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Tuberculosis in patients with systemic lupus erythematosus
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tb), with approximately 10 million new cases reported worldwide annually. Patients with immunocompromised states or those receiving immunosuppressive therapy for autoimmune diseases are at higher risk of M. tb infection or reactivation. The chronic autoimmune disease, systemic lupus erythematosus (SLE), is associated with a higher risk of M. tb infection and TB disease during conventional treatment with corticosteroids and immunosuppressants. However, whether risk of TB is influenced by the immune disturbances associated with active SLE when patients are not receiving immunosuppressant treatment remains unclear. In this review, we describe the pathogenesis of TB and SLE and consider how autoimmune responses in SLE could influence TB risk.
New Vaccine Strategies to Improve, Boost, or Replace BCG
Over a century after it was first introduced, the live attenuated vaccine Bacille Calmette-Guérin (BCG) remains the only licenced vaccine against tuberculosis (TB). BCG is currently administered to more than 100 million children worldwide every year, yet the precise degree to which it protects against TB and the immune mechanisms underlying such protection remain unclear. While BCG is effective in some populations some of the time, overall, it has failed to control the global TB epidemic, and a more effective vaccine strategy is urgently needed. There are several viable pathways to a more effective TB vaccine represented in the current preclinical and clinical pipelines. These include improvements to BCG itself using genetic modifications to generate recombinant strains, administering BCG by different routes, or revaccination regimens that prolong the protective effects of BCG further into adolescence or adulthood. Alternatively, BCG may be boosted with heterologous subunit vaccines or be replaced altogether with live attenuated/inactivated strains of other mycobacteria or with DNA or RNA vaccines. In this chapter, we discuss each of these approaches and summarize current data on novel TB vaccines that aim to improve, boost, or replace BCG with a focus on the most promising candidates in preclinical development.
Therapeutic Effects of Neuro-Cells on Amyloid Pathology, BDNF Levels, and Insulin Signalling in APPswe/PSd1E9 Mice
Stem cell therapies, including mesenchymal (MSCs) and haematopoietic stem cells (HSCs), have shown promise in neurodegenerative diseases. Here, we investigated the therapeutic effects of a defined combination of unmanipulated MSCs and CD34+ HSCs, termed Neuro-Cells (NC), in a murine model of Alzheimer’s disease (AD), the APPswe/PS1dE9 mouse. At 12 months of age, mice received intracisternal injections of NC (1.39 × 106 MSCs + 5 × 105 HSCs) or vehicle. After 45 days, behavioural testing, immunohistochemical analyses of amyloid plaque density (APD), and cortical gene expression profiling were conducted. NC-treated APP/PS1 mice exhibited preserved object recognition memory and reduced anxiety-like behaviours, contrasting with deficits observed in untreated transgenic controls. Histologically, NC treatment significantly reduced the density of small amyloid plaques (<50 μm2) in the hippocampus and thalamus, and total plaque burden in the thalamus. Gene expression analysis revealed that NC treatment normalised or reversed disease-associated changes in insulin receptor (IR) signalling and neurotrophic pathways. Specifically, NC increased expression of Bdnf, Irs2, and Pgc-1α, while attenuating aberrant upregulation of Insr, Igf1r, and markers of ageing and AD-related pathology (Sirt1, Gdf15, Arc, Egr1, Cldn5). These findings indicate that NC therapy mitigates behavioural and molecular hallmarks of AD, potentially via restoration of BDNF and insulin receptor-mediated signalling.
Dysfunctional mitochondria in ageing T cells: a perspective on mitochondrial quality control mechanisms.
Dysfunctional mitochondria are a hallmark of T cell ageing and contribute to organismal ageing. This arises from the accumulation of reactive oxygen species (ROS), impaired mitochondrial dynamics, and inefficient removal of dysfunctional mitochondria. Both cell-intrinsic and cell-extrinsic mechanisms for removing mitochondria and their byproducts have been identified in T cells. In this review, we explore how T cells manage mitochondrial damage through changes in mitochondrial metabolism, mitophagy, asymmetric mitochondrial inheritance, and mitochondrial transfer, highlighting the impact of these mechanisms on T cell ageing and overall organismal ageing. We also discuss current therapeutic strategies aimed at removing dysfunctional mitochondria and their byproducts and propose potential new therapeutic targets that may reverse immune ageing or organismal ageing.
Cytoskeletal control in adult microglia is essential to restore neurodevelopmental synaptic and cognitive deficits
Synaptic dysfunction is a hallmark of neurodevelopmental disorders (NDDs), often linked to genes involved in cytoskeletal regulation. While the role of these genes has been extensively studied in neurons, microglial functions such as phagocytosis are also dependent on cytoskeletal dynamics. We demonstrate that disturbance of actin cytoskeletal regulation in microglia, modeled by genetically impairing the scaffold protein Disrupted-in-Schizophrenia 1 (DISC1), which integrates actin-binding proteins, causes a shift in actin regulatory balance favoring filopodial versus lamellipodial actin organization. The resulting microglia-specific dysregulation of actin dynamics leads to excessive uptake of synaptic proteins. Genetically engineered DISC1-deficient mice show diminished hippocampal excitatory transmission and associated spatial memory deficits. Reintroducing wild-type microglia-like cells via bone marrow transplantation in adult DISC1-deficient mice restores the synaptic function of neurons and rescues cognitive performance. These findings reveal a pivotal role for microglial actin cytoskeletal remodeling in preserving synaptic integrity and cognitive health. Targeting microglial cytoskeletal dynamics may effectively address cognitive impairments associated with NDDs, even in adulthood.
Structural basis for HIV-1 capsid adaption to a deficiency in IP6 packaging.
Inositol hexakisphosphate (IP6) promotes HIV-1 assembly by stabilizing the immature Gag lattice and becomes enriched within virions, where it is required for mature capsid assembly. Previously, we identified Gag mutants that package little IP6 yet assemble particles, though they are non-infectious due to defective capsid formation. Here, we report a compensatory mutation, G225R, in the C-terminus of capsid protein (CA) that restores capsid assembly and infectivity in these IP6-deficient mutants. G225R also enhances in vitro assembly of CA into capsid-like particles at far lower IP6 concentrations than required for wild-type CA. CryoEM structures of G225R CA hexamers and lattices at 2.7 Å resolution reveal that the otherwise disordered C-terminus becomes structured, stabilizing hexamer-hexamer interfaces. Molecular dynamics simulations support this mechanism. These findings uncover how HIV-1 can adapt to IP6 deficiency and highlight a previously unrecognized structural role of the CA C-terminus, while offering tools for capsid-related studies.
Frailty and frailty syndromes in persons with haemophilia: a review.
Advances in treatment for persons with haemophilia (PWH) have improved life expectancy, but PWH face new challenges, including frailty. Frailty is a health state of increased functional vulnerability. It is associated with ageing and is linked to adverse outcomes such as falls, hospitalisation and institutionalisation. Although well-characterised in the general population, its prevalence and impact in PWH remain underexplored. Emerging evidence suggests PWH currently have increased frailty, particularly those with severe disease and joint damage from inadequate early prophylaxis. This review examines frailty in PWH including the impact of frailty syndromes (falls, immobility, incontinence, cognitive impairment, polypharmacy) and the potential role of the haemophilia multidisciplinary team in screening and management. The Clinical Frailty Score can be used by non-specialists and can aid in early identification and subsequent intervention including referral to Geriatric Medicine when appropriate. Importantly, interventions such as the comprehensive geriatric assessment have been shown to reverse or slow progression of frailty with improved health outcomes. An individualised multidisciplinary approach, including falls prevention, tailored exercise regimes, and medication review, is key. Cognitive impairment and dementia may impact self-management, necessitating dementia-friendly healthcare strategies. Given the growing population of older PWH, it is crucial to increase awareness of frailty for both the haemophilia multidisciplinary team and PWH, to facilitate screening, evidence-based interventions, optimisation of care pathways, and ensure comprehensive multidisciplinary support to improve quality of life. Future studies should address the specific needs of ageing PWH, including women, and further investigate the impact of frailty on clinical outcomes in PWH.
Direct visualization of HIV-1 core nuclear import and its interplay with the nuclear pore.
Direct visualization of HIV-1 nuclear import through the nuclear pore complex (NPC) presents a technical challenge due to the rarity of this process. To enable systematic investigation, we developed a robust in situ system that mimics HIV-1 nuclear import in a near-native context using isolated HIV-1 virus like particles (VLP) cores and permeabilized CD4 + T lymphocyte (CEM) cells. This approach supports docking and translocation of abundant viral cores through nuclear pores into the nucleus. For high-resolution visualization, we implemented an integrated correlative approach to guide cryo-focused ion beam (cryo-FIB) milling and cryo-electron tomography (cryo-ET) imaging, enabling precise targeting and structural characterization of individual nuclear import events. Using this workflow, we visualized 510 HIV-1 VLP cores at distinct stages of nuclear import, capturing key snapshots of the full progression of nuclear import. Subsequent statistical and structural analyses allow classification of core morphologies and identification of translocation-associated remodeling in nuclear pores. This work provides a methodological foundation for dissecting HIV-1 and potentially other viruses nuclear import processes and post-entry events in a controlled and quantitative manner.
Mechanical confinement governs phenotypic plasticity in melanoma.
Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.