SARS-CoV-2 N protein recruits G3BP to double membrane vesicles to promote translation of viral mRNAs.

Ras-GTPase-activating protein SH3-domain-binding proteins (G3BP) are critical for the formation of stress granules (SGs) through their RNA- and ribosome-binding properties. SARS-CoV-2 nucleocapsid (N) protein exhibits strong binding affinity for G3BP and inhibits infection-induced SG formation soon after infection. To study the impact of the G3BP-N interaction on viral replication and pathogenesis in detail, we generated a mutant SARS-CoV-2 (RATA) that specifically lacks the G3BP-binding motif in the N protein.

Stress granule formation helps to mitigate neurodegeneration.

Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known.

Multi-compartmental diversification of neutralizing antibody lineages dissected in SARS-CoV-2 spike-immunized macaques.

The continued evolution of SARS-CoV-2 underscores the need to understand qualitative aspects of the humoral immune response elicited by spike immunization. Here, we combine monoclonal antibody (mAb) isolation with deep B cell receptor (BCR) repertoire sequencing of rhesus macaques immunized with prefusion-stabilized spike glycoprotein. Longitudinal tracing of spike-sorted B cell lineages in multiple immune compartments demonstrates increasing somatic hypermutation and broad dissemination of vaccine-elicited B cells in draining and non-draining lymphoid compartments, including the bone marrow, spleen and, most notably, periaortic lymph nodes.

Structural basis of broad SARS-CoV-2 cross-neutralization by affinity-matured public antibodies.

Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial.

Stress granule formation helps to mitigate neurodegeneration.

Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known.

Antigen receptor stimulation induces purifying selection against pathogenic mitochondrial tRNA mutations.

Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNAAla and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNALeu, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination.

Caprin-1 binding to the critical stress granule protein G3BP1 is influenced by pH.

G3BP is the central node within stress-induced protein-RNA interaction networks known as stress granules (SGs). The SG-associated proteins Caprin-1 and USP10 bind mutually exclusively to the NTF2 domain of G3BP1, promoting and inhibiting SG formation, respectively. Herein, we present the crystal structure of G3BP1-NTF2 in complex with a Caprin-1-derived short linear motif (SLiM).

At-home sampling to meet geographical challenges for serological assessment of SARS-CoV-2 exposure in a rural region of northern Sweden, March to May 2021: a retrospective cohort study.

BackgroundThe current SARS-CoV-2 pandemic has highlighted a need for easy and safe blood sampling in combination with accurate serological methodology. Venipuncture for testing is usually performed by trained staff at healthcare centres. Long travel distances to healthcare centres in rural regions may introduce a bias of testing towards relatively large communities with closer access.

A Multiparametric and High-Throughput Platform for Host-Virus Binding Screens.

Speed is key during infectious disease outbreaks. It is essential, for example, to identify critical host binding factors to pathogens as fast as possible. The complexity of host plasma membrane is often a limiting factor hindering fast and accurate determination of host binding factors as well as high-throughput screening for neutralizing antimicrobial drug targets.

SARS-CoV-2 spike HexaPro formulated in aluminium hydroxide and administered in an accelerated vaccination schedule partially protects Syrian Hamsters against viral challenge despite low neutralizing antibody responses.

SARS-CoV-2 continues to pose a threat to human health as new variants emerge and thus a diverse vaccine pipeline is needed. We evaluated SARS-CoV-2 HexaPro spike protein formulated in Alhydrogel (aluminium oxyhydroxide) in Syrian hamsters, using an accelerated two dose regimen (given 10 days apart) and a standard regimen (two doses given 21 days apart). Both regimens elicited spike- and RBD-specific IgG antibody responses of similar magnitude, but virus neutralization was low or undetectable.

SLiM-binding pockets: an attractive target for broad-spectrum antivirals.

Short linear motif (SLiM)-mediated interactions offer a unique strategy for viral intervention due to their compact interfaces, ease of convergent evolution, and key functional roles. Consequently, many viruses extensively mimic host SLiMs to hijack or deregulate cellular pathways and the same motif-binding pocket is often targeted by numerous unrelated viruses. A toolkit of therapeutics targeting commonly mimicked SLiMs could provide prophylactic and therapeutic broad-spectrum antivirals and vastly improve our ability to treat ongoing and future viral outbreaks.

Silver nanoparticles with excellent biocompatibility block pseudotyped SARS-CoV-2 in the presence of lung surfactant.

Silver (Ag) is known to possess antimicrobial properties which is commonly attributed to soluble Ag ions. Here, we showed that Ag nanoparticles (NPs) potently inhibited SARS-CoV-2 infection using two different pseudovirus neutralization assays. We also evaluated a set of Ag nanoparticles of different sizes with varying surface properties, including polyvinylpyrrolidone (PVP)-coated and poly (ethylene glycol) (PEG)-modified Ag nanoparticles, and found that only the bare (unmodified) nanoparticles were able to prevent virus infection.

Immunoglobulin germline gene polymorphisms influence the function of SARS-CoV-2 neutralizing antibodies.

The human immunoglobulin heavy-chain (IGH) locus is exceptionally polymorphic, with high levels of allelic and structural variation. Thus, germline IGH genotypes are personal, which may influence responses to infection and vaccination. For an improved understanding of inter-individual differences in antibody responses, we isolated SARS-CoV-2 spike-specific monoclonal antibodies from convalescent health care workers, focusing on the IGHV1-69 gene, which has the highest level of allelic variation of all IGHV genes.

Multi-target direct-acting SARS-CoV-2 antivirals against the nucleotide-binding pockets of virus-specific proteins.

The nucleotide-binding pockets (NBPs) in virus-specific proteins have proven to be the most successful antiviral targets for several viral diseases. Functionally important NBPs are found in various structural and non-structural proteins of SARS-CoV-2. In this study, the first successful multi-targeting attempt to identify effective antivirals has been made against NBPs in nsp12, nsp13, nsp14, nsp15, nsp16, and nucleocapsid (N) proteins of SARS-CoV-2.

Protection against SARS-CoV-2 transmission by a parenteral prime-Intranasal boost vaccine strategy.

Background: Licensed vaccines against SARS-CoV-2 effectively protect against severe disease, but display incomplete protection against virus transmission. Mucosal vaccines providing immune responses in the upper airways are one strategy to protect against transmission.

Methods: We administered Spike HexaPro trimer formulated in a cationic liposomal adjuvant as a parenteral (subcutaneous - s.

Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes.

The tripartite motif (TRIM) family of E3 ubiquitin ligases is well known for its roles in antiviral restriction and innate immunity regulation, in addition to many other cellular pathways. In particular, TRIM25-mediated ubiquitination affects both carcinogenesis and antiviral response. While individual substrates have been identified for TRIM25, it remains unclear how it regulates diverse processes.

Economic evaluation of the e-Health StandingTall balance exercise programme for fall prevention in people aged 70 years and over.

Background: globally, falls and fall-related injuries are the leading cause of injury-related morbidity and mortality in older people. In our ageing society healthcare costs are increasing, therefore programmes that reduce falls and are considered value for money are needed.

Objective: to complete an economic evaluation of an e-Health balance exercise programme that reduced falls and injurious falls in community-dwelling older people compared to usual care from a health and community-care funder perspective.

Nanobodies in the limelight: Multifunctional tools in the fight against viruses.

Antibodies are natural antivirals generated by the vertebrate immune system in response to viral infection or vaccination. Unsurprisingly, they are also key molecules in the virologist's molecular toolbox. With new developments in methods for protein engineering, protein functionalization and application, smaller antibody-derived fragments are moving in focus.

Multivariate mining of an alpaca immune repertoire identifies potent cross-neutralizing SARS-CoV-2 nanobodies.

Conventional approaches to isolate and characterize nanobodies are laborious. We combine phage display, multivariate enrichment, next-generation sequencing, and a streamlined screening strategy to identify numerous anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nanobodies. We characterize their potency and specificity using neutralization assays and hydrogen/deuterium exchange mass spectrometry (HDX-MS).

Probabilistic classification of anti-SARS-CoV-2 antibody responses improves seroprevalence estimates.

Objectives: Population-level measures of seropositivity are critical for understanding the epidemiology of an emerging pathogen, yet most antibody tests apply a strict cutoff for seropositivity that is not learnt in a data-driven manner, leading to uncertainty when classifying low-titer responses. To improve upon this, we evaluated cutoff-independent methods for their ability to assign likelihood of SARS-CoV-2 seropositivity to individual samples.

Methods: Using robust ELISAs based on SARS-CoV-2 spike (S) and the receptor-binding domain (RBD), we profiled antibody responses in a group of SARS-CoV-2 PCR+ individuals ( = 138).

Beta RBD boost broadens antibody-mediated protection against SARS-CoV-2 variants in animal models.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with resistance to neutralizing antibodies are threatening to undermine vaccine efficacy. Vaccination and infection have led to widespread humoral immunity against the pandemic founder (Wu-Hu-1). Against this background, it is critical to assess the outcomes of subsequent immunization with variant antigens.

Alphavirus RNA replication in vertebrate cells.

Alphaviruses are positive-strand RNA viruses, typically transmitted by mosquitoes between vertebrate hosts. They encode four essential replication proteins, the non-structural proteins nsP1-4, which possess the enzymatic activities of RNA capping, RNA helicase, site-specific protease, ADP-ribosyl removal and RNA polymerase. Alphaviruses have been key models in the study of membrane-associated RNA replication, which is a conserved feature among the positive-strand RNA viruses of animals and plants.

Colloidal dispersion of poly(ionic liquid)/Cu composite particles for protective surface coating against SAR-CoV-2.

Herein, we report a waterproof anti-SARS-CoV-2 protective film prepared by spray-coating of an aqueous colloidal dispersion of poly(ionic liquid)/copper (PIL/Cu) composite nanoparticles onto a substrate. The PIL dispersion was prepared by suspension polymerization of 3-dodecyl-1-vinylimdiazolium bromide in water at 70°C. The copper acetate salt was added into the PIL nanoparticle dispersion and in situ reduced into copper nanoparticles anchoring onto the PIL nanoparticles.