Browsing by Subject "REPLICATION"

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  • van den Berg, Stephanie M.; de Moor, Marleen H. M.; McGue, Matt; Pettersson, Erik; Terracciano, Antonio; Verweij, Karin J. H.; Amin, Najaf; Derringer, Jaime; Esko, Tonu; van Grootheest, Gerard; Hansell, Narelle K.; Huffman, Jennifer; Konte, Bettina; Lahti, Jari; Luciano, Michelle; Matteson, Lindsay K.; Viktorin, Alexander; Wouda, Jasper; Agrawal, Arpana; Allik, Jueri; Bierut, Laura; Broms, Ulla; Campbell, Harry; Smith, George Davey; Eriksson, Johan G.; Ferrucci, Luigi; Franke, Barbera; Fox, Jean-Paul; de Geus, Eco J. C.; Giegling, Ina; Gow, Alan J.; Grucza, Richard; Hartmann, Annette M.; Heath, Andrew C.; Heikkilä, Kauko; Iacono, William G.; Janzing, Joost; Jokela, Markus; Kiemeney, Lambertus; Lehtimaki, Terho; Madden, Pamela A. F.; Magnusson, Patrik K. E.; Northstone, Kate; Nutile, Teresa; Ouwens, Klaasjan G.; Palotie, Aarno; Pattie, Alison; Pesonen, Anu-Katriina; Polasek, Ozren; Pulkkinen, Lea; Pulkki-Raback, Laura; Raitakari, Olli T.; Realo, Anu; Rose, Richard J.; Ruggiero, Daniela; Seppala, Ilkka; Slutske, Wendy S.; Smyth, David C.; Sorice, Rossella; Starr, John M.; Sutin, Angelina R.; Tanaka, Toshiko; Verhagen, Josine; Vermeulen, Sita; Vuoksimaa, Eero; Widen, Elisabeth; Willemsen, Gonneke; Wright, Margaret J.; Zgaga, Lina; Rujescu, Dan; Metspalu, Andres; Wilson, James F.; Ciullo, Marina; Hayward, Caroline; Rudan, Igor; Deary, Ian J.; Räikkönen, Katri; Vasquez, Alejandro Arias; Costa, Paul T.; Keltikangas-Jarvinen, Liisa; van Duijn, Cornelia M.; Penninx, Brenda W. J. H.; Krueger, Robert F.; Evans, David M.; Kaprio, Jaakko; Pedersen, Nancy L.; Martin, Nicholas G.; Boomsma, Dorret I. (2014)
  • Helanterä, Ilkka; Hirsch, Hans H.; Auvinen, Eeva; Mannonen, Laura; Nummi, Maaret; Wernli, Marion; Ortiz, Fernanda; Räisänen-Sokolowski, Anne; Lempinen, Marko; Lautenschlager, Irmeli (2016)
    Background:The significance of JC polyomavirus (JCPyV) after kidney transplantation ranges from irrelevant to full-blown nephropathy or PML. Objectives: To investigate the clinical significance of high-level JCPyV viruria and JCPyV primary infections after kidney transplantation. Study design: JCPyV viruria was detected in routine screening by quantitative real-time PCR in 40/238 kidney transplant recipients and was high-level (> 10(7)copies/ml) in 17 patients. A protocol biopsy at the time of JCPyV viruria was available from 10 patients. Results: Peak urine viral loads were 1.0 x 10(7)-2.5 x 10(9)copies/ml in the 17 high-level viruria patients. 6/15 (40%) patients with high-level JCPyV viruria with pretransplant sera available were JCPyV IgG negative suggesting that JCPyV viruria resulted from the donor graft in most cases. No acute graft dysfunction was associated with JCPyV viruria. No positive SV40 staining was detected in protocol biopsies, and nospecific histopathology was associated with high-level viruria; JCPyV nephropathy was not found. No differences were seen in histopathology or graft function at 3 years in patients with high-level viruria compared to non-JCPyV viruric patients transplanted during the same time period, and outcome was similar in patients with presumably primary and reactivated JCPyV. The mean estimated GFR at last follow-up was 44 ml/min (range 12-60 ml/min). One graft with high-level viruria was lost 9 years posttransplant due to recurrent IgA nephropathy Conclusions: High-level JCPyV viruria seems to be associated with primary JCPyV infection reflecting the average seroprevalence of 60%, but is not stringently associated with inferior graft function or survival, or histopathological changes. c 2016 Elsevier B.V. All rights reserved.
  • Maki, Koichiro; Nava, Michele M.; Villeneuve, Clementine; Chang, Minki; Furukawa, Katsuko S.; Ushida, Takashi; Wickström, Sara A. (2021)
    Articular cartilage protects and lubricates joints for smooth motion and transmission of loads. Owing to its high water content, chondrocytes within the cartilage are exposed to high levels of hydrostatic pressure, which has been shown to promote chondrocyte identity through unknown mechanisms. Here, we investigate the effects of hydrostatic pressure on chondrocyte state and behavior, and discover that application of hydrostatic pressure promotes chondrocyte quiescence and prevents maturation towards the hyperlrophic state. Mechanistically, hydrostatic pressure reduces the amount of trimethylated H3K9 (K3K9me3)-marked constitutive heterochromatin and concomitantly increases H3K27me3-marked facultative heterochromatin. Reduced levels of H3K9me3 attenuates expression of pre-hypertrophic genes, replication and transcription, thereby reducing replicative stress. Conversely, promoting replicative stress by inhibition of topoisomerase II decreases Sox9 expression, suggesting that it enhances chondrocyte maturation. Our results reveal how hydrostatic pressure triggers chromatin remodeling to impact cell fate and function. This article has an associated First Person interview with the first author of the paper.
  • Qian, Kui; Pietila, Tuuli; Rönty, Mikko Juhani; Michon, Frederic; Frilander, Mikko J.; Ritari, Jarmo; Tarkkanen, Jussi; Paulin, Lars; Auvinen, Petri; Auvinen, Eeva (2013)
  • Shakeel, Shabih; Evans, James D.; Hazelbaker, Mark; Kao, C. Cheng; Vaughan, Robert C.; Butcher, Sarah J. (2018)
    Human parechoviruses (HPeV) are picornaviruses with a highly-ordered RNA genome contained within icosahedrally-symmetric capsids. Ordered RNA structures have recently been shown to interact with capsid proteins VP1 and VP3 and facilitate virus assembly in HPeV1. Using an assay that combines reversible cross-linking, RNA affinity purification and peptide mass fingerprinting (RCAP), we mapped the RNA-interacting regions of the capsid proteins from the whole HPeV1 virion in solution. The intrinsically-disordered N-termini of capsid proteins VP1 and VP3, and unexpectedly, VP0, were identified to interact with RNA. Comparing these results to those obtained using recombinantly-expressed VP0 and VP1 confirmed the virion binding regions, and revealed unique RNA binding regions in the isolated VP0 not previously observed in the crystal structure of HPeV1. We used RNA fluorescence anisotropy to confirm the RNA-binding competency of each of the capsid proteins’ N-termini. These findings suggests that dynamic interactions between the viral RNA and the capsid proteins modulate virus assembly, and suggest a novel role for VP0.
  • Lillsunde, Katja-Emilia; Tomašič, Tihomir; Kikelj, Danijel; Tammela, Päivi (2017)
    Marine organisms and their metabolites are a diverse source of scaffolds for potential pharmacological molecular probes and, less frequently, for pharmaceutical lead compounds. In this study, 157 synthetic analogues of marine sponge-derived alkaloids clathrodin and oroidin were screened against replicon models of two RNA viruses, hepatitis C (HCV) and Chikungunya virus (CHIKV) as part of a larger screening project. Four compounds were found to selectively inhibit the HCV replicon (IC50 1.6-4.6 µM). These belong to the 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole class of compounds originally designed to target the ATP-binding site of bacterial DNA gyrase. The ATP-binding site of this bacterial protein has high structural similarity to the ATP-binding site of heat shock protein 90 (Hsp90), a host-cell chaperone universally required for viral replication, which led us to examine inhibition of Hsp90 as the compounds’ potential mechanism of action. Binding of the four hit compounds to Hsp90 was evaluated through microscale thermophoresis and molecular modelling, which supported our hypothesis of interaction with Hsp90 (Kd 18-79 µM) as basis for the compounds’ antiviral activity. The presented novel structural class of small molecules that target the Hsp90 ATP-binding site has excellent potential for further antiviral drug development because of the compounds’ low toxicity and synthetic accessibility.
  • Shrestha, Kul; Tuominen, Minna; Kauppi, Liisa (2021)
    DNA mismatch repair (MMR) proteins play an important role in maintaining genome stability, both in somatic and in germline cells. Loss of MLH1, a central MMR protein, leads to infertility and to microsatellite instability (MSI) in spermatocytes, however, the effect of Mlh1 heterozygosity on germline genome stability remains unexplored. To test the effect of Mlh1 heterozygosity on MSI in mature sperm, we combined mouse genetics with single-molecule PCR that detects allelic changes at unstable microsatellites. We discovered 4.5% and 5.9% MSI in sperm of 4- and 12-month-old Mlh1(+/-) mice, respectively, and that Mlh1 promoter methylation in Mlh1(+/-) sperm correlated with higher MSI. No such elevated MSI was seen in non-proliferating somatic cells. Additionally, we show contrasting dynamics of deletions versus insertions at unstable microsatellites (mononucleotide repeats) in sperm.
  • Fang, Hu; Barbour, Jayne A.; Poulos, Rebecca C.; Katainen, Riku; Aaltonen, Lauri A.; Wong, Jason W. H. (2020)
    Author summary Cancer arises through the accumulation of somatic mutations. The way that these somatic mutations form can vary greatly in different cancers. One of the most mutagenic processes that have been identified is caused by mutations within a replicative DNA polymerase known as Polymerase Epsilon (POLE). Cancers with such mutations present with hundreds of thousands of somatic mutations in their genome. Previous cancer genomics studies have identified a number of mutation hotspots in POLE, however how these different POLE mutants behave in affecting mutation distribution has not been studied. Here, we describe the genome-wide mutation profiles of distinct POLE mutant cancers. We find that different mutants indeed result in different mutation profiles and that this can be explained by the different fidelities of these mutants in replicating specific DNA sequences. Significantly, these differences have important implications in cancer formation as we found that a POLE mutation is strongly associated with a specific truncation of the TP53 cancer driver gene. This study furthers our understanding of the POLE mutagenic process in cancer and provide important insights into carcinogenesis in cancers with such mutations.
  • Liimatainen, Hanna; Weseslindtner, Lukas; Strassl, Robert; Aberle, Stephan W.; Bond, Gregor; Auvinen, Eeva (2020)
    Background BKPyV is associated with polyomavirus-associated nephropathy (PVAN), a major cause of graft rejection in kidney transplant recipients (KTRs). Mutations occur in the transcriptional control region (TCR) of BKPyV, but whether they are required for the development of PVAN is not completely understood. To this end, we characterized BKPyV TCRs from KTRs to assess whether TCR mutations are associated with PVAN. Study design We analyzed urine and plasma samples of fifteen KTRs with biopsy-confirmed PVAN, presumptive PVAN, or probable PVAN in order to explore the contents of the BKPyV virome. BKPyV TCRs were amplified and deep sequenced to characterize the viral strains. Alterations in block structures and transcription factor binding sites were investigated. Results The majority of sequences in both urine and plasma samples represented archetype BKPyV TCR. Minor populations harboring rearranged TCRs were detected in all patient groups. In one biopsy-confirmed PVAN patient rearranged TCRs predominated, and in another patient half of all reads represented rearranged sequences. Conclusions Although archetype BKPyV predominated in most patients, highest proportions and highest numbers of rearranged strains were detected in association with PVAN. TCR mutations seem not necessary for the development of PVAN, but immunosuppression may allow increased viral replication giving rise to TCR variants with enhanced replication efficiency.
  • Hamdan, Firas; Ylösmäki, Erkko; Chiaro, Jacopo; Giannoula, Yvonne; Long, Maeve; Fusciello, Manlio; Feola, Sara; Martins, Beatriz; Feodoroff, Michaela; Antignani, Gabriella; Russo, Salvatore; Kari, Otto; Lee, Moon; Järvinen, Petrus; Nisen, Harry; Kreutzman, Anna; Leusen, Jeanette; Mustjoki, Satu; McWilliams, Thomas G.; Grönholm, Mikaela; Cerullo, Vincenzo (2021)
    Background Despite the success of immune checkpoint inhibitors against PD-L1 in the clinic, only a fraction of patients benefit from such therapy. A theoretical strategy to increase efficacy would be to arm such antibodies with Fc-mediated effector mechanisms. However, these effector mechanisms are inhibited or reduced due to toxicity issues since PD-L1 is not confined to the tumor and also expressed on healthy cells. To increase efficacy while minimizing toxicity, we designed an oncolytic adenovirus that secretes a cross-hybrid Fc-fusion peptide against PD-L1 able to elicit effector mechanisms of an IgG1 and also IgA1 consequently activating neutrophils, a population neglected by IgG1, in order to combine multiple effector mechanisms. Methods The cross-hybrid Fc-fusion peptide comprises of an Fc with the constant domains of an IgA1 and IgG1 which is connected to a PD-1 ectodomain via a GGGS linker and was cloned into an oncolytic adenovirus. We demonstrated that the oncolytic adenovirus was able to secrete the cross-hybrid Fc-fusion peptide able to bind to PD-L1 and activate multiple immune components enhancing tumor cytotoxicity in various cancer cell lines, in vivo and ex vivo renal-cell carcinoma patient-derived organoids. Results Using various techniques to measure cytotoxicity, the cross-hybrid Fc-fusion peptide expressed by the oncolytic adenovirus was shown to activate Fc-effector mechanisms of an IgA1 (neutrophil activation) as well as of an IgG1 (natural killer and complement activation). The activation of multiple effector mechanism simultaneously led to significantly increased tumor killing compared with FDA-approved PD-L1 checkpoint inhibitor (Atezolizumab), IgG1-PDL1 and IgA-PDL1 in various in vitro cell lines, in vivo models and ex vivo renal cell carcinoma organoids. Moreover, in vivo data demonstrated that Ad-Cab did not require CD8+ T cells, unlike conventional checkpoint inhibitors, since it was able to activate other effector populations. Conclusion Arming PD-L1 checkpoint inhibitors with Fc-effector mechanisms of both an IgA1 and an IgG1 can increase efficacy while maintaining safety by limiting expression to the tumor using oncolytic adenovirus. The increase in tumor killing is mostly attributed to the activation of multiple effector populations rather than activating a single effector population leading to significantly higher tumor killing.
  • Lippert, Timothy P.; Marzec, Paulina; Idilli, Aurora I.; Sarek, Grzegorz; Vancevska, Aleksandra; Bower, Mark; Farrell, Paul J.; Ojala, Päivi M.; Feldhahn, Niklas; Boulton, Simon J. (2021)
    To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. similar to 85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining similar to 15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi's sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours. similar to 15% of cancers induce alternative lengthening of telomeres (ALT) to activate telomere maintenance. Here, the authors reveal that infection with Kaposi's sarcoma herpesvirus (KSHV) induces acquisition of ALT-like features in previously non-ALT cell lines.
  • Prokopyeva, E. A.; Romanovskaya, A. A.; Sharshov, K. A.; Zaykovskaya, A. V.; Alekseev, A. Yu.; Shestopalov, A. M. (2017)
    Here we compare the results of pathological and virological examinations of mice experimentally infected with either wild-type or mouse-adapted pandemic A(H1N1) pdm09 viruses and highly pathogenic avian influenza (HPAI) virus A(H5N1). Mice were sacrificed on days 1, 3, 6, and 10 post infection or whenever morbidity was severe enough to justify euthanasia. Morbidity rates were calculated on the basis of clinical signs (weight loss, poor hair coat, hunched posture and paresis); virus-induced disease was characterised by the histopathology of lung; virus dissemination was determined by virus isolation on organ samples of lung, brain, liver, kidney and spleen. All mice infected with mouse-adapted A(H1N1) pdm09 died in the course of the experiment, whereas 20% of animals survived the infection with A(H5N1). Echinocyte formation changed the rheological properties of blood in animals infected with either mouse-adapted A(H1N1) pdm09 or A(H5N1). To sum up, the adaptation of pandemic A(H1N1) pdm09 virus can confer an enhanced virulence similar to or even exceeding that of HPAI A(H5N1) virus.
  • Van Nuffel, Anouk; Arien, Kevin K.; Stove, Veronique; Schindler, Michael; O'Neill, Eduardo; Schmoekel, Jan; Van de Walle, Inge; Naessens, Evelien; Vanderstraeten, Hanne; Van Landeghem, Kathleen; Taghon, Tom; Pulkkinen, Kati; Saksela, Kalle; Garcia, J. Victor; Fackler, Oliver T.; Kirchhoff, Frank; Verhasselt, Bruno (2013)
  • Wolthers, Katja C.; Susi, Petri; Jochmans, Dirk; Koskinen, Janne; Landt, Olfert; Sanchez, Neus; Palm, Kaia; Neyts, Johan; Butcher, Sarah J. (2019)
    Several research groups in Europe are active on different aspects of human picornavirus research. The AIROPico (Academia-Industry R&D Opportunities for Picornaviruses) consortium combined the disciplines of pathogenesis, diagnostics and therapy development in order to fill the gaps in our understanding of how picornaviruses cause human disease and how to combat them. AIROPico was the first EU consortium dedicated to human picornavirus research and development, and has largely accelerated and improved R&D on picornavirus biology, diagnostics and therapy. In this article, we present the progress on pathogenesis, diagnostics and treatment strategy developments for human picornaviruses resulting from the structured, translational research approach of the AIROPico consortium. We here summarize new insights in protection against infection by maternal or cross-protective antibodies, the visualisation of interactions between virus and neutralizing antibodies by cryoEM structural imaging, and the outcomes from a picornavirus-infected human 3D organoid. Progress in molecular detection and a fast typing assay for rhinovirus species are presented, as well as the identification of new compounds potentially interesting as therapeutic compounds.
  • Lohmus, Andres; Varjosalo, Markku; Mäkinen, Kristiina (2016)
    The definition of the precise molecular composition of membranous replication compartments is a key to understanding the mechanisms of virus multiplication. Here, we set out to investigate the protein composition of the potyviral replication complexes. We purified the potyviral 6K2 protein-induced membranous structures from Potato virus A (PVA)-infected Nicotiana benthamiana plants. For this purpose, the 6K2 protein, which is the main inducer of potyviral membrane rearrangements, was expressed in fusion with an N-terminal Twin-Strep-tag and Cerulean fluorescent protein (SC6K) from the infectious PVA cDNA. A non-tagged Cerulean-6K2 (C6K) virus and the SC6K protein alone in the absence of infection were used as controls. A purification scheme exploiting discontinuous sucrose gradient centrifugation followed by Strep-tag-based affinity chromatography was developed. Both (+)- and (-)-strand PVA RNA and viral protein VPg were co-purified specifically with the affinity tagged PVA-SC6K. The purified samples, which contained individual vesicles and membrane clusters, were subjected to mass spectrometry analysis. Data analysis revealed that many of the detected viral and host proteins were either significantly enriched or fully specifically present in PVA-SC6K samples when compared with the controls. Eight of eleven potyviral proteins were identified with high confidence from the purified membrane structures formed during PVA infection. Ribosomal proteins were identified from the 6K2-induced membranes only in the presence of a replicating virus, reinforcing the tight coupling between replication and translation. A substantial number of proteins associating with chloroplasts and several host proteins previously linked with potyvirus replication complexes were co-purified with PVA-derived SC6K, supporting the conclusion that the host proteins identified in this study may have relevance in PVA replication.
  • Ko, Meehyun; Chang, So Young; Byun, Soo Young; Ianevski, Aleksandr; Choi, Inhee; d'Orengiani, Anne-Laure Pham Hung d'Alexandry; Ravlo, Erlend; Wang, Wei; Bjoras, Magnar; Kainov, Denis E.; Shum, David; Min, Ji-Young; Windisch, Marc P. (2021)
    Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI > 100), atovaquone, an anti-malarial (TI > 34), and ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.
  • Helanterä, Ilkka; Hirsch, Hans H.; Wernli, Marion; Ortiz, Fernanda; Lempinen, Marko; Räisänen-Sokolowski, Anne; Auvinen, Eeva; Mannonen, Laura; Lautenschlager, Irmeli (2016)
    BK polyomavirus (BKPyV) commonly reactivates after kidney transplantation, and can cause polyomavirus-associated nephropathy (PyVAN), whereas after allogeneic stem cell transplantation the most frequent manifestation of BKPyV is polyomavirus-associated hemorrhagic cystitis (PyVHC). Despite high-level BKPyV replication in both, the pathogenesis and manifestation of both BKPyV entities appears to differ substantially. We describe an unusual case of simultaneous PyVAN and PyVHC presenting with acute symptoms in a BKPyV-IgG positive recipient eight months after kidney transplantation from a haploidentical living donor, who was BKPyV-IgG negative. Symptoms of cystitis and viremia subsided rapidly after reduction of immunosuppression. (C) 2015 Elsevier B.V. All rights reserved.
  • Szirovicza, Leonora; Hetzel, Udo; Kipar, Anja; Martinez-Sobrido, Luis; Vapalahti, Olli; Hepojoki, Jussi (2020)
    Satellite viruses, most commonly found in plants, rely on helper viruses to complete their replication cycle. The only known example of a human satellite virus is the hepatitis D virus (HDV), and it is generally thought to require hepatitis B virus (HBV) to form infectious particlee03250-19s. Until 2018, HDV was the sole representative of the genus Deltavirus and was thought to have evolved in humans, the only known HDV host. The subsequent identification of HDV-like agents in birds, snakes, fish, amphibians, and invertebrates indicated that the evolutionary history of deltaviruses is likely much longer than previously hypothesized. Interestingly, none of the HDV-like agents were found in coinfection with an HBV-like agent, suggesting that these viruses use different helper virus(es). Here we show, using snake deltavirus (SDeV), that HBV and hepadnaviruses represent only one example of helper viruses for deltaviruses. We cloned the SDeV genome into a mammalian expression plasmid, and by transfection could initiate SDeV replication in cultured snake and mammalian cell lines. By superinfecting persistently SDeV-infected cells with reptarenaviruses and hartmaniviruses, or by transfecting their surface proteins, we could induce production of infectious SDeV particles. Our findings indicate that deltaviruses can likely use a multitude of helper viruses or even viral glycoproteins to form infectious particles. This suggests that persistent infections, such as those caused by arenaviruses and orthohantaviruses used in this study, and recurrent infections would be beneficial for the spread of deltaviruses. It seems plausible that further human or animal disease associations with deltavirus infections will be identified in the future.IMPORTANCE Deltaviruses need a coinfecting enveloped virus to produce infectious particles necessary for transmission to a new host. Hepatitis D virus (HDV), the only known deltavirus until 2018, has been found only in humans, and its coinfection with hepatitis B virus (HBV) is linked with fulminant hepatitis. The recent discovery of deltaviruses without a coinfecting HBV-like agent in several different taxa suggested that deltaviruses could employ coinfection by other enveloped viruses to complete their life cycle. In this report, we show that snake deltavirus (SDeV) efficiently utilizes coinfecting reptarena- and hartmaniviruses to form infectious particles. Furthermore, we demonstrate that cells expressing the envelope proteins of arenaviruses and orthohantaviruses produce infectious SDeV particles. As the envelope proteins are responsible for binding and infecting new host cells, our findings indicate that deltaviruses are likely not restricted in their tissue tropism, implying that they could be linked to animal or human diseases other than hepatitis.
  • Zimmer, Jutta; Tacconi, Eliana M. C.; Folio, Cecilia; Badie, Sophie; Porru, Manuela; Klare, Kerstin; Tumiati, Manuela; Markkanen, Enni; Halder, Swagata; Ryan, Anderson; Jackson, Stephen P.; Ramadan, Kristijan; Kuznetsov, Sergey G.; Biroccio, Annamaria; Sale, Julian E.; Tarsounas, Madalena (2016)
    G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition.
  • Prokopec, Stephenie D.; Pohjanvirta, Raimo; Mahiout, Selma; Pettersson, Lars; Boutros, Paul C. (2019)
    IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of Cyp1a1. We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population.