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Överby, Anna K.
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Publications (10 of 42) Show all publications
Rodrigues, R., Danskog, K., Överby, A. K. & Arnberg, N. (2019). Characterizing the cellular attachment receptor for Langat virus. PLoS ONE, 14(6), Article ID e0217359.
Open this publication in new window or tab >>Characterizing the cellular attachment receptor for Langat virus
2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0217359Article in journal (Refereed) Published
Abstract [en]

Tick-borne encephalitis infections have increased the last 30 years. The mortality associated to this viral infection is 0.5 to 30% with a risk of permanent neurological sequelae, however, no therapeutic is currently available. The first steps of virus-cell interaction, such as attachment and entry, are of importance to understand pathogenesis and tropism. Several molecules have been shown to interact with tick-borne encephalitis virus (TBEV) at the plasma membrane surface, yet, no studies have proven that these are specific entry receptors. In this study, we set out to characterize the cellular attachment receptor(s) for TBEV using the naturally attenuated member of the TBEV complex, Langat virus (LGTV), as a model. Inhibiting or cleaving different molecules from the surface of A549 cells, combined with inhibition assays using peptide extracts from high LGTV binding cells, revealed that LGTV attachment to host cells is dependent on plasma membrane proteins, but not on glycans or glycolipids, and suggested that LGTV might use different cellular attachment factors on different cell types. Based on this, we developed a transcriptomic approach to generate a list of candidate attachment and entry receptors. Our findings shed light on the first step of the flavivirus life-cycle and provide candidate receptors that might serve as a starting point for future functional studies to identify the specific attachment and/or entry receptor for LGTV and TBEV.

Place, publisher, year, edition, pages
Public Library Science, 2019
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-161188 (URN)10.1371/journal.pone.0217359 (DOI)000470086200012 ()31163044 (PubMedID)
Funder
Swedish Research Council, 349-2007-8673
Available from: 2019-06-28 Created: 2019-06-28 Last updated: 2019-07-10Bibliographically approved
Ruzek, D., Zupanc, T. A., Borde, J., Chrdle, A., Eyer, L., Karganova, G., . . . Zajkowska, J. (2019). Tick-borne encephalitis in Europe and Russia: review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Research, 164, 23-51
Open this publication in new window or tab >>Tick-borne encephalitis in Europe and Russia: review of pathogenesis, clinical features, therapy, and vaccines
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2019 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 164, p. 23-51Article, review/survey (Refereed) Published
Abstract [en]

Tick-borne encephalitis (TBE) is an illness caused by tick-borne encephalitis virus (TBEV) infection which is often limited to a febrile illness, but may lead to very aggressive downstream neurological manifestations. The disease is prevalent in forested areas of Europe and northeastern Asia, and is typically caused by infection involving one of three TBEV subtypes, namely the European (TBEV-Eu), the Siberian (TBEV-Sib), or the Far Eastern (TBEV-FE) subtypes. In addition to the three main TBEV subtypes, two other subtypes; i.e., the Baikalian (TBEV-Bkl) and the Himalayan subtype (TBEV-Him), have been described recently. In Europe, TBEV-Eu infection usually results in only mild TBE associated with a mortality rate of < 2%. TBEV-Sib infection also results in a generally mild TBE associated with a non-paralytic febrile form of encephalitis, although there is a tendency towards persistent TBE caused by chronic viral infection. TBE-FE infection is considered to induce the most severe forms of TBE. Importantly though, viral subtype is not the sole determinant of TBE severity; both mild and severe cases of TBE are in fact associated with infection by any of the subtypes. In keeping with this observation, the overall TBE mortality rate in Russia is similar to 2%, in spite of the fact that TBEV-Sib and TBEV-FE subtypes appear to be inducers of more severe TBE than TBEV-Eu. On the other hand, TBEV-Sib and TBEV-FE subtype infections in Russia are associated with essentially unique forms of TBE rarely seen elsewhere if at all, such as the hemorrhagic and chronic (progressive) forms of the disease. For post-exposure prophylaxis and TBE treatment in Russia and Kazakhstan, a specific anti-TBEV immunoglobulin is currently used with well-documented efficacy, but the use of specific TBEV immunoglobulins has been discontinued in Europe due to concerns regarding antibody-enhanced disease in naive individuals. Therefore, new treatments are essential. This review summarizes available data on the pathogenesis and clinical features of TBE, plus different vaccine preparations available in Europe and Russia. In addition, new treatment possibilities, including small molecule drugs and experimental immunotherapies are reviewed. The authors caution that their descriptions of approved or experimental therapies should not be considered to be recommendations for patient care.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Tick-borne encephalitis, Tick-borne encephalitis virus, Clinical course, Antiviral therapy, Vaccines, pathogenesis
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-158743 (URN)10.1016/j.antiviral.2019.01.014 (DOI)000463303700003 ()30710567 (PubMedID)
Available from: 2019-05-21 Created: 2019-05-21 Last updated: 2019-05-21Bibliographically approved
Lindqvist, R., Kurhade, C., Gilthorpe, J. D. & Överby, A. K. (2018). Cell-type- and region-specific restriction of neurotropic flavivirus infection by viperin. Journal of Neuroinflammation, 15, Article ID 80.
Open this publication in new window or tab >>Cell-type- and region-specific restriction of neurotropic flavivirus infection by viperin
2018 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 15, article id 80Article in journal (Refereed) Published
Abstract [en]

Background: Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against flavivirus infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple flaviviruses in vitro. Its activity in vivo restricts neurotropic infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against infection by several model neurotropic flaviviruses.

Methods: Viral burden and IFN induction were analyzed in vivo in wild-type and viperin(-/-) mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV).

Results: Viperin activity restricted nonlethal LGTV infection in the spleen and the olfactory bulb following infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV.

Conclusions: Our findings show that viperin restricts replication of neurotropic flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Viperin, Interferon, Flavivirus, Neurons, Astrocytes
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-146436 (URN)10.1186/s12974-018-1119-3 (DOI)000427904500001 ()29544502 (PubMedID)
Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2019-05-07Bibliographically approved
Lund, H., Pieber, M., Parsa, R., Han, J., Grommisch, D., Ewing, E., . . . Harris, R. A. (2018). Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nature Communications, 9, Article ID 4845.
Open this publication in new window or tab >>Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 4845Article in journal (Refereed) Published
Abstract [en]

Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-154942 (URN)10.1038/s41467-018-07295-7 (DOI)000450405300002 ()30451869 (PubMedID)2-s2.0-85056717930 (Scopus ID)
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Kurhade, C., Schreier, S., Lee, Y.-P., Zegenhagen, L., Hjertqvist, M., Dobler, G., . . . Överby, A. K. (2018). Correlation of Severity of Human Tick-Borne Encephalitis Virus Disease and Pathogenicity in Mice. Emerging Infectious Diseases, 24(9), 1709-1712
Open this publication in new window or tab >>Correlation of Severity of Human Tick-Borne Encephalitis Virus Disease and Pathogenicity in Mice
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2018 (English)In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 24, no 9, p. 1709-1712Article in journal (Refereed) Published
Abstract [en]

We compared 2 tick-borne encephalitis virus strains isolated from 2 different foci that cause different symptoms in tick-borne encephalitis patients, from neurologic to mild gastrointestinal symptoms. We compared neuroinvasiveness, neurovirulence, and proinflammatory cytokine response in mice and found unique differences that contribute to our understanding of pathogenesis.

Place, publisher, year, edition, pages
Centers for Disease control and Prevention, 2018
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-151539 (URN)10.3201/eid2409.171825 (DOI)000441877400015 ()30124404 (PubMedID)
Funder
The Kempe FoundationsThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2018-09-11 Created: 2018-09-11 Last updated: 2018-09-11Bibliographically approved
Peña Cárcamo, J. R., Morell, M. L., Vázquez, C. A., Vatansever, S., Upadhyay, A. S., Överby, A. K., . . . García, C. C. (2018). The interplay between viperin antiviral activity, lipid droplets and Junín mammarenavirus multiplication. Virology, 514, 216-229
Open this publication in new window or tab >>The interplay between viperin antiviral activity, lipid droplets and Junín mammarenavirus multiplication
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2018 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 514, p. 216-229Article in journal (Refereed) Published
Abstract [en]

Junín arenavirus infections are associated with high levels of interferons in both severe and fatal cases. Upon Junín virus (JUNV) infection a cell signaling cascade initiates, that ultimately attempts to limit viral replication and prevent infection progression through the expression of host antiviral proteins. The interferon stimulated gene (ISG) viperin has drawn our attention as it has been highlighted as an important antiviral protein against several viral infections. The studies of the mechanistic actions of viperin have described important functional domains relating its antiviral and immune-modulating actions through cellular lipid structures. In line with this, through silencing and overexpression approaches, we have identified viperin as an antiviral ISG against JUNV. In addition, we found that lipid droplet structures are modulated during JUNV infection, suggesting its relevance for proper virus multiplication. Furthermore, our confocal microscopy images, bioinformatics and functional results also revealed viperin-JUNV protein interactions that might be participating in this antiviral pathway at lipid droplet level. Altogether, these results will help to better understand the factors mediating innate immunity in arenavirus infection and may lead to the development of pharmacological agents that can boost their effectiveness thereby leading to new treatments for this viral disease.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Junín virus, viperin, lipids droplets
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-144841 (URN)10.1016/j.virol.2017.10.012 (DOI)000423010200024 ()29202415 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-06-09Bibliographically approved
Lindquist, R. & Överby, A. K. (2018). The Role of Viperin in Antiflavivirus Responses. DNA and Cell Biology, 37(9), 725-730
Open this publication in new window or tab >>The Role of Viperin in Antiflavivirus Responses
2018 (English)In: DNA and Cell Biology, ISSN 1044-5498, E-ISSN 1557-7430, Vol. 37, no 9, p. 725-730Article in journal (Refereed) Published
Abstract [en]

Viperin is an interferon (IFN)-stimulated gene product, which is part of the first line of the intracellular response against viral infection. It is a potent antiviral protein, strongly upregulated after IFN-stimulation and virus infection. Viperin is antivirally active against many different viruses from different families and has been shown to inhibit several flaviviruses. Flaviviruses are an important group of arthropod-borne viruses that cause millions of infections annually. In this review, we focus on the recent advances of the antiviral mechanisms of viperin against these flaviviruses, both pointing to similarities and differences between viruses within the same genera.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2018
Keywords
viperin, interferon-stimulated gene, interferon, flavivirus, antiviral response, radical SAM enzyme
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-152264 (URN)10.1089/dna.2018.4328 (DOI)000443729600001 ()30059238 (PubMedID)
Funder
Swedish Research Council, 2017-02438Swedish Foundation for Strategic Research , FFL12-0089
Available from: 2018-10-03 Created: 2018-10-03 Last updated: 2018-10-03Bibliographically approved
Lindqvist, R., Upadhyay, A. S. & Överby, A. K. (2018). Tick-Borne Flaviviruses and the Type I Interferon Response. Viruses, 10(7), Article ID 340.
Open this publication in new window or tab >>Tick-Borne Flaviviruses and the Type I Interferon Response
2018 (English)In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 10, no 7, article id 340Article, review/survey (Refereed) Published
Abstract [en]

Flaviviruses are globally distributed pathogens causing millions of human infections every year. Flaviviruses are arthropod-borne viruses and are mainly transmitted by either ticks or mosquitoes. Mosquito-borne flaviviruses and their interactions with the innate immune response have been well-studied and reviewed extensively, thus this review will discuss tick-borne flaviviruses and their interactions with the host innate immune response.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
tick-borne flavivirus, innate immunity, interferon, tick-borne encephalitis virus, powassan virus, omsk morrhagic fever virus, kyasanur forest disease virus, louping ill virus, viperin
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-152422 (URN)10.3390/v10070340 (DOI)000445153200002 ()29933625 (PubMedID)
Funder
The Kempe Foundations, SMK-1654The Kempe Foundations, JCK-1827Swedish Research Council, 2011-2795Swedish Research Council, 2017-02438Swedish Foundation for Strategic Research , ICA10-0059Swedish Foundation for Strategic Research , FFL12-0089
Available from: 2018-10-05 Created: 2018-10-05 Last updated: 2018-10-05Bibliographically approved
Panayiotou, C., Lindqvist, R., Kurhade, C., Vonderstein, K., Pasto, J., Edlund, K., . . . Överby, A. K. (2018). Viperin restricts Zika virus and tick-borne encephalitis virus replication by targeting NS3 for proteasomal degradation. Journal of Virology, 92(7), Article ID e02054-17.
Open this publication in new window or tab >>Viperin restricts Zika virus and tick-borne encephalitis virus replication by targeting NS3 for proteasomal degradation
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2018 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 7, article id e02054-17Article in journal (Refereed) Published
Abstract [en]

Flaviviruses are arthropod-borne viruses that constitute a major global health problem, with millions of human infections annually. Their pathogenesis ranges from mild illness to severe manifestations such as hemorrhagic fever and fatal encephalitis. Type I interferons (IFNs) are induced in response to viral infection and stimulate the expression of interferon-stimulated genes (ISGs), including that encoding viperin (virus-inhibitory protein, endoplasmic reticulum associated, IFN inducible), which shows antiviral activity against a broad spectrum of viruses, including several flaviviruses. Here we describe a novel antiviral mechanism employed by viperin against two prominent flaviviruses, tick-borne encephalitis virus (TBEV) and Zika virus (ZIKV). Viperin was found to interact and colocalize with the structural proteins premembrane (prM) and envelope (E) of TBEV, as well as with nonstructural (NS) proteins NS2A, NS2B, and NS3. Interestingly, viperin expression reduced the NS3 protein level, and the stability of the other interacting viral proteins, but only in the presence of NS3. We also found that although viperin interacted with NS3 of mosquito-borne flaviviruses (ZIKV, Japanese encephalitis virus, and yellow fever virus), only ZIKV was sensitive to the antiviral effect of viperin. This sensitivity correlated with viperin's ability to induce proteasome-dependent degradation of NS3. ZIKV and TBEV replication was rescued completely when NS3 was overexpressed, suggesting that the viral NS3 is the specific target of viperin. In summary, we present here a novel antiviral mechanism of viperin that is selective for specific viruses in the genus Flavivirus, affording the possible availability of new drug targets that can be used for therapeutic intervention.

IMPORTANCE Flaviviruses are a group of enveloped RNA viruses that cause severe diseases in humans and animals worldwide, but no antiviral treatment is yet available. Viperin, a host protein produced in response to infection, effectively restricts the replication of several flaviviruses, but the exact molecular mechanisms have not been elucidated. Here we have identified a novel mechanism employed by viperin to inhibit the replication of two flaviviruses: tick-borne encephalitis virus (TBEV) and Zika virus (ZIKV). Viperin induced selective degradation via the proteasome of TBEV and ZIKV non-structural 3 (NS3) protein, which is involved in several steps of the viral life cycle. Furthermore, viperin also reduced the stability of several other viral proteins in a NS3-dependent manner, suggesting a central role of NS3 in viperin's antiflavivirus activity. Taking the results together, our work shows important similarities and differences among the members of the genus Flavivirus and could lead to the possibility of therapeutic intervention.

Place, publisher, year, edition, pages
American Society for Microbiology, 2018
Keywords
ISG, viperin, NS3, flavivirus, proteasomal degradation, interferons
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-142921 (URN)10.1128/JVI.02054-17 (DOI)000428409800027 ()29321318 (PubMedID)
Note

Originally included in thesis in manuscript form.

Errata: Panayiotou C, Lindqvist R, Kurhade C, Vonderstein K, Pasto J, Edlund K, Upadhyay AS, Överby AK. 2018. Viperin restricts Zika virus and tick-borne encephalitis virus replication by targeting NS3 for proteasomal degradation. J Virol 92 (12): e00501-18. DOI:10.1128/JVI.00501-18.

Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2018-06-25Bibliographically approved
Vonderstein, K., Nilsson, E., Hubel, P., Nygård Skalman, L., Upadhyay, A., Pasto, J., . . . Överby, A. K. (2018). Viperin targets flavivirus virulence by inducing assembly of non-infectious capsid particles. Journal of Virology, 92(1), Article ID e01751-17.
Open this publication in new window or tab >>Viperin targets flavivirus virulence by inducing assembly of non-infectious capsid particles
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2018 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 1, article id e01751-17Article in journal (Refereed) Published
Abstract [en]

Efficient antiviral immunity requires interference with virus replication at multiple layers targeting diverse steps in the viral life cycle. Here we describe a novel flavivirus inhibition mechanism that results in interferon-mediated obstruction of tick-borne encephalitis virus particle assembly, and involves release of malfunctional membrane associated capsid (C) particles. This mechanism is controlled by the activity of the interferon-induced protein viperin, a broad spectrum antiviral interferon stimulated gene. Through analysis of the viperin-interactome, we identified the Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1), as the cellular protein targeted by viperin. Viperin-induced antiviral activity as well as C-particle release was stimulated by GBF1 inhibition and knock down, and reduced by elevated levels of GBF1. Our results suggest that viperin targets flavivirus virulence by inducing the secretion of unproductive non-infectious virus particles, by a GBF1-dependent mechanism. This yet undescribed antiviral mechanism allows potential therapeutic intervention.Importance The interferon response can target viral infection on almost every level, however, very little is known about interference of flavivirus assembly. Here we show that interferon, through the action of viperin, can disturb assembly of tick-borne encephalitis virus. The viperin protein is highly induced after viral infection and exhibit broad-spectrum antiviral activity. However, the mechanism of action is still elusive and appear to vary between the different viruses, indicating that cellular targets utilized by several viruses might be involved. In this study we show that viperin induce capsid particle release by interacting and inhibiting the function of the cellular protein Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1). GBF1 is a key protein in the cellular secretory pathway and essential in the life cycle of many viruses, also targeted by viperin, implicating GBF1 as a novel putative drug target.

Place, publisher, year, edition, pages
American Society of Microbiology, 2018
Keywords
COPI,  COPII,  GBF1,  assembly,  capsid,  flavivirus,  interferon,  tick-borne encephalitis virus,  viperi
National Category
Microbiology in the medical area Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-143054 (URN)10.1128/JVI.01751-17 (DOI)000417922700037 ()29046456 (PubMedID)
Funder
Swedish Research Council, 2011-2795Swedish Foundation for Strategic Research , ICA10-0059, FFL12-0089, FFL09-0181
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-06-09Bibliographically approved
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