Paramyxovirus matrix proteins modulate host cell translation via exon-junction complex interactions in the cytoplasm.

Viruses have evolved myriad strategies to exploit the translation machinery of host cells to potentiate their replication. However, how paramyxovirus (PMVs) modulate cellular translation for their own benefit has not been systematically examined. Utilizing puromycylation labeling, overexpression of individual viral genes, and infection with wild-type virus versus its gene-deleted counterpart, we found that PMVs significantly inhibit host cells' nascent peptide synthesis during infection, with the viral matrix being the primary contributor to this effect.

Gender-related self-reported mental health inequalities in primary care in England: a cross-sectional analysis using the GP Patient Survey.

Background: Transgender, non-binary, and gender diverse people face discrimination and barriers to accessing health care. Existing evidence suggests higher rates of mental health conditions among these groups compared with binary and cisgender groups. However, information is limited by poor gender recording in health records and surveys.

Evaluating socioeconomic inequalities in influenza vaccine uptake during the COVID-19 pandemic: A cohort study in Greater Manchester, England.

Background: There are known socioeconomic inequalities in annual seasonal influenza (flu) vaccine uptake. The Coronavirus Disease 2019 (COVID-19) pandemic was associated with multiple factors that may have affected flu vaccine uptake, including widespread disruption to healthcare services, changes to flu vaccination eligibility and delivery, and increased public awareness and debate about vaccination due to high-profile COVID-19 vaccination campaigns. However, to the best of our knowledge, no existing studies have investigated the consequences for inequalities in flu vaccine uptake, so we aimed to investigate whether socioeconomic inequalities in flu vaccine uptake have widened since the onset of the COVID-19 pandemic.

Correction: Ethnic inequalities in COVID-19 vaccine uptake and comparison to seasonal influenza vaccine uptake in Greater Manchester, UK: A cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.

Ethnic inequalities in COVID-19 vaccine uptake and comparison to seasonal influenza vaccine uptake in Greater Manchester, UK: A cohort study.

Background: COVID-19 vaccine uptake is lower amongst most minority ethnic groups compared to the White British group in England, despite higher COVID-19 mortality rates. Here, we add to existing evidence by estimating inequalities for 16 minority ethnic groups, examining ethnic inequalities within population subgroups, and comparing the magnitudes of ethnic inequalities in COVID-19 vaccine uptake to those for routine seasonal influenza vaccine uptake.

Methods And Findings: We conducted a retrospective cohort study using the Greater Manchester Care Record, which contains de-identified electronic health record data for the population of Greater Manchester, England.

Effects of BNT162b2 mRNA vaccine on COVID-19 infection and hospitalisation amongst older people: matched case control study for England.

Background: The BNT162b2 mRNA vaccine has been shown to be effective at preventing serious COVID-19 events in clinical trials. There is less evidence on effectiveness in real-world settings, especially for older people. Here, we aimed to estimate vaccine effectiveness in the context of the rapid NHS mass-vaccination programme in England, exploiting age-based vaccination eligibility thresholds to minimise and correct for selection bias.

Ethnic inequalities in health-related quality of life among older adults in England: secondary analysis of a national cross-sectional survey.

Background: The population of older adults (ie, those aged ≥55 years) in England is becoming increasingly ethnically diverse. Previous reports indicate that ethnic inequalities in health exist among older adults, but information is limited by the paucity of data from small minority ethnic groups. This study aimed to analyse inequalities in health-related quality of life (HRQoL) and five determinants of health in older adults across all ethnic groups in England.

Dissecting ELANE neutropenia pathogenicity by human HSC gene editing.

Severe congenital neutropenia (SCN) is a life-threatening disorder most often caused by dominant mutations of ELANE that interfere with neutrophil maturation. We conducted a pooled CRISPR screen in human hematopoietic stem and progenitor cells (HSPCs) that correlated ELANE mutations with neutrophil maturation potential. Highly efficient gene editing of early exons elicited nonsense-mediated decay (NMD), overcame neutrophil maturation arrest in HSPCs from ELANE-mutant SCN patients, and produced normal hematopoietic engraftment function.

Orally efficacious broad-spectrum allosteric inhibitor of paramyxovirus polymerase.

Paramyxoviruses such as human parainfluenza virus type-3 (HPIV3) and measles virus (MeV) are a substantial health threat. In a high-throughput screen for inhibitors of HPIV3 (a major cause of acute respiratory infection), we identified GHP-88309-a non-nucleoside inhibitor of viral polymerase activity that possesses unusual broad-spectrum activity against diverse paramyxoviruses including respiroviruses (that is, HPIV1 and HPIV3) and morbilliviruses (that is, MeV). Resistance profiles of distinct target viruses overlapped spatially, revealing a conserved binding site in the central cavity of the viral polymerase (L) protein that was validated by photoaffinity labelling-based target mapping.

Zoonotic Potential of Emerging Paramyxoviruses: Knowns and Unknowns.

The risk of spillover of enzootic paramyxoviruses and the susceptibility of recipient human and domestic animal populations are defined by a broad collection of ecological and molecular factors that interact in ways that are not yet fully understood. Nipah and Hendra viruses were the first highly lethal zoonotic paramyxoviruses discovered in modern times, but other paramyxoviruses from multiple genera are present in bats and other reservoirs that have unknown potential to spillover into humans. We outline our current understanding of paramyxovirus reservoir hosts and the ecological factors that may drive spillover, and we explore the molecular barriers to spillover that emergent paramyxoviruses may encounter.

Antibody-antigen kinetics constrain intracellular humoral immunity.

During infection with non-enveloped viruses, antibodies stimulate immunity from inside cells by activating the cytosolic Fc receptor TRIM21. This intracellular humoral response relies on opsonized viral particles reaching the cytosol intact but the antigenic and kinetic constraints involved are unknown. We have solved the structure of a potent TRIM21-dependent neutralizing antibody in complex with human adenovirus 5 hexon and show how these properties influence immune activity.

Nipah virus matrix protein: expert hacker of cellular machines.

Nipah virus (NiV, Henipavirus) is a highly lethal emergent zoonotic paramyxovirus responsible for repeated human outbreaks of encephalitis in South East Asia. There are no approved vaccines or treatments, thus improved understanding of NiV biology is imperative. NiV matrix protein recruits a plethora of cellular machinery to scaffold and coordinate virion budding.

TRIM21 Immune Signaling Is More Sensitive to Antibody Affinity Than Its Neutralization Activity.

Ab-coated viruses can be detected in the cytosol by the FcR tripartite motif-containing 21 (TRIM21), which rapidly recruits the proteasomal machinery and triggers induction of immune signaling. As such, TRIM21 plays a key role in intracellular protection by targeting invading viruses for destruction and alerting the immune system. A hallmark of immunity is elicitation of a balanced response that is proportionate to the threat, to avoid unnecessary inflammation.

TRIM21 Promotes cGAS and RIG-I Sensing of Viral Genomes during Infection by Antibody-Opsonized Virus.

Encapsidation is a strategy almost universally employed by viruses to protect their genomes from degradation and from innate immune sensors. We show that TRIM21, which targets antibody-opsonized virions for proteasomal destruction, circumvents this protection, enabling the rapid detection and degradation of viral genomes before their replication. TRIM21 triggers an initial wave of cytokine transcription that is antibody, rather than pathogen, driven.

Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21.

Tripartite motif (TRIM) 21 is a cytosolic antibody receptor that neutralizes antibody-coated viruses that penetrate the cell and simultaneously activates innate immunity. Here we show that the conjugation of TRIM21 with K63-linked ubiquitin (Ub-(63)Ub) catalyzed by the sequential activity of nonredundant E2 Ub enzymes is required for its dual antiviral functions. TRIM21 is first labeled with monoubiquitin (monoUb) by the E2 Ube2W.

Intracellular antibody immunity.

Antibodies allow the immune system to target pathogens despite their tremendous diversity and rapid evolution. Once bound to a pathogen, antibodies induce a broad range of effector mechanisms, including phagocytosis and complement. However, these mechanisms are all initiated in the extracellular space, meaning that pathogens like viruses evade them upon infection of their target cells.

Intracellular antibody receptor TRIM21 prevents fatal viral infection.

Host species have evolved mechanisms that can inhibit pathogen replication even after a cell has been successfully invaded. Here we show that tripartite-motif protein 21 (TRIM21), a ubiquitously expressed E3 ubiquitin ligase that targets viruses inside the cytosol, protects mice against fatal viral infection. Upon infection with mouse adenovirus-1, naive mice lacking TRIM21 succumb to encephalomyelitis within 7 d.

Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21.

During pathogen infection, antibodies can be carried into the infected cell, where they are detected by the ubiquitously expressed cytosolic antibody receptor TRIM21. Here we found that recognition of intracellular antibodies by TRIM21 activated immune signaling. TRIM21 catalyzed the formation of Lys63 (K63)-linked ubiquitin chains and stimulated the transcription factor pathways of NF-κB, AP-1, IRF3, IRF5 and IRF7.