MRC Human Immunology Unit

Immune responses to parasite infection involve the increased production of basophils and eosinophils. These two myeloid cell types have key roles in type 2 anti-parasite immunity1 and rely on GATA family transcription factors for their specification2,3. The first committed step in basophil and eosinophil production is generation of basophil-eosinophil-mast cell progenitors (BEMPs) from oligopotent erythroid-primed multipotent progenitors (EMPPs). However, it is not well established how immune responses act on progenitors to initiate type 2 myelopoiesis. Here we show that infection with the helminth Heligmosomoides polygyrus increases EMPP commitment to myeloid fate at the expense of erythropoiesis. Uponinfection with H. polygyrus, the IL-33 alarmin accumulated in the bone marrow, causing EMPPs to upregulate the GATA co-factor LMO4 and preferentially differentiate into myeloid cells. LMO4 was sufficient to instruct myeloid fate in EMPPs by interacting with GATA2, displacing the FOG1 co-factor and redistributing GATA binding from megakaryocyte-erythroid-specific to basophil, eosinophil and mast cell (BEM)-specific chromatin. Accordingly, mice carrying a GATA2 mutation that selectively impairs the LMO4-GATA2 interaction were deficient in GATA factor allocation to BEM chromatin, myeloid lineage commitment, basophil and eosinophil production, and parasite control. This identifies LMO4 as an IL-33-regulated master regulator of type 2 myelopoiesis, and transcription factor reallocation as a mechanism of lineage commitment.

DNA origami scaffolds displaying HIV antigens stimulate focused antibody responses in mice.

SummaryGene expression shapes the nervous system at every biological level, from molecular and cellular processes defining neuronal identity and function to systems-level wiring and circuit dynamics underlying behavior. Here, we generate the first high-resolution, single-cell transcriptomic atlas of the adult Drosophila melanogaster central brain by integrating multiple datasets, achieving an unprecedented 10-fold coverage of every neuron in this complex tissue. We show that a neuron’s genetic identity overwhelmingly reflects its developmental origin, preserving a genetic address based on both lineage and birth order. We reveal foundational rules linking neurogenesis to transcriptional identity and provide a framework for systematically defining neuronal types. This atlas provides a powerful resource for mapping the cellular substrates of behavior by integrating annotations of hemilineage, cell types/subtypes, and molecular signatures of underlying physiological properties. It lays the groundwork for a long-sought bridge between developmental processes and the functional circuits that give rise to behavior.

Abstract Poly (ADP-Ribose) Polymerase inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HRR)-deficient cancers by causing PARP1 to become trapped on chromatin, resulting in irreparable replication-associated DNA damage. Although increased clearance of trapped PARP1 from chromatin reduces the sensitivity of cancer cells to PARPi, details surrounding this process remain unclear. PARPi exposure is known to cause increased autophagy flux, whilst autophagy inhibition can hypersensitise cells to PARPi. Using various biochemical, cell biological and live imaging-based assays, we found that trapped PARP1 is cleared by nucleophagy, the selective autophagy of nuclear substrates. Specifically, the nucleophagy of trapped PARP1 was orchestrated by the selective autophagy receptor TEX264 and its partner segregase p97/VCP. TEX264 mediates this process by directly interacting with trapped PARP1, thus bridging PARP1 to the autophagosomal resident protein LC3 for processing via autophagy. Impeding this process, either chemically or genetically, heightened PARP1 trapping, leading to accumulation of protein aggregates, replication-associated DNA damage and cell lethality, re-sensitising PARPi-resistant cells to various PARPi. In conclusion, we show that nucleophagy acts in a cytoprotective manner to directly target PARPi-induced trapped PARP1 for degradation.

In order to determine if undernutrition affects the presence, breadth and magnitude of antibodies to SARS-CoV-2 and variants, we studied SARS-CoV-2 specific antibody responses in a large island wide serosurvey in children in Sri Lanka. Using the WHO UNITY protocol, we recruited 5207 children, aged 10 to 20 years, and assessed anthropometric measures, seropositive rates, ACE2 blocking antibodies and antibodies to omicron variants, in vaccinated and unvaccinated children. 3111/3119 (99.7%) vaccinated and 2008/2088 (96.2%) of unvaccinated children were seropositive for SARS-CoV-2, although the detection of ACE2 blocking antibodies were significantly higher in vaccinated children (2984/3111, 95.9%) compared to unvaccinated (1346/2008, 67.0%). 1057 (22.1%) had a BMI < 3rd centile for age, and therefore were classified as underweight. Unvaccinated children, with < 3rd BMI centile had significantly lower ACE2 blocking antibodies than other groups. There were no differences in the antibody titres to XBB.1.5 or BA.2.75 based on the BMI category. The high seropositivity rates, with high antibody titres to SARS-CoV-2 variants in unvaccinated children indicates possible multiple infections with SARS-CoV-2. The implications of lower antibody levels in underweight children should be further investigated.

BackgroundLong covid has emerged as a complex health condition for millions of people worldwide following the COVID-19 pandemic. Previously, we have categorised healthcare pathways for patients after discharge from hospital with COVID-19 across 45 UK sites. The aim of this work was to estimate the clinical and cost-effectiveness of these pathways.MethodsWe examined prospectively collected data from 1013 patients at 12 months postdischarge on whether they felt fully recovered (self-report), number of newly diagnosed conditions (NDC), quality of life (EuroQoL-five dimension-five level (EQ-5D-5L) utility score compared with pre-COVID estimate) and healthcare resource costs (healthcare records). An analysis of the cost-effectiveness was performed by combining the healthcare resource cost and 1-year EQ-5D (giving a quality-adjusted life-year (QALY)) using statistical models that accounted for observed confounding.ResultsAt 1 year, 29% of participants felt fully recovered, and 41% of patients had an NDC. The most comprehensive services, where all patients could potentially access assessment, rehabilitation and mental health services, were more clinically effective when compared with either no service or light touch services (mean (SE) QALY 0.789 (0.012) vs 0.725 (0.026)), with an estimated cost per QALY of £1700 (95% uncertainty interval: dominated to £24 800).ConclusionOur analysis supports the need for proactive, stratified, comprehensive follow-up, particularly assessment and rehabilitation for adults after hospitalisation with COVID-19, showing these services are likely to be both clinically and cost-effective according to commonly accepted thresholds.

SummarySepsis is a leading cause of death and disability worldwide, so identifying preventable risk factors is important. Iron is essential for immune function and microbial growth, and iron status varies substantially between individuals, across demographics, and is therapeutically modifiable. Here, we review the current understanding of iron status and associated risks of bloodstream infection, sepsis and severe COVID-19 highlighting relevant population-based studies and Mendelian randomisation studies. Both low and high iron status are associated with increased risk of sepsis. Low iron status is associated with sepsis, bloodstream infections and pneumonia. High iron status and mutations affecting hepcidin regulation are linked to increased risk of bloodstream infections, sepsis and COVID-19. Both iron status pathologies and sepsis are global health issues, and the epidemiological studies described indicate they may be linked. More population-scale investigations on iron status, infection and immunity, especially in areas of high iron deficiency and infectious burden are warranted.

Healthy alveolar repair relies on the ability of alveolar stem cells to differentiate into specialized epithelial cells for gas exchange. In chronic fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF), this regenerative process is abnormal but the underlying mechanisms remain unclear. Here, using human lung tissue that represents different stages of disease and a 33-plex single-cell imaging mass cytometry (IMC), we present a high-resolution, temporo-spatial cell atlas of the regenerating alveolar niche. With unbiased mathematical methods which quantify statistically enriched interactions, CD206himacrophage subtype and an alveolar basal intermediate epithelial cell emerge as the most statistically robust spatial association in the epithelial and immune cell interactome, found across all stages of disease. Spatially resolved receptor-ligand analysis further offers an in silico mechanism by which these macrophages may influence epithelial regeneration. These findings provide a foundational step toward understanding immune-epithelial dynamics in aberrant alveolar regeneration in IPF.

Abstract Influenza neuraminidase is a crucial target for protective antibodies, yet the development of recombinant neuraminidase protein as a vaccine has been held back by instability and variable expression. We have taken a pragmatic approach to improving expression and stability of neuraminidase by grafting antigenic surface loops from low-expressing neuraminidase proteins onto the scaffold of high-expressing counterparts. The resulting hybrid proteins retained the antigenic properties of the loop donor while benefiting from the high-yield expression, stability, and tetrameric structure of the loop recipient. These hybrid proteins were recognised by a broad set of human monoclonal antibodies elicited by influenza infection or vaccination, with X-ray structures validating the accurate structural conformation of the grafted loops and the enzymatic cavity. Immunisation of mice with neuraminidase hybrids induced inhibitory antibodies to the loop donor and conferred protected against lethal influenza challenge. This pragmatic technique offers a robust solution for improving the expression and stability of influenza neuraminidase proteins for vaccine development.