A5029350779- SARS-CoV-2 and COVID-19 Research
- Mosquito-borne diseases and control
- interferon and immune responses
- Viral Infections and Immunology Research
- COVID-19 Clinical Research Studies
- Monoclonal and Polyclonal Antibodies Research
- Viral gastroenteritis research and epidemiology
- RNA Research and Splicing
- Viral Infections and Vectors
- SARS-CoV-2 detection and testing
- Bacteriophages and microbial interactions
- HIV Research and Treatment
- Animal Virus Infections Studies
- RNA modifications and cancer
- Viral Infections and Outbreaks Research
- RNA and protein synthesis mechanisms
- Autophagy in Disease and Therapy
- RNA regulation and disease
- Immunotherapy and Immune Responses
- Immune Response and Inflammation
- Animal Disease Management and Epidemiology
- COVID-19 Impact on Reproduction
- COVID-19 epidemiological studies
- Virus-based gene therapy research
- Vector-Borne Animal Diseases
Karolinska Institutet
2015-2024
University Medical Center Utrecht
2024
Karolinska University Hospital
2020
Rockefeller University
2019
University of Borås
2019
Royal Hobart Hospital
2006-2014
Swedish Institute
2007
The Pirbright Institute
2000
Biotechnology and Biological Sciences Research Council
2000
Mammalian stress granules (SGs) contain stalled translation preinitiation complexes that are assembled into discrete by specific RNA-binding proteins such as G3BP. We now show cells lacking both G3BP1 and G3BP2 cannot form SGs in response to eukaryotic initiation factor 2α phosphorylation or eIF4A inhibition, but still SG-competent when challenged with severe heat osmotic stress. Rescue experiments using mutants G3BP1-F33W, a mutant unable bind G3BP partner Caprin1 USP10, rescues SG...
Abstract SARS-CoV-2 enters host cells through an interaction between the spike glycoprotein and angiotensin converting enzyme 2 (ACE2) receptor. Directly preventing this presents attractive possibility for suppressing replication. Here, we report isolation characterization of alpaca-derived single domain antibody fragment, Ty1, that specifically targets receptor binding (RBD) spike, directly ACE2 engagement. Ty1 binds RBD with high affinity, occluding ACE2. A cryo-electron microscopy...
Abstract SARS-CoV-2 may pose an occupational health risk to healthcare workers. Here, we report the seroprevalence of antibodies, self-reported symptoms and exposure among workers at a large acute care hospital in Sweden. The IgG antibodies against was 19.1% 2149 recruited between April 14th May 8th 2020, which higher than reported regional during same time period. Symptoms associated with were anosmia (odds ratio (OR) 28.4, 95% CI 20.6–39.5) ageusia (OR 19.2, 14.3–26.1). Seroprevalence also...
Abstract The coronavirus SARS-CoV-2 is the cause of ongoing COVID-19 pandemic. Therapeutic neutralizing antibodies constitute a key short-to-medium term approach to tackle COVID-19. However, traditional antibody production hampered by long development times and costly production. Here, we report rapid isolation characterization nanobodies from synthetic library, known as sybodies (Sb), that target receptor-binding domain (RBD) spike protein. Several binders with low nanomolar affinities...
SARS-CoV-2 is responsible for several million deaths to date globally, and both fomite transmission from surfaces as well airborne aerosols may be largely the spread of virus. Here, nanoparticle coatings three antimicrobial materials (Ag, CuO ZnO) are deposited on solid flat porous filter media, their activity against viability compared with a viral plaque assay. These nanocoatings manufactured by aerosol self-assembly during flame synthesis. Nanosilver particles coating exhibit strongest...
Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show potential for virus escape. This emphasizes need molecules with distinct and novel neutralization mechanisms. Here we describe isolation of a nanobody that interacts simultaneously two RBDs from different trimers SARS-CoV-2, rapidly inducing formation trimer-dimers leading loss their ability attach host cell receptor, ACE2. We this potently...
Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The and its sublineages have spike glycoproteins that are highly diverged from pandemic founder first-generation vaccine strain, resulting in significant evasion monoclonal antibody therapeutics vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public"...
Alphavirus infection results in the shutoff of host protein synthesis favor viral translation. Here, we show that during Semliki Forest virus (SFV) infection, translation inhibition is largely due to activation cellular stress response via phosphorylation eukaryotic initiation factor 2alpha subunit (eIF2alpha). Infection mouse embryo fibroblasts (MEFs) expressing a nonphosphorylatable mutant eIF2alpha does not result efficient shutoff, despite production. Furthermore, SFV enhancer element...
Dynamic, mRNA-containing stress granules (SGs) form in the cytoplasm of cells under environmental stresses, including viral infection. Many viruses appear to employ mechanisms disrupt formation SGs on their mRNAs, suggesting that they represent a cellular defense against Here, we report early Semliki Forest virus infection, C-terminal domain nonstructural protein 3 (nsP3) forms complex with Ras-GAP SH3-domain–binding (G3BP) and sequesters it into RNA replication complexes manner inhibits...
Rotavirus is a major cause of diarrhea worldwide and exhibits pronounced small intestinal epithelial cell (IEC) tropism. Both human infants neonatal mice are highly susceptible, whereas adult individuals remain asymptomatic shed only low numbers viral particles. Here we investigated age-dependent mechanisms the innate immune response to rotavirus infection in an oral mouse model. Expression receptor for dsRNA, Toll-like (Tlr) 3 was epithelium suckling but strongly increased during postnatal...
The Ras-GAP SH3 domain–binding proteins (G3BP) are essential regulators of the formation stress granules (SG), cytosolic aggregates and RNA that induced upon cellular stress, such as virus infection. Many viruses, including Semliki Forest (SFV), block SG induction by targeting G3BP. In this work, we demonstrate G3BP-binding motif SFV nsP3 consists two FGDF motifs, in which both phenylalanine glycine residue for binding. addition, show binding partner USP10 is also mediated an motif....
Autophagy is a cellular degradation process with an increasingly recognised importance in many biological pathways such as nutrient sensing, stress responses and development. We present straightforward assay for autophagy which combines the sensitivity of EGFP-LC3 reporter protein throughput capacity quantitative power flow cytometry. Because saponin extraction specific non-autophagosome associated EGFP-LC3-I form protein, cytometry can be used to measure total fluorescence extracted...
Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence last decade. We recently identified nontoxic plant alkaloid berberine as an antiviral substance against CHIKV a high-throughput screen. Here, we show that is effective multiple cell types variety strains, also at high multiplicity infection, consolidating potential drug. excluded any effect this compound on entry or activity viral replicase. A human phosphokinase array...
Multivalent molecules with repetitive structures including bacterial capsular polysaccharides and viral capsids elicit antibody responses through B cell receptor (BCR) crosslinking in the absence of T help. We report that immunization these cell–independent type 2 (TI-2) antigens causes up-regulation endogenous retrovirus (ERV) RNAs antigen-specific mouse cells. These are detected via a mitochondrial antiviral signaling protein (MAVS)–dependent RNA sensing pathway or reverse-transcribed...
ABSTRACT The Old World alphaviruses block stress granule assembly by sequestration of RasGAP SH3-domain binding protein (G3BP). Here, we show that the proline-rich sequences in hypervariable domain nonstructural 3 (nsP3) both Semliki Forest virus and Chikungunya were dispensable for to G3BP. nsP3 variants with or without this colocalized Furthermore, C-terminal repeat motifs sufficient G3BP binding.
ABSTRACT Many viruses affect or exploit the phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway, a crucial prosurvival signaling cascade. We report that this pathway was strongly activated in cells upon infection with Old World alphavirus Semliki Forest virus (SFV), even under conditions complete nutrient starvation. mapped activation to hyperphosphorylated/acidic domain C-terminal tail SFV nonstructural protein nsP3. Viruses deletion (SFV-Δ50) but not other...
Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, most current large-scale methods do not identify this important class protein-protein interactions. Uncovering mediated interactions provides both a molecular understanding viral with their and the foundation for developing novel antiviral reagents. Here we describe discovery approach covering 23 coronavirus strains that high resolution information on direct virus-host We 269...
ABSTRACT Infection of cells by foot-and-mouth disease virus (FMDV) results in the rapid inhibition host cell protein synthesis. This process is accompanied early cleavage translation initiation factor eIF4G, a component cap-binding complex eIF4F. mediated leader (L) protease. Subsequently, as proteins accumulate, secondary cleavages eIF4G occur. Furthermore, eIF4A (46 kDa), second eIF4F, also cleaved these later stages infection cycle. The 33-kDa product has lost fragment from its N...
ABSTRACT The type I interferons (IFNs) are potent mediators of antiviral immunity, and many viruses have developed means to block their expression or effects. Semliki Forest virus (SFV) infection induces rapid profound silencing host cell gene expression, a process believed be important for the inhibition IFN response. In SFV-infected cells, large proportion nonstructural protein nsp2 is found in nucleus, but role this localization has not been described. work we demonstrate that viral...
With the wide availability of massively parallel sequencing technologies, genetic mapping has become rate limiting step in mammalian forward genetics. Here we introduce a method for real-time identification N-ethyl-N-nitrosourea-induced mutations that cause phenotypes mice. All are identified by whole exome G1 progenitor and their zygosity is established G2/G3 mice before phenotypic assessment. Quantitative qualitative traits, including lethal effects, single or multiple combined pedigrees...
Using chemical germ-line mutagenesis, we screened mice for defects in the humoral immune response to a type II T-independent immunogen and an experimental alphavirus vector. A total of 26 mutations that impair immunity were recovered, 19 these have been positionally cloned. Among phenovariants bumble , cellophane Worker ascribed Nfkbid Zeb1 Ruvbl2 respectively. We show IκBNS, nuclear IκB-like protein encoded by is required development marginal zone peritoneal B-1 B cells additionally...
Recent findings have highlighted the role of Old World alphavirus non-structural protein 3 (nsP3) as a host defence modulator that functions by disrupting stress granules, subcellular phase-dense RNA/protein structures formed upon environmental stress. This disruption mechanism was largely explained through nsP3-mediated recruitment G3BP via two tandem FGDF motifs. Here, we present 1.9 Å resolution crystal structure NTF2-like domain G3BP-1 in complex with 25-residue peptide derived from...
G3BP-1 and -2 (hereafter referred to as G3BP) are multifunctional RNA-binding proteins involved in stress granule (SG) assembly. Viruses from diverse families target G3BP for recruitment replication or transcription complexes order block SG assembly but also acquire pro-viral effects via other unknown functions of G3BP. The Old World alphaviruses, including Semliki Forest virus (SFV) chikungunya (CHIKV) recruit into viral complexes, an interaction between FGDF motifs the C-terminus...