ-1 resulted in reduced OSBP levels and exhibited potent antiviral effects against multiple coronaviruses. Through our investigation, we identified specific interactions between OSBP and SARS-CoV-2 Nsps, particularly Nsp3, Nsp4, and Nsp6, which are involved in double-membrane vesicle formation-a crucial step in viral replication. Additionally, we observed that Nsp3 a.a.1-1363, Nsp4, and Nsp6 target vesicle-associated membrane protein (VAMP)-associated protein B (VAP-B), which anchors OSBP to the ER membrane. Interestingly, the interaction between OSBP and VAP-B is disrupted by Nsp3 a.a.1-1363 and partially impaired by Nsp6. Furthermore, we identified SARS-CoV-2 orf7a, orf7b, and orf3a as additional OSBP targets, with OSBP contributing to their stabilization. CONCLUSION: Our study highlights the significance of OSBP in coronavirus replication and identifies it as a promising target for the development of antiviral therapies against SARS-CoV-2 and other coronaviruses. These findings underscore the potential of OSBP-targeted interventions in combating coronavirus infections.
AU  - Ma-Lauer, Y.*
AU  - Li, P.*
AU  - Niemeyer, D.*
AU  - Richter, A.*
AU  - Pusl, K.*
AU  - von Brunn, B.*
AU  - Ru, Y.*
AU  - Xiang, C.*
AU  - Schwinghammer, S.*
AU  - Liu, J.*
AU  - Baral, P.*
AU  - Berthold, E.
AU  - Qiu, H.*
AU  - Roy, A.*
AU  - Kremmer, E.*
AU  - Flaswinkel, H.*
AU  - Drosten, C.*
AU  - Jin, Z.*
AU  - von Brunn, A. *
C1  - 71445
C2  - 56178
CY  - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland
TI  - Oxysterole-binding protein targeted by SARS-CoV-2 viral proteins regulates coronavirus replication.
JO  - Front. Cell. Infect. Microbiol.
VL  - 14
PB  - Frontiers Media Sa
PY  - 2024
SN  - 2235-2988
ER  - 

TY  - JOUR
AB  - Rationale: Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively. Methods: Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing Renilla luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing Renilla luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication. Results: Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model. Conclusion: The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.
AU  - Berthold, E.
AU  - Ma-Lauer, Y.*
AU  - Chakraborty, A.
AU  - von Brunn, B.*
AU  - Hilgendorff, A.
AU  - Hatz, R.A.*
AU  - Behr, J.*
AU  - Hausch, F.*
AU  - Staab-Weijnitz, C.A.
AU  - von Brunn, A. *
C1  - 66334
C2  - 53138
TI  - Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models.
JO  - Front. Cell. Infect. Microbiol.
VL  - 12
PY  - 2022
SN  - 2235-2988
ER  - 

TY  - JOUR
AB  - Effective growth and replication of obligate intracellular pathogens depend on host cell metabolism. How this is connected to host cell mitochondrial function has not been studied so far. Recent studies suggest that growth of intracellular bacteria such as Chlamydia pneumoniae is enhanced in a low oxygen environment, arguing for a particular mechanistic role of the mitochondrial respiration in controlling intracellular progeny. Metabolic changes in C. pneumoniae infected epithelial cells were analyzed under normoxic (O 2 ≈ 20%) and hypoxic conditions (O 2 < 3%). We observed that infection of epithelial cells with C. pneumoniae under normoxia impaired mitochondrial function characterized by an enhanced mitochondrial membrane potential and ROS generation. Knockdown and mutation of the host cell ATP synthase resulted in an increased chlamydial replication already under normoxic conditions. As expected, mitochondrial hyperpolarization was observed in non-infected control cells cultured under hypoxic conditions, which was beneficial for C. pneumoniae growth. Taken together, functional and genetically encoded mitochondrial dysfunction strongly promotes intracellular growth of C. pneumoniae.
AU  - Käding, N.*
AU  - Kaufhold, I.*
AU  - Müller, C.
AU  - Szaszák, M.*
AU  - Shima, K.*
AU  - Weinmaier, T.*
AU  - Lomas, R.*
AU  - Conesa, A.*
AU  - Schmitt-Kopplin, P.
AU  - Rattei, T.*
AU  - Rupp, J.*
C1  - 52550
C2  - 44070
CY  - Lausanne
TI  - Growth of Chlamydia pneumoniae is enhanced in cells with impaired mitochondrial function.
JO  - Front. Cell. Infect. Microbiol.
VL  - 7
PB  - Frontiers Media Sa
PY  - 2017
SN  - 2235-2988
ER  - 

TY  - JOUR
AB  - Avian paramyxovirus serotype 4 (APMV-4) is found sporadically in wild birds worldwide, and it is an economically important poultry pathogen. Despite the existence of several published strains, very little is known about the distribution, host species, and transmission of APMV-4 strains. To better understand the relationships among these factors, we conducted an APMV-4 surveillance of wild birds and domestic poultry in six provinces of China suspected of being intercontinental flyways and sites of interspecies transmission. APMV-4 surveillance was conducted in 9,160 wild birds representing seven species, and 1,461 domestic poultry in live bird markets (LMBs) from December 2013 to June 2016. The rate of APMV-4 isolation was 0.10% (11/10,621), and viruses were isolated from swan geese, bean geese, cormorants, mallards, and chickens. Sequencing and phylogenetic analyses of the 11 isolated viruses indicated that all the isolates belonging to genotype I were epidemiologically connected with wild bird-origin viruses from the Ukraine and Italy. Moreover, chicken-origin APMV-4 strains isolated from the LBMs were highly similar to wild bird-origin viruses from nearby lakes with free-living wild birds. In additional, a hemagglutination-negative APMV-4 virus was identified. These findings, together with recent APMV-4 studies, suggest potential virus interspecies transmission between wild birds and domestic poultry, and reveal possible epidemiological intercontinental connections between APMV-4 transmission by wild birds.
AU  - Yin, R.*
AU  - Zhang, P.*
AU  - Liu, X.*
AU  - Chen, Y.*
AU  - Tao, Z.*
AU  - Ai, L.*
AU  - Li, J.*
AU  - Yang, Y.*
AU  - Li, M.*
AU  - Xue, C.*
AU  - Qian, J.*
AU  - Wang, X.*
AU  - Chen, J.*
AU  - Li, Y.*
AU  - Xiong, Y.*
AU  - Zhang, J.*
AU  - Stöger, T.
AU  - Bi, Y.*
AU  - Ding, Z.*
C1  - 51307
C2  - 42952
CY  - Lausanne
TI  - Dispersal and transmission of avian paramyxovirus serotype 4 among wild birds and domestic poultry.
JO  - Front. Cell. Infect. Microbiol.
VL  - 7
PB  - Frontiers Media Sa
PY  - 2017
SN  - 2235-2988
ER  -