Browsing by Subject "ENTRY"

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  • Siljamaki, Elina; Rintanen, Nina; Kirsi, Maija; Upla, Paula; Wang, Wei; Karjalainen, Mikko; Ikonen, Elina; Marjomaki, Varpu (2013)
  • Ianevski, Aleksandr; Yao, Rouan; Biza, Svetlana; Zusinaite, Eva; Mannik, Andres; Kivi, Gaily; Planken, Anu; Kurg, Kristiina; Tombak, Eva-Maria; Ustav, Mart; Shtaida, Nastassia; Kulesskiy, Evgeny; Jo, Eunji; Yang, Jaewon; Lysvand, Hilde; Loseth, Kirsti; Oksenych, Valentyn; Aas, Per Arne; Tenson, Tanel; Vitkauskiene, Astra; Windisch, Marc P.; Fenstad, Mona Hoysaeter; Nordbo, Svein Arne; Ustav, Mart; Bjoras, Magnar; Kainov, Denis E. (2020)
    Combination therapies have become a standard for the treatment for HIV and hepatitis C virus (HCV) infections. They are advantageous over monotherapies due to better efficacy, reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify new synergistic combinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), echovirus 1 (EV1), hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1) in vitro. We observed synergistic activity of nelfinavir with convalescent serum and with purified neutralizing antibody 23G7 against SARS-CoV-2 in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of nelfinavir with EIDD-2801 or remdesivir in Calu-3 cells. In addition, we showed synergistic activity of vemurafenib with emetine, homoharringtonine, anisomycin, or cycloheximide against EV1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar or niclosamide are synergistic against HCV infection in hepatocyte-derived Huh-7.5 cells, and that combinations of monensin with lamivudine or tenofovir are synergistic against HIV-1 infection in human cervical TZM-bl cells. These results indicate that synergy is achieved when a virus-directed antiviral is combined with another virus- or host-directed agent. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status.
  • Parviainen, Suvi; Autio, Karoliina; Vähä-Koskela, Markus; Guse, Kilian; Pesonen, Sari; Rosol, Thomas J.; Zhao, Fang; Hemminki, Akseli (2015)
    Vaccinia virus is a large, enveloped virus of the poxvirus family. It has broad tropism and typically virus replication culminates in accumulation and lytic release of intracellular mature virus (IMV), the most abundant form of infectious virus, as well as release by budding of extracellular enveloped virus (EEV). Vaccinia viruses have been modified to replicate selectively in cancer cells and clinically tested as oncolytic agents. During preclinical screening of relevant cancer targets for a recombinant Western Reserve strain deleted for both copies of the thymidine kinase and vaccinia growth factor genes, we noticed that confluent monolayers of SCCF1 cat squamous carcinoma cells were not destroyed even after prolonged infection. Interestingly, although SCCF1 cells were not killed, they continuously secreted virus into the cell culture supernatant. To investigate this finding further, we performed detailed studies by electron microscopy. Both intracellular and secreted virions showed morphological abnormalities on ultrastructural inspection, suggesting compromised maturation and morphogenesis of vaccinia virus in SCCF1 cells. Our data suggest that SCCF1 cells produce a morphologically abnormal virus which is nevertheless infective, providing new information on the virus-host cell interactions and intracellular biology of vaccinia virus.
  • Paton, M.D.; Harri, A.-M.; Savijärvi, H. (2018)
    Abstract Martian boundary layer wind speed and direction measurements, from a variety of locations, seasons and times, are provided. For each lander sent to Mars over the last four decades a unique record of the winds blowing during their descent is preserved at each landing site. By comparing images acquired from orbiting spacecraft of the impact points of jettisoned hardware, such as heat shields and parachutes, to a trajectory model the winds can be measured. We start our investigations with the Viking lander 1 mission and end with Schiaparelli. In-between we extract wind measurements based on observations of the Beagle 2, Spirit, Opportunity, Phoenix and Curiosity landing sites. With one exception the wind at each site during the lander’s descent were found to be  < 8 m s − 1 . High speed winds were required to explain the displacement of jettisoned hardware at the Phoenix landing site. We found a tail wind ( > 20 m s − 1 ), blowing from the north-west was required at a high altitude ( > 2 km) together with a gust close to the surface ( < 500 m altitude) originating from the north. All in all our investigations yielded a total of ten unique wind measurements in the PBL. One each from the Viking landers and one each from Beagle 2, Spirit, Opportunity and Schiaparelli. Two wind measurements, one above about 1 km altitude and one below, were possible from observations of the Curiosity and Phoenix landing site. Our findings are consistent with a turbulent PBL in the afternoon and calm PBL in the morning. When comparing our results to a GCM we found a good match in wind direction but not for wind speed. The information provided here makes available wind measurements previously unavailable to Mars atmosphere modellers and investigators.
  • Ianevski, Aleksandr; Zusinaite, Eva; Kuivanen, Suvi; Strand, Mårten; Lysvand, Hilde; Teppor, Mona; Kakkola, Laura; Paavilainen, Henrik; Laajala, Mira; Kallio-Kokko, Hannimari; Valkonen, Miia; Kantele, Anu; Telling, Kaidi; Lutsar, Irja; Letjuka, Pille; Metelitsa, Natalja; Oksenych, Valentyn; Bjørås, Magnar; Nordbø, Svein Arne; Dumpis, Uga; Vitkauskiene, Astra; Öhrmalm, Christina; Bondeson, Kåre; Bergqvist, Anders; Aittokallio, Tero; Cox, Rebecca J.; Evander, Magnus; Hukkanen, Veijo; Marjomaki, Varpu; Julkunen, Ilkka; Vapalahti, Olli; Tenson, Tanel; Merits, Andres; Kainov, Denis (2018)
    Abstract According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-in-human antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases.
  • Basu, Shreya (2021)
    This paper investigates the incentives of e-commerce platforms to show personalized recommendations and its effects on performance. A theoretical framework is developed that characterizes the optimal decision policy of a firm, given current state of shoppers. The key finding is that the firm must always show recommendations to shoppers in the high state above a certain price or value threshold. In the low state, recommending is optimal if the "salience effect" is above a threshold that maximizes discounted future stream of profits. An empirical model provides support to the theoretical findings, highlighting the reputation effects of personalized recommendations, using browsing and purchase data from a Finnish multi-product platform. While recommendations are associated with a 29% increase in firm revenue, relevance of such recommendations potentially boost revenue by a significant 30%. Furthermore, strong evidence is presented that consumer state is endogenous in firm revenue regressions. A three-step IV process extracts the direct effect of consumer state on revenue which shows positive association between reputation effects and firm performance.
  • Jiang, Miao; Kolehmainen, Pekka; Kakkola, Laura; Maljanen, Sari; Melen, Krister; Smura, Teemu; Julkunen, Ilkka; Österlund, Pamela (2021)
    The primary target organ of coronavirus disease 2019 (COVID-19) infection is the respiratory tract. Currently, there is limited information on the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect and regulate innate immunity in human immune cells and lung epithelial cells. Here, we compared the ability of four Finnish isolates of SARS-CoV-2 from COVID-19 patients to replicate and induce interferons (IFNs) and other cytokines in different human cells. All isolates failed to replicate in dendritic cells, macrophages, monocytes, and lymphocytes, and no induction of cytokine gene expression was seen. However, most of the isolates replicated in Calu-3 cells, and they readily induced type I and type III IFN gene expression. The hCoV-19/Finland/FIN-25/2020 isolate, originating from a traveler from Milan in March 2020, showed better ability to replicate and induce IFN and inflammatory responses in Calu-3 cells than other isolates of SARS-CoV-2. Our data increase the knowledge on the pathogenesis and antiviral mechanisms of SARS-CoV-2 infection in human cell systems. IMPORTANCE With the rapid spread of the coronavirus disease 2019 (COVID-19) pandemic, information on the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and regulation of innate immunity in human immune cells and lung epithelial cells is needed. In the present study, we show that SARS-CoV-2 failed to productively infect human immune cells, but different isolates of SARS-CoV-2 showed differential ability to replicate and regulate innate interferon responses in human lung epithelial Calu-3 cells. These findings will open up the way for further studies on the mechanisms of pathogenesis of SARS-CoV-2 in human cells.
  • Shakeel, Shabih; Seitsonen, Jani J. T.; Kajander, Tommi; Laurinmaki, Pasi; Hyypia, Timo; Susi, Petri; Butcher, Sarah J. (2013)
    Coxsackievirus A9 (CVA9) is an important pathogen of the Picornaviridae family. It utilizes cellular receptors from the integrin v family for binding to its host cells prior to entry and genome release. Among the integrins tested, it has the highest affinity for v6, which recognizes the arginine-glycine-aspartic acid (RGD) loop present on the C terminus of viral capsid protein, VP1. As the atomic model of CVA9 lacks the RGD loop, we used surface plasmon resonance, electron cryo-microscopy, and image reconstruction to characterize the capsid-integrin interactions and the conformational changes on genome release. We show that the integrin binds to the capsid with nanomolar affinity and that the binding of integrin to the virion does not induce uncoating, thereby implying that further steps are required for release of the genome. Electron cryo-tomography and single-particle image reconstruction revealed variation in the number and conformation of the integrins bound to the capsid, with the integrin footprint mapping close to the predicted site for the exposed RGD loop on VP1. Comparison of empty and RNA-filled capsid reconstructions showed that the capsid undergoes conformational changes when the genome is released, so that the RNA-capsid interactions in the N termini of VP1 and VP4 are lost, VP4 is removed, and the capsid becomes more porous, as has been reported for poliovirus 1, human rhinovirus 2, enterovirus 71, and coxsackievirus A7. These results are important for understanding the structural basis of integrin binding to CVA9 and the molecular events leading to CVA9 cell entry and uncoating.
  • Watanabe, Yasunori; Raghwani, Jayna; Allen, Joel D.; Seabright, Gemma E.; Li, Sai; Moser, Felipe; Huiskonen, Juha T.; Strecker, Thomas; Bowden, Thomas A.; Crispin, Max (2018)
    Lassa virus is an Old World arenavirus endemic to West Africa that causes severe hemorrhagic fever. Vaccine development has focused on the envelope glycoprotein complex (GPC) that extends from the virion envelope. The often inadequate antibody immune response elicited by both vaccine and natural infection has been, in part, attributed to the abundance of N-linked glycosylation on the GPC. Here, using a virus-like-particle system that presents Lassa virus GPC in a native-like context, we determine the composite population of each of the N-linked glycosylation sites presented on the trimeric GPC spike. Our analysis reveals the presence of underprocessed oligomannose-type glycans, which form punctuated clusters that obscure the proteinous surface of both the GP1 attachment and GP2 fusion glycoprotein subunits of the Lassa virus GPC. These oligomannose clusters are seemingly derived as a result of sterically reduced accessibility to glycan processing enzymes, and limited amino acid diversification around these sites supports their role protecting against the humoral immune response. Combined, our data provide a structure-based blueprint for understanding how glycans render the glycoprotein spikes of Lassa virus and other Old World arenaviruses immunologically resistant targets.
  • Bauer, Michael; Flatt, Justin W.; Seiler, Daria; Cardel, Bettina; Emmenlauer, Mario; Boucke, Karin; Suomalainen, Maarit; Hemmi, Silvio; Greber, Urs F. (2019)
    Adenoviruses (AdVs) cause respiratory, ocular, and gastrointestinal tract infection and inflammation in immunocompetent people and life-threatening disease upon immunosuppression. AdV vectors are widely used in gene therapy and vaccination. Incoming particles attach to nuclear pore complexes (NPCs) of post-mitotic cells, then rupture and deliver viral DNA (vDNA) to the nucleus or misdeliver to the cytosol. Our genome-wide RNAi screen in AdV-infected cells identified the RING-type E3 ubiquitin ligase Mind bomb 1 (Mib1) as a proviral host factor for AdV infection. Mib1 is implicated in Notch-Delta signaling, ciliary biogenesis, and RNA innate immunity. Mib1 depletion arrested incoming AdVs at NPCs. Induced expression of full-length but not ligase-defective Mib1 in knockout cells triggered vDNA uncoating from NPC-tethered virions, nuclear import, misdelivery of vDNA, and vDNA expression. Mib1 is an essential host factor for AdV uncoating in human cells, and it provides a new concept for licensing virion DNA delivery through the NPC.