umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Nilsson, Emma
Alternative names
Publications (10 of 10) Show all publications
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
Show others...
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
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
Show others...
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
Asghar, N., Lee, Y.-P., Nilsson, E., Lindqvist, R., Melik, W., Kröger, A., . . . Johansson, M. (2016). The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus. Scientific Reports, 6, Article ID 39265.
Open this publication in new window or tab >>The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus
Show others...
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 39265Article in journal (Refereed) Published
Abstract [en]

The tick-borne encephalitis virus (TBEV) is a flavivirus transmitted to humans, usually via tick bites. The virus causes tick-borne encephalitis (TBE) in humans, and symptoms range from mild flu-like symptoms to severe and long-lasting sequelae, including permanent brain damage. It has been suggested that within the population of viruses transmitted to the mammalian host, quasispecies with neurotropic properties might become dominant in the host resulting in neurological symptoms. We previously demonstrated the existence of TBEV variants with variable poly(A) tracts within a single blood-fed tick. To characterize the role of the poly(A) tract in TBEV replication and virulence, we generated infectious clones of Toro-2003 with the wild-type (A)(3)C(A)(6) sequence (Toro-6A) or with a modified (A)(3)C(A)(38) sequence (Toro-38A). Toro-38A replicated poorly compared to Toro-6A in cell culture, but Toro-38A was more virulent than Toro-6A in a mouse model of TBE. Next-generation sequencing of TBEV genomes after passaging in cell culture and/or mouse brain revealed mutations in specific genomic regions and the presence of quasispecies that might contribute to the observed differences in virulence. These data suggest a role for quasispecies development within the poly(A) tract as a virulence determinant for TBEV in mice.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-129706 (URN)10.1038/srep39265 (DOI)000389971500001 ()
Available from: 2017-01-10 Created: 2017-01-09 Last updated: 2018-06-09Bibliographically approved
Lenman, A., Liaci, A. M., Liu, Y., Årdahl, C., Rajan, A., Nilsson, E., . . . Arnberg, N. (2015). Human Adenovirus 52 Uses Sialic Acid-containing Glycoproteins and the Coxsackie and Adenovirus Receptor for Binding to Target Cells. PLoS Pathogens, 11(2), Article ID e1004657.
Open this publication in new window or tab >>Human Adenovirus 52 Uses Sialic Acid-containing Glycoproteins and the Coxsackie and Adenovirus Receptor for Binding to Target Cells
Show others...
2015 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 2, article id e1004657Article in journal (Refereed) Published
Abstract [en]

Most adenoviruses attach to host cells by means of the protruding fiber protein that binds to host cells via the coxsackievirus and adenovirus receptor (CAR) protein. Human adenovirus type 52 (HAdV-52) is one of only three gastroenteritis-causing HAdVs that are equipped with two different fiber proteins, one long and one short. Here we show, by means of virion-cell binding and infection experiments, that HAdV-52 can also attach to host cells via CAR, but most of the binding depends on sialylated glycoproteins. Glycan microarray, flow cytometry, surface plasmon resonance and ELISA analyses reveal that the terminal knob domain of the long fiber (52LFK) binds to CAR, and the knob domain of the short fiber (52SFK) binds to sialylated glycoproteins. X-ray crystallographic analysis of 52SFK in complex with 2-O-methylated sialic acid combined with functional studies of knob mutants revealed a new sialic acid binding site compared to other, known adenovirus: glycan interactions. Our findings shed light on adenovirus biology and may help to improve targeting of adenovirus-based vectors for gene therapy.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-103565 (URN)10.1371/journal.ppat.1004657 (DOI)000352083400038 ()25674795 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-21 Last updated: 2018-06-07Bibliographically approved
Nilsson, E. C. (2011). Cellular receptors for viruses with ocular tropism. (Doctoral dissertation). Umeå: Umeå university
Open this publication in new window or tab >>Cellular receptors for viruses with ocular tropism
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Several viruses from different virus families are known to cause ocular infections, e.g. members of the Adenoviridae, Picornaviridae and the Herpesviridae families. These infections are spread by contact and in the case of adenoviruses (Ads) and picornaviruses they are also highly contagious. The ocular infections caused by Ads and picornaviruses are called epidemic keratoconjunctivitis (EKC) and acute hemorrhagic conjunctivitis (AHC), respectively. Historically, EKC is caused mainly by three types of Ads from species D: Ad8, Ad19 and Ad37. The infection is characterized by keratitis and conjunctivitis but also involves pain, edema, lacrimation and blurred vision. AHC is caused mainly by two types of picornaviruses: coxsackievirus A24v (CVA24v) and enterovirus 70 (EV70), and is characterized by pain, redness, excessive tearing, swelling and subconjunctival hemorrhages. In addition, blurred vision, keratitis, malaise, myalgia, fever, headache and upper respiratory tract symptoms can also be experienced. Both infections are problematic in many parts of the world, affecting millions of people every year. Despite the great need, the only treatment available today is supportive treatment; no antiviral drugs are available to combat these common viral infections.

Ad37 has previously been reported to use sialic acid (SA) as its cellular receptor. Since there is no antiviral treatment available against EKC we wanted to evaluate the inhibitory effect of SA-based antiviral compounds on Ad37 binding to and infection of ocular cells. We found that multivalent compounds consisting of SA linked to a globular carrier molecule, in this case human serum albumin, efficiently blocked Ad37 binding and infection at low concentrations. Further attempts were then made to improve the effect by chemically modifying SA monosaccharides. However, no enhanced inhibitory effect was accomplished and the conclusion was that the best inhibitors are based on unmodified SA. We next hypothesized that development of efficient SA-based binding inhibitors may require detailed knowledge about the structure of the SA-containing receptor. Using a battery of biological and biochemical experiments, including glycan array, binding and infection assays, X-ray crystallography and surface plasmon resonance (SPR); we identified a specific glycan involved in the binding and infection of Ad37. This glycan turned out to be a branched, di-SA-containing motif corresponding to the glycan motif of the ganglioside GD1a. However, the ganglioside itself did not function as a cellular receptor, as shown by a number of binding and infection assays. Instead, the receptor consisted of one or more glycoproteins that contain the GD1a glycan motif. This glycan docked with both its SAs into the trimeric Ad37 knob resulting in a very strong interaction as compared to most other protein-glycan interactions. Hopefully, this finding will aid development of more potent inhibitors of Ad37 binding and infection.

The receptor for CVA24v, one of the main causative agents of AHC, has been unknown until now. We showed that this ocular virus, like Ad37, is also able to use SA as a receptor on corneal cells but not on conjunctival cells. This suggested that CVA24v may use two different receptors. As for Ad37, the receptor used by CVA24v on corneal cells also appears to be one or more sialic acid-containing glycoproteins. We believe that these findings may be a starting point for design and development of candidate drugs for topical treatment of AHC.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2011. p. 123
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1414
Keywords
Adenovirus, picornavirus, receptors, antivirals
National Category
Microbiology in the medical area
Research subject
Molecular Biology; Infectious Diseases; Microbiology
Identifiers
urn:nbn:se:umu:diva-42818 (URN)978-91-7459-182-8 (ISBN)
Public defence
2011-05-13, Major Groove, by 6L, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2011-04-15 Created: 2011-04-13 Last updated: 2018-06-08Bibliographically approved
Nilsson, E. C., Storm, R. J., Bauer, J., Johansson, S. M., Lookene, A., Ångström, J., . . . Arnberg, N. (2011). The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis (Letter). Nature Medicine, 17(1), 105-109
Open this publication in new window or tab >>The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis (Letter)
Show others...
2011 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 17, no 1, p. 105-109Article in journal (Refereed) Published
Abstract [en]

Adenovirus type 37 (Ad37) is a leading cause of epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular disease. Whereas most other adenoviruses infect cells by engaging CD46 or the coxsackie and adenovirus receptor (CAR), Ad37 binds previously unknown sialic acid-containing cell surface molecules. By glycan array screening, we show here that the receptor-recognizing knob domain of the Ad37 fiber protein specifically binds a branched hexasaccharide that is present in the GD1a ganglioside and that features two terminal sialic acids. Soluble GD1a glycan and GD1a-binding antibodies efficiently prevented Ad37 virions from binding and infecting corneal cells. Unexpectedly, the receptor is constituted by one or more glycoproteins containing the GD1a glycan motif rather than the ganglioside itself, as shown by binding, infection and flow cytometry experiments. Molecular modeling, nuclear magnetic resonance and X-ray crystallography reveal that the two terminal sialic acids dock into two of three previously established sialic acid-binding sites in the trimeric Ad37 knob. Surface plasmon resonance analysis shows that the knob-GD1a glycan interaction has high affinity. Our findings therefore form a basis for the design and development of sialic acid-containing antiviral drugs for topical treatment of EKC.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-38769 (URN)10.1038/nm.2267 (DOI)21151139 (PubMedID)
Available from: 2011-01-03 Created: 2010-12-28 Last updated: 2018-06-08Bibliographically approved
Johansson, S., Nilsson, E., Qian, W., Guilligay, D., Crepin, T., Cusack, S., . . . Elofsson, M. (2009). Design, synthesis, and evaluation of N-acyl modified sialic acids as inhibitors of adenoviruses causing epidemic keratoconjunctivitis. Journal of Medicinal Chemistry, 52(12), 3666-3678
Open this publication in new window or tab >>Design, synthesis, and evaluation of N-acyl modified sialic acids as inhibitors of adenoviruses causing epidemic keratoconjunctivitis
Show others...
2009 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 52, no 12, p. 3666-3678Article in journal (Refereed) Published
Abstract [en]

The adenovirus serotype Ad37 binds to and infects human corneal epithelial (HCE) cells through attachment to cellular glycoproteins carrying terminal sialic acids. By use of the crystallographic structure of the sialic acid-interacting domain of the Ad37 fiber protein in complex with sialyllactose, a set of N-acyl modified sialic acids were designed to improve binding affinity through increased hydrophobic interactions. These N-acyl modified sialic acids and their corresponding multivalent human serum albumin (HSA) conjugates were synthesized and tested in Ad37 cell binding and cell infectivity assays. Compounds bearing small substituents were as effective inhibitors as sialic acid. X-ray crystallography and overlays with the Ad37-sialyllactose complex showed that the N-acyl modified sialic acids were positioned in the same orientation as sialic acid. Their multivalent counterparts achieved a strong multivalency effect and were more effective to prevent infection than the monomers. Unfortunately, they were less active as inhibitors than multivalent sialic acid.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-42373 (URN)10.1021/jm801609s (DOI)19456100 (PubMedID)
Available from: 2011-04-07 Created: 2011-04-07 Last updated: 2018-06-08Bibliographically approved
Nilsson, E. C., Jamshidi, F., Johansson, S. M. C., Oberste, M. S. & Arnberg, N. (2008). Sialic acid is a cellular receptor for coxsackievirus A24 variant, an emerging virus with pandemic potential. Journal of Virology, 82(6), 3061-3068
Open this publication in new window or tab >>Sialic acid is a cellular receptor for coxsackievirus A24 variant, an emerging virus with pandemic potential
Show others...
2008 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 82, no 6, p. 3061-3068Article in journal (Refereed) Published
Abstract [en]

Binding to target cell receptors is a critical step in the virus life cycle. Coxsackievirus A24 variant (CVA24v) has pandemic potential and is a major cause of acute hemorrhagic conjunctivitis, but its cellular receptor has hitherto been unknown. Here we show that CVA24v fails to bind to and infect CHO cells defective in sialic acid expression. Binding of CVA24v to and infection of corneal epithelial cells are efficiently inhibited by treating cells with a sialic acid-cleaving enzyme or sialic acid-binding lectins and by treatment of the virus with soluble, multivalent sialic acid. Protease treatment of cells efficiently inhibited virus binding, suggesting that the receptor is a sialylated glycoprotein. Like enterovirus type 70 and influenza A virus, CVA24v can cause pandemics. Remarkably, all three viruses use the same receptor. Since several unrelated viruses with tropism for the eye use this receptor, sialic acid-based antiviral drugs that prevent virus entry may be useful for topical treatment of such infections.

Place, publisher, year, edition, pages
Baltimore: American Society for Microbiology, 2008
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-21102 (URN)10.1128/JVI.02470-07 (DOI)18184708 (PubMedID)
Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2018-06-09Bibliographically approved
Johansson, S. M., Nilsson, E. C., Elofsson, M., Ahlskog, N., Kihlberg, J. & Arnberg, N. (2007). Multivalent sialic acid conjugates inhibit adenovirus type 37 from binding to and infecting human corneal epithelial cells. Antiviral Research, 73(2), 92-100
Open this publication in new window or tab >>Multivalent sialic acid conjugates inhibit adenovirus type 37 from binding to and infecting human corneal epithelial cells
Show others...
2007 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 73, no 2, p. 92-100Article in journal (Refereed) Published
Abstract [en]

Adenovirus type 37 is one of the main causative agents of epidemic keratoconjunctivitis. In a series of publications, we have reported that this virus uses sialic acid as a cellular receptor. Here we demonstrate in vitro that on a molar basis, multivalent sialic acid conjugated to human serum albumin prevents adenovirus type 37 from binding to and infecting human corneal epithelial cells 1000-fold more efficiently than monosaccharidic sialic acid. We also demonstrate that the extraordinary inhibitory effect of multivalent sialic acid is due to the ability of this compound to aggregate virions. We conclude that multivalent sialic acid may be a potential new antiviral drug, for use in the treatment of epidemic keratoconjunctivitis caused by the adenoviruses that use sialic acid as cellular receptor.

Keywords
Adenovirus, EKC, Sialic acid, Multivalent
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-12970 (URN)10.1016/j.antiviral.2006.08.004 (DOI)
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2018-06-09Bibliographically approved
Johansson, S., Nilsson, E., Qian, W., Arnberg, N., Kihlberg, J. & Elofsson, M.Design, synthesis and evaluation of N-acyl modified sialic acids as inhibitors of EKC-causing adenoviruses.
Open this publication in new window or tab >>Design, synthesis and evaluation of N-acyl modified sialic acids as inhibitors of EKC-causing adenoviruses
Show others...
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-3172 (URN)
Available from: 2008-05-08 Created: 2008-05-08 Last updated: 2018-06-09Bibliographically approved
Organisations

Search in DiVA

Show all publications