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Journal articleBalmes A, Rodriguez JG, Seifert J, et al., 2024,
Role of the NO-GC/cGMP signaling pathway in platelet biomechanics
, PLATELETS, Vol: 35, ISSN: 0953-7104 -
Journal articleJoulia R, Lloyd CM, 2024,
Basophils: regulators of lung inflammation over space and time
, Journal of Experimental Medicine, Vol: 221, ISSN: 0022-1007In this issue of JEM, Schuijs et al. (https://doi.org/10.1084/jem.20240103) highlight a novel role for basophils during allergic immune responses to house dust mites (HDM). They reveal that interleukin-33 (IL-33)-activated basophils facilitate the recruitment and extravasation of Th2 cells into the lungs during a specific time frame via their interactions with pulmonary endothelial cells.
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Journal articleNdow G, Shimakawa Y, Leith D, et al., 2024,
Clinical outcomes of untreated adults living with chronic hepatitis B in The Gambia: an analysis of data from the prospective PROLIFICA cohort study
, The Lancet Gastroenterology and Hepatology, Vol: 9, Pages: 1133-1146, ISSN: 2468-1253Background: Expanding antiviral therapy to people with chronic hepatitis B virus (HBV) infection who are ineligible to receive treatment under current international criteria has been increasingly debated. Evidence to support this approach is scarce, especially in Africa. We aimed to address this knowledge gap by analysing the clinical outcomes of people with chronic hepatitis B in The Gambia who were untreated and ineligible for antiviral therapy at diagnosis. Methods: Between Dec 7, 2011, and Jan 24, 2014, we implemented the prospective PROLIFICA cohort study in The Gambia. Participants with chronic hepatitis B aged 16 years or older were recruited after large-scale, community-based HBV screening; blood bank-based HBV screening in Edward Francis Small Teaching Hospital, Banjul; and prospective follow-up of HBsAg-positive individuals via historical, population-based HBsAg serosurveys in two rural villages (Keneba and Manduar). Participants underwent HBV serology and other laboratory tests, fasting FibroScan, and abdominal ultrasound. Survival data were collected between Dec 7, 2011, and Aug 17, 2021. Between Oct 9, 2018, and Aug 17, 2021, all HBsAg-positive participants enrolled in the 2011–14 cohort were invited for a reassessment. For this analysis, we included HBsAg-positive people and excluded all participants who were eligible for treatment according to the 2012 European Association for the Study of the Liver (EASL) criteria at baseline and those who were treated irrespective of treatment eligibility. The primary outcome was all-cause mortality, assessed in all treatment-ineligible and treatment-naive participants with follow-up data. The secondary outcome, analysed in those who were reassessed, was disease progression, defined as becoming eligible for antivirals per 2017 EASL criteria; having an increase in liver fibrosis of at least one stage; or having a clinical diagnosis of hepatic decompensation or hepatocellular carcinoma. Findings: 943 HBsAg-posit
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Journal articleOMahony E, Ryan F, Hemandas H, et al., 2024,
Cryptic congenital malaria infection causing fever of unknown origin in an infant
, Journal of Pediatrics, Vol: 275, ISSN: 0022-3476A 10-week-old male infant presented multiple times to a United Kingdom (UK)hospital with prolonged fever for one month, occurring at irregular intervals and in the absence of any other noticeable symptoms. He was the first child of non-consanguineous, Nigerian parents, with neither parent having traveled outside the UK for two years prior to pregnancy. Routine antenatal serology and scans were unremarkable, and the mother was well during pregnancy with no febrile illnesses or health concerns reported. The boy was born at term via elective cesarean section due to breech positioning (birth weight 3.75 kg), with an uncomplicated perinatal period. He received the BCG vaccine at 6 weeks of age as standard care due to having parents born in a country with high rates of tuberculosis, but was otherwise unvaccinated; his initial 8-week vaccinations were delayed because he was febrile.
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Journal articleDrysdale SB, Thwaites RS, Price J, et al., 2024,
What have we learned from animal studies of immune responses to respiratory syncytial virus infection?
, Journal of Clinical Virology, Vol: 175, ISSN: 1386-6532Respiratory syncytial virus (RSV) is a common cause of severe respiratory tract infection at the extremes of age and in vulnerable populations. However, it is difficult to predict the clinical course and most infants who develop severe disease have no pre-existing risk factors. With the recent licencing of RSV vaccines and monoclonal antibodies, it is important to identify high-risk individuals in order to prioritise those who will most benefit from prophylaxis. The immune response to RSV and the mechanisms by which the virus prevents the establishment of immunological memory have been extensively investigated but remain incompletely characterised. In animal models, beneficial and harmful immune responses have both been demonstrated. While only chimpanzees are fully permissive for human RSV replication, most research has been conducted in rodents, or in calves infected with bovine RSV. Based on these studies, components of innate and adaptive immune systems, cytokines, chemokines and metabolites, and specific genetic and transcriptomic signatures are identified as potential predictive indicators of RSV disease severity. These findings may inform the development of future human studies and contribute to the early identification of patients at high risk of severe infection. This narrative review summarises the factors involved in the immune response to RSV infection in these models and highlights the relationship between potential biomarkers and disease severity.
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Journal articleZhong Z, Hocking B, Brown C, et al., 2024,
Synthesis and Functionalization of Sulfoximine-Bicyclo[1.1.0]butanes: Functionalizable, Tuneable and Cysteine-Selective Chiral Warheads
, Angewandte Chemie International Edition, ISSN: 1433-7851Electrophilic covalent warheads with appropriate reactivity and selectivity are crucial to the investigation of protein function and the discovery of therapeutics. Here we report the synthesis of sulfoximine bicyclo[1.1.0]butanes (BCBs) as novel thiol reactive chiral warheads, achieved in one-pot from methylsulfoximines. Unusually the warhead can then be derivatized, keeping the BCB intact, over 3 vectors: i) sulfoximine N-modification instills a broad range of strain-release reactivity; ii) sp2-cross-coupling reactions on aryl-BCB-sulfoximines allows direct diversification, and iii) functionalization of the BCB motif itself is achieved by metalation and trapping with electrophiles. The BCB sulfoximines are shown to react selectively with cysteine including in a protein model (CDK2) under biocompatible conditions. Preliminary data indicate suitability for chemoproteomic applications, and enantioselective cysteine-labelling. The reactivity of sulfoximine BCBs with electron withdrawing groups on nitrogen is comparable to acrylamides with low to moderate reactivity.
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Journal articleMurphy A, Beardall W, Rei M, et al., 2024,
Predicting cell type-specific epigenomic profiles accounting for distal genetic effects
, Nature Communications, ISSN: 2041-1723 -
Journal articleWilkinson R, 2024,
Imaging in early tuberculosis.
, Thorax, Vol: 79, Pages: 1114-1115 -
Journal articleKoskeridis F, Fancy N, Tan PF, et al., 2024,
Multi-trait association analysis reveals shared genetic loci between Alzheimer’s disease and cardiovascular traits
, Nature Communications, Vol: 15, ISSN: 2041-1723Several cardiovascular traits and diseases co-occur with Alzheimer’s disease. We mapped their shared genetic architecture using multi-trait genome-wide association studies. Subsequent fine-mapping and colocalisation highlighted 16 genetic loci associated with both Alzheimer’s and cardiovascular diseases. We prioritised rs11786896, which colocalised with Alzheimer’s disease, atrial fibrillation and expression of PLEC in the heart left ventricle, and rs7529220, which colocalised with Alzheimer’s disease, atrial fibrillation and expression of C1Q family genes. Single-cell RNA-sequencing data, co-expression network and protein-protein interaction analyses provided evidence for different mechanisms of PLEC, which is upregulated in left ventricular endothelium and cardiomyocytes with heart failure and in brain astrocytes with Alzheimer’s disease. Similar common mechanisms are implicated for C1Q in heart macrophages with heart failure and in brain microglia with Alzheimer’s disease. These findings highlight inflammatory and pleomorphic risk determinants for the co-occurrence of Alzheimer’s and cardiovascular diseases and suggest PLEC, C1Q and their interacting proteins as potential therapeutic targets.
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Journal articleMarshall EKP, Nunes C, Burbaud S, et al., 2024,
Microbial metabolism disrupts cytokine activity to impact host immune response
, Proceedings of the National Academy of Sciences of USA, Vol: 121, ISSN: 0027-8424Host–pathogen interactions are shaped by the metabolic status of both the host and pathogen. The host must regulate metabolism to fuel the immune response, while the pathogen must extract metabolic resources from the host to enable its own survival. In this study, we focus on the metabolic interactions of Mycobacterium abscessus with Drosophila melanogaster. We identify MAB_1132c as an asparagine transporter required for pathogenicity in M. abscessus. We show that this requirement is specifically associated with damage to the host: flies infected with MAB_1132c knockout bacteria, or with wild-type bacteria grown in asparagine-restricted conditions, are longer lived without showing a significant change in bacterial load. This is associated with a reduction in the host innate immune response, demonstrated by the decreased transcription of antimicrobial peptides as well as a significant reduction in the ability of the infection to disrupt systemic insulin signaling. Much of the increase in host survival during infection with asparagine-limited M. abscessus can be attributed to alterations in unpaired cytokine signaling. This demonstrates that asparagine transport in M. abscessus prior to infection is not required for replicative fitness in vivo but does significantly influence the interaction with the host immune responses.
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