MHC class I antigen processing is an underappreciated area of nonviral host-pathogen interactions, bridging both immunology and cell biology, where the pathogen's natural life cycle involves little ...presence in the cytoplasm. The effective response to MHC-I foreign antigen presentation is not only cell death but also phenotypic changes in other cells and stimulation of the memory cells ready for the next antigen reoccurrence. This review looks at the MHC-I antigen processing pathway and potential alternative sources of the antigens, focusing on
(
) as an intracellular pathogen that co-evolved with humans and developed an array of decoy strategies to survive in a hostile environment by manipulating host immunity to its own advantage. As that happens
the selective antigen presentation process, reinforcement of the effective antigen recognition on MHC-I molecules may stimulate subsets of effector cells that act earlier and more locally. Vaccines against tuberculosis (TB) could potentially eliminate this disease, yet their development has been slow, and success is limited in the context of this global disease's spread. This review's conclusions set out potential directions for MHC-I-focused approaches for the next generation of vaccines.
Low-dose vitamin D supplementation is already recommended in older adults for prevention of fractures and falls, but clinical trials investigating whether higher doses could provide additional ...protection against acute respiratory infection (ARI) are lacking.
To conduct a clinical trial of high-dose versus low-dose vitamin D3 supplementation for ARI prevention in residents of sheltered-accommodation housing blocks ('schemes') and their carers in London, UK.
Fifty-four schemes (137 individual participants) were allocated to the active intervention (vitamin D3 2.4 mg once every 2 months +10 μg daily for residents, 3 mg once every 2 months for carers), and 54 schemes with 103 participants were allocated to control (placebo once every 2 months +vitamin D3 10 μg daily for residents, placebo once every 2 months for carers) for 1 year. Primary outcome was time to first ARI; secondary outcomes included time to first upper/lower respiratory infection (URI/LRI, analysed separately), and symptom duration.
Inadequate vitamin D status was common at baseline: 220/240 (92%) participants had serum 25(OH)D concentration <75 nmol/L. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with increased risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI.
Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI.
clinicaltrials.gov NCT01069874.
•We report that 65% of a cohort of older adults living in sheltered accommodation in London, UK, were vitamin D deficient (serum 25-hydroxyvitamin D concentrations <50nmol/L).•Sampling in ...winter/spring, non-white ethnic origin and lack of vitamin D supplement use were independently associated with lower vitamin D status.•None of a panel of 15 single nucleotide polymorphisms in DBP, DHCR7, CYP2R1, CYP27B1, CYP24A1 or VDR associated with serum 25-hydroxyvitamin D concentrations in this population.•Vigorous efforts should be made to improve uptake of vitamin D supplements among older adults in the UK in order to protect them against vitamin D deficiency.
Despite the high prevalence of vitamin D deficiency among older adults in the UK, studies investigating the determinants of vitamin D status in this group are lacking. We conducted a cross-sectional study in 222 older adults living in sheltered accommodation in London, UK, who were screened for participation in a clinical trial of vitamin D supplementation for the prevention of acute respiratory infection. Details of potential demographic and lifestyle determinants of vitamin D status were collected by questionnaire and blood samples were taken for analysis of serum 25-hydroxyvitamin D (25OHD) concentration and DNA extraction. Fifteen single nucleotide polymorphisms (SNP) in 6 genes (DBP, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR) previously reported to associate with circulating 25(OH)D concentration were typed using Taqman allelic discrimination assays. Linear regression was used to identify environmental and genetic factors independently associated with serum 25(OH)D concentration. Mean serum 25(OH)D concentration was 42.7nmol/L (SD 22.0); 144/222 (64.9%) participants had serum 25(OH)D concentrations <50nmol/L. The following factors were independently associated with lower serum 25(OH)D concentration: non-white ethnicity (−8.6nmol/L, 95% CI −14.9 to −2.3, P=0.008); lack of vitamin D supplement consumption (−17.1nmol/L, 95% CI −23.3 to −10.9, P<0.001) vs. taking a daily supplement; sampling in Q1/January–March (−12.2nmol/L, 95% CI −21.5 to −2.9, P=0.01), and sampling in Q4/October–December (−10.3nmol/L, 95% CI −20.2 to −0.4, P=0.04) vs. sampling in Q3/July–September. None of the 15 SNP investigated independently associated with serum 25(OH)D concentration after correcting for multiple comparisons. In conclusion, vitamin D deficiency was highly prevalent among the older adults in this study; non-White ethnicity, lack of vitamin D supplement consumption and sampling in winter and spring independently associated with lower vitamin D status.
Novel rapid diagnostics for active tuberculosis (TB) are required to overcome the time delays and inadequate sensitivity of current microbiological tests that are critically dependent on sampling the ...site of disease. Multiparametric blood transcriptomic signatures of TB have been described as potential diagnostic tests. We sought to identify the best transcript candidates as host biomarkers for active TB, extend the evaluation of their specificity by comparison with other infectious diseases, and to test their performance in both pulmonary and extrapulmonary TB.
Support vector machine learning, combined with feature selection, was applied to new and previously published blood transcriptional profiles in order to identify the minimal TB‑specific transcriptional signature shared by multiple patient cohorts including pulmonary and extrapulmonary TB, and individuals with and without HIV-1 coinfection.
We identified and validated elevated blood basic leucine zipper transcription factor 2 (
) transcript levels as a single sensitive biomarker that discriminated active pulmonary and extrapulmonary TB from healthy individuals, with receiver operating characteristic (ROC) area under the curve (AUC) scores of 0.93 to 0.99 in multiple cohorts of HIV-1-negative individuals, and 0.85 in HIV-1-infected individuals. In addition, we identified and validated a potentially novel 4-gene signature comprising CD177, haptoglobin, immunoglobin J chain, and galectin 10 that discriminated active pulmonary and extrapulmonary TB from other febrile infections, giving ROC AUCs of 0.94 to 1.
Elevated blood
transcript levels provide a sensitive biomarker that discriminates active TB from healthy individuals, and a potentially novel 4-gene transcriptional signature differentiates between active TB and other infectious diseases in individuals presenting with fever.
MRC, Wellcome Trust, Rosetrees Trust, British Lung Foundation, NIHR.
We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 ...(SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.
A common challenge in drug design pertains to finding chemical modifications to a ligand that increases its affinity to the target protein. An underutilized advance is the increase in structural ...biology throughput, which has progressed from an artisanal endeavor to a monthly throughput of hundreds of different ligands against a protein in modern synchrotrons. However, the missing piece is a framework that turns high-throughput crystallography data into predictive models for ligand design. Here, we designed a simple machine learning approach that predicts protein-ligand affinity from experimental structures of diverse ligands against a single protein paired with biochemical measurements. Our key insight is using physics-based energy descriptors to represent protein-ligand complexes and a learning-to-rank approach that infers the relevant differences between binding modes. We ran a high-throughput crystallography campaign against the SARS-CoV-2 main protease (M
), obtaining parallel measurements of over 200 protein-ligand complexes and their binding activities. This allows us to design one-step library syntheses which improved the potency of two distinct micromolar hits by over 10-fold, arriving at a noncovalent and nonpeptidomimetic inhibitor with 120 nM antiviral efficacy. Crucially, our approach successfully extends ligands to unexplored regions of the binding pocket, executing large and fruitful moves in chemical space with simple chemistry.
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