Damping excessive viral-induced IFN-γ rescues the impaired anti-Aspergillus host immune response in influenza-associated pulmonary aspergillosis.

BACKGROUND: Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection in critically ill influenza patients that is of incompletely understood pathogenesis. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain unacceptably high. We aimed to unravel the IAPA immunopathogenesis as a means to develop adjunctive immunomodulatory therapies. METHODS: We used a murine model of IAPA to investigate how influenza predisposes to the development of invasive pulmonary aspergillosis. Immunocompetent mice were challenged with an intranasal instillation of influenza on day 0 followed by an orotracheal inoculation with Aspergillus 4 days later. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (µCT) and fungal burden with bioluminescence imaging (BLI). At endpoint, high parameter immunophenotyping, spatial transcriptomics, histopathology, dynamic phagosome biogenesis assays with live imaging, immunofluorescence staining, specialized functional phagocytosis and killing assays were performed. FINDINGS: We uncovered an early exuberant influenza-induced interferon-gamma (IFN-γ) production as the major driver of immunopathology in IAPA and delineated the molecular mechanisms. Specifically, excessive IFN-γ production resulted in a defective Th17-immune response, depletion of macrophages, and impaired killing of Aspergillus conidia by macrophages due to the inhibition of NADPH oxidase-dependent activation of LC3-associated phagocytosis (LAP). Markedly, mice with partial or complete genetic ablation of IFN-γ had a restored Th17-immune response, LAP-dependent mechanism of killing and were fully protected from invasive fungal infection. INTERPRETATION: Together, these results identify exuberant viral induced IFN-γ production as a major driver of immune dysfunction in IAPA, paving the way to explore the use of excessive viral-induced IFN-γ as a biomarker and new immunotherapeutic target in IAPA. FUNDING: This research was funded by the Research Foundation Flanders (FWO), project funding under Grant G053121N to JW, SHB and GVV; G057721N, G0G4820N to GVV; 1506114 N to KL and GVV; KU Leuven internal funds (C24/17/061) to GVV, clinical research funding to JW, Research Foundation Flanders (FWO) aspirant mandate under Grant 1186121N/1186123 N to LS, 11B5520N to FS, 1SF2222N to EV and 11M6922N/11M6924N to SF, travel grants V428023N, K103723N, K217722N to LS. FLvdV was supported by a Vidi grant of the Netherlands Association for Scientific Research. FLvdV, JW, AC and GC were supported by the Europeans Union's Horizon 2020 research and innovation program under grant agreement no 847507 HDM-FUN. AC was also supported by the Fundação para a Ciência e a Tecnologia (FCT), with the references UIDB/50026/2020, UIDP/50026/2020, PTDC/MED-OUT/1112/2021 (https://doi.org/10.54499/PTDC/MED-OUT/1112/2021), and 2022.06674.PTDC (http://doi.org/10.54499/2022.06674.PTDC); and the "la Caixa" Foundation under the agreement LCF/PR/HR22/52420003 (MICROFUN).

Anti-interferon gamma-inducible protein 16 antibodies: Identification of a novel autoantigen in idiopathic interstitial pneumonia and its clinical characteristics based on a multicenter cohort study.

Autoantibodies are detected in idiopathic interstitial pneumonias (IIPs) without a clear connective tissue disease diagnosis, and their clinical significance is unclear. This study aimed to identify a novel autoantibody in IIPs. We screened 295 IIP patients using a 35S-methionine labeled protein immunoprecipitation assay. Candidate autoantigens were identified via protein array and confirmed by immunoprecipitation. Six sera from 295 IIP patients immunoprecipitated common tetrameric proteins (100 kDa). The protein array identified interferon gamma-inducible protein 16 (IFI16) as the candidate autoantigen. Patients with anti-IFI16 antibodies received immunosuppressants less frequently. Five-year survival rates were 50 %, 69 %, and 63 % (P = 0.60), and acute exacerbation-free rates were 50 %, 96 %, and 84 % (P = 0.15) for patients with anti-IFI16, anti-aminoacyl tRNA antibodies, and others. Anti-IFI16 is a novel autoantibody in IIPs. Patients with this antibody often receive less immunosuppressive therapy and could have a poor prognosis. Further research is needed to refine patient stratification and management.

IFNλ signaling in neutrophils enhances the pathogenesis of Bordetella pertussis infection.

Interferon lambda (IFN-λ) plays diverse roles in bacterial infections. Previously we showed that IFN-λ is induced in the lungs of B. pertussis-infected adult mice and exacerbates inflammation. Here, we report that mice lacking the IFN-λ receptor (IFNLR1) specifically on neutrophils (MRP8creIFNLR1fl/fl mice) exhibit reduced lung bacterial load and inflammation compared to WT mice during B. pertussis infection. In B. pertussis-infected wild type (WT) mice, lung type I and III IFN responses were higher than in MRP8creIFNLR1fl/fl mice, correlating with increased lung inflammatory pathology. There was an increased proportion of IFN-γ-producing neutrophils in the lungs of MRP8creIFNLR1fl/fl mice compared to WT mice. IFNLR1-/- neutrophils incubated with B. pertussis exhibited higher killing compared to WT neutrophils. Treatment of WT neutrophils with IFN-λ further decreased their bacterial killing capacity and treatment of WT mice with IFN-λ increased lung bacterial loads. Contributing to the differential killing, we found that IFNLR1-/- neutrophils exhibit higher levels of reactive oxygen species, myeloperoxidase [1], matrix metalloproteinase-9 (MMP9) activity, neutrophil extracellular traps (NETs), and IFN-γ secretion than WT neutrophils, and inhibiting NADPH oxidase inhibited bacterial killing in IFNLR1-/- neutrophils. B. pertussis induced IFN-λ secretion and IFNLR1 gene expression in mouse and human neutrophils and this was dependent on the bacterial virulence protein pertussis toxin (PTX). PTX enhanced bacterial loads in WT but not in MRP8creIFNLR1fl/fl or IFNLR1-/- mice. Thus, PTX disrupts neutrophil function by enhancing type III IFN signaling, which prevents neutrophils from effectively clearing B. pertussis during infection, leading to higher bacterial loads and exacerbation of lung inflammation.

Post-Transcriptional Induction of the Antiviral Host Factor GILT/IFI30 by Interferon Gamma.

Gamma-interferon-inducible lysosomal thiol reductase (GILT) plays pivotal roles in both adaptive and innate immunities. GILT exhibits constitutive expression within antigen-presenting cells, whereas in other cell types, its expression is induced by interferon gamma (IFN-γ). Gaining insights into the precise molecular mechanism governing the induction of GILT protein by IFN-γ is of paramount importance for adaptive and innate immunities. In this study, we found that the 5' segment of GILT mRNA inhibited GILT protein expression regardless of the presence of IFN-γ. Conversely, the 3' segment of GILT mRNA suppressed GILT protein expression in the absence of IFN-γ, but it loses this inhibitory effect in its presence. Although the mTOR inhibitor rapamycin suppressed the induction of GILT protein expression by IFN-γ, the expression from luciferase sequence containing the 3' segment of GILT mRNA was resistant to rapamycin in the presence of IFN-γ, but not in its absence. Collectively, this study elucidates the mechanism behind GILT induction by IFN-γ: in the absence of IFN-γ, GILT mRNA is constitutively transcribed, but the translation process is hindered by both the 5' and 3' segments. Upon exposure to IFN-γ, a translation inhibitor bound to the 3' segment is liberated, and a translation activator interacts with the 3' segment to trigger the initiation of GILT translation.

Utility of Cerebrospinal Fluid Unstimulated Interferon-Gamma (IRISA-TB) as a Same-Day Test for Tuberculous Meningitis in a Tuberculosis-Endemic, Resource-Poor Setting.

Background: Tuberculous meningitis (TBM) mortality is high and current diagnostics perform suboptimally. We evaluated the diagnostic performance of a DNA-based assay (GeneXpert Ultra) against a new same-day immunodiagnostic assay that detects unstimulated interferon-gamma (IRISA-TB). Methods: In a stage 1 evaluation, IRISA-TB was evaluated in biobanked samples from Zambia (n = 82; tuberculosis [TB] and non-TBM), and specificity in a South African biobank (n = 291; non-TBM only). Given encouraging results, a stage 2 evaluation was performed in suspected TBM patients from Zimbabwe and Malawi (n = 668). Patients were classified as having definite, probable or possible TBM, or non-TBM based on their microbiological results, cerebrospinal fluid (CSF) chemistry, and whether they received treatment. Results: In the stage 1 evaluation, sensitivity and specificity of IRISA-TB were 75% and 87% in the Zambian samples, and specificity was 100% in the South African samples. In the stage 2 validation, IRISA-TB sensitivity (95% confidence interval [CI]) was significantly higher than Xpert Ultra (76.2% [55.0%-89.4%] vs 25% [8.9%-53.3%]; P = .0048) when trace readouts were considered negative. Specificity (95% CI) was similar for both assays (91.4% [88.8%-93.4%] vs 86.9% [83.4%-89.8%]). When the Xpert Ultra polymerase chain reaction product was verified by sequencing, the positive predictive value of trace readouts in CSF was 27.8%. Sensitivity of IRISA-TB was higher in human immunodeficiency virus (HIV)-infected versus uninfected participants (85.8% vs 66.7%). Conclusions: As a same-day rule-in test, IRISA-TB had significantly better sensitivity than Xpert Ultra in a TB/HIV-endemic setting. An immunodiagnostic approach to TBM is promising, and further studies are warranted.

Interferon-Gamma-Inducible Protein-10 (IP-10) and Tumor Necrosis Factor-α (TNF-α) as Serological Predictors of Active Disease Status in Localized Scleroderma.

We investigated the ability of a panel of immune-related cytokines and chemokines to predict the disease activity state in localized scleroderma (LS) subjects followed longitudinally. A total of 194 sera samples were obtained from 45 LS subjects with diverse types of LS (40% linear, 20% mixed, 16% craniofacial, 13% generalized, and 11% circumscribed) in our cohort. Cytokines/chemokines that were significantly elevated at the baseline active disease visit compared to the inactive disease state at follow-up were Interferon-Gamma-Inducible Protein (IP)-10 (p < 0.021) and Tumor Necrosis Factor (TNF)-α (p < 0.033). Mixed effect logit modeling identified IP-10 (Odds Ratio (OR) [95% confidence interval] = 2.1 [1.4, 3.2], p < 0.001), TNF-α (OR = 1.8 [1.1, 3.0], p = 0.016), and Monocyte Chemoattractant Protein (MCP)-1 (OR = 2.0 [1.1, 3.9], p = 0.034) as significant predictors of active disease status. These findings support earlier correlations between IP-10 and TNF-α with disease activity parameters in a cross-sectional Luminex™ serological study and may enhance clinical decision-making when disease activity is challenging to assess by clinical examination alone.

Effects of combined cytotoxic T-lymphocyte antigen 4 and programed death 1 ligand-receptor blockade on interferon-gamma production in bovine leukemia virus-infected cattle.

Background and Aim: In chronic viral infections, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) significantly suppress immune responses. The CTLA-4 receptor abundance in regulatory T cells showed a positive association with viral load and a negative association with interferon-gamma (IFN-γ) production in bovine leukemia virus (BLV)-infected cattle. Blocking this receptor boosted IFN-γ production, recovering immune response against this illness. In human cancer patients, not everyone responded positively to non-immunotherapy using CTLA-4 receptor antibodies. The present study analyzed the synergistic effects of CTLA-4 and PD-L1 receptor blockade on IFN-γ production in BLV+ cattle in vitro. Materials and Methods: The genes for bovine CTLA-4 and PD-L1 were artificially produced. The amino acid sequences of the extracellular receptor domains were sourced from the National Center for Biotechnology Information PubMed database. The western blotting and liquid chromatography with tandem mass spectrometry (LC-MS/MS) techniques were employed for the characterization of recombinant CTLA-4 (rCTLA-4) and recombinant PD-L1 (rPD-L1) proteins. The immunoinhibitory effects of recombinant proteins in Staphylococcus enterotoxin B (SEB)-stimulated cattle peripheral blood mononuclear cells (PBMCs) were investigated. Enzyme-linked immunosorbent assay (ELISA) was used to analyze monoclonal antibodies against rCTLA-4 and rPD-L1. Antibodies generated from peripheral blood mononuclear cells of healthy and BLV-seropositive cows were employed to evaluate their blocking capabilities. Results: The resulting recombinant proteins specifically reacted with commercial homogeneous monoclonal antibodies (mAbs) using ELISA and anti-His-tag mAbs using western blotting. Analysis of the proteins using LC-MS/MS revealed correspondence with the sequences of rCTLA-4 and rPD-L1 located in the Mascot database. rCTLA-4 and rPD-L1 proteins inhibited IFN-γ production in bovine PBMCs of activated SEB. When PBMCs from cows were cultured with activated SEB containing rCTLA-4 and rPD-L1, the mAbs increased IFN-γ production in PBMCs. The combined cultivation of mAbs and PBMCs from BLV+ cattle enhanced IFN-γ production in the cells. Conclusion: These findings suggest that the combined blockade of bovine CTLA-4 and PD-L1 receptors can be used as a therapy for bovine leukemia. However, it was shown that a single PBMC sample from a BLV-positive donor did not amplify the synergistic effect. Therefore, it is necessary to perform further studies on a larger population and assessing a wider range of cytokines.

Interferon-gamma release assays as a tool for differential diagnosis of gastrointestinal tuberculosis.

In this editorial, we comment on an article published in a recent issue of the World Journal of Clinical Cases. There is a pressing need for reliable tools for diagnosing tuberculosis (TB) of the gastrointestinal tract. Despite advancements in the diagnosis and treatment, TB remains a global health challenge. Ali et al demonstrated that TB may mimic gastrointestinal conditions, such as gastric outlet obstruction, causing a delay in the diagnosis. Furthermore, the latter complication is frequently observed during infections, including Helicobacter pylori, and rarely is related to TB, as in the presented case. In line with this, we think that laboratory tests based on interferon-gamma release assays can be a helpful tool for diagnosing latent TB paced in the gastrointestinal tract. Innovative strategies and approaches for diagnosing latent/active extra pulmonary TB are crucial for establishing the diagnosis early and enhancing treatment strategies to mitigate the global burden of TB.

Severe Clinical Phenotypes of Heterozygous Females With X-Linked Chronic Granulomatous Disease.

CLINICAL IMPLICATIONS: Female X-linked chronic granulomatous disease (XL-CGD) carriers may develop severe clinical disease including infections with CGD-defining pathogens and inflammatory disorders. Similar to males with XL-CGD, female carriers warrant ongoing evaluation and prophylaxis where indicated.

Defining age-specific reference intervals for biomarkers distinguishing bacterial from viral infection in paediatrics.

Differentiating bacterial from viral infections in children is a common clinical challenge. Novel host immune biomarkers have the potential to aid thediagnosis of infection aetiology and identify children who require antibiotics. Data on novel infection biomarkers gender and age-specific correlations, and reference intervals in healthy paediatrics is lacking. This study reports the plasma levels of three novel biomarkers that can aid in the differentiation of bacterial and viral infection in a healthy group of paediatrics. The levels of (Interferon-Gamma Inducible Protein 10 kDa (IP-10), Lipocalin-2 (LCN2) and TNF-Related Apoptosis-Inducing Ligand (TRAIL) were quantified in 199 plasma samples from healthy paediatrics aged 2 to 16 years old from across the UK. Reference intervals (2.5th and 97.5th) were determined, and biomarker levels were examined for sex and age associations. Reference intervals for IP-10, LCN2 and TRAIL for ages 2-16 years were 36.7-168.1 pg/ml, 14.2-123.3 ng/ml, 57.4-71.4 pg/ml respectively. No biomarker showed an association with sex and IP-10 did not show any association with age. TRAIL levels had a weak continuous negative correlation with age and LCN2 levels had a continuous positive correlation with age. Specific cut-offs for LCN2 in two age categories were identified, while TRAIL did not require age partitions. This study provides age-appropriate reference intervals for three biomarkers of infection in healthy children. These findings have the potential to improve the impact of future research on these biomarkers, the accuracy of clinical decision-making in children with infection, paediatric patient care and outcomes, and antimicrobial stewardship.

Persistent tailoring of MSC activation through genetic priming.

Mesenchymal stem/stromal cells (MSCs) are an attractive platform for cell therapy due to their safety profile and unique ability to secrete broad arrays of immunomodulatory and regenerative molecules. Yet, MSCs are well known to require preconditioning or priming to boost their therapeutic efficacy. Current priming methods offer limited control over MSC activation, yield transient effects, and often induce the expression of pro-inflammatory effectors that can potentiate immunogenicity. Here, we describe a genetic priming method that can both selectively and sustainably boost MSC potency via the controlled expression of the inflammatory-stimulus-responsive transcription factor interferon response factor 1 (IRF1). MSCs engineered to hyper-express IRF1 recapitulate many core responses that are accessed by biochemical priming using the proinflammatory cytokine interferon-γ (IFN-γ). This includes the upregulation of anti-inflammatory effector molecules and the potentiation of MSC capacities to suppress T cell activation. However, we show that IRF1-mediated genetic priming is much more persistent than biochemical priming and can circumvent IFN-γ-dependent expression of immunogenic MHC class II molecules. Together, the ability to sustainably activate and selectively tailor MSC priming responses creates the possibility of programming MSC activation more comprehensively for therapeutic applications.

A combination of four Toxoplasma gondii nuclear-targeted effectors protects against interferon gamma-driven human host cell death.

In both mice and humans, Type II interferon gamma (IFNγ) is crucial for the regulation of Toxoplasma gondii (T. gondii) infection, during acute or chronic phases. To thwart this defense, T. gondii secretes protein effectors hindering the host's immune response. For example, T. gondii relies on the MYR translocon complex to deploy soluble dense granule effectors (GRAs) into the host cell cytosol or nucleus. Recent genome-wide loss-of-function screens in IFNγ-primed primary human fibroblasts identified MYR translocon components as crucial for parasite resistance against IFNγ-driven vacuole clearance. However, these screens did not pinpoint specific MYR-dependent GRA proteins responsible for IFNγ signaling blockade, suggesting potential functional redundancy. Our study reveals that T. gondii depends on the MYR translocon complex to prevent parasite premature egress and host cell death in human cells stimulated with IFNγ post-infection, a unique phenotype observed in various human cell lines but not in murine cells. Intriguingly, inhibiting parasite egress did not prevent host cell death, indicating this mechanism is distinct from those described previously. Genome-wide loss-of-function screens uncovered TgIST, GRA16, GRA24, and GRA28 as effectors necessary for a complete block of IFNγ response. GRA24 and GRA28 directly influenced IFNγ-driven transcription, GRA24's action depended on its interaction with p38 MAPK, while GRA28 disrupted histone acetyltransferase activity of CBP/p300. Given the intricate nature of the immune response to T. gondii, it appears that the parasite has evolved equally elaborate mechanisms to subvert IFNγ signaling, extending beyond direct interference with the JAK/STAT1 pathway, to encompass other signaling pathways as well.IMPORTANCEToxoplasma gondii, an intracellular parasite, affects nearly one-third of the global human population, posing significant risks for immunocompromised patients and infants infected in utero. In murine models, the core mechanisms of IFNγ-mediated immunity against T. gondii are consistently preserved, showcasing a remarkable conservation of immune defense mechanisms. In humans, the recognized restriction mechanisms vary among cell types, lacking a universally applicable mechanism. This difference underscores a significant variation in the genes employed by T. gondii to shield itself against the IFNγ response in human vs murine cells. Here, we identified a specific combination of four parasite-secreted effectors deployed into the host cell nucleus, disrupting IFNγ signaling. This disruption is crucial in preventing premature egress of the parasite and host cell death. Notably, this phenotype is exclusive to human cells, highlighting the intricate and unique mechanisms T. gondii employs to modulate host responses in the human cellular environment.

IFNγ induces epithelial reprogramming driving CXCL11-mediated T cell migration.

The cytokine interferon-gamma (IFNγ) plays a multifaceted role in intestinal immune responses ranging from anti- to pro-inflammatory depending on the setting. Here, using a 3D co-culture system based on human intestinal epithelial organoids, we explore the capacity of IFNγ-exposure to reprogram intestinal epithelia and thereby directly modulate lymphocyte responses. IFNγ treatment of organoids led to transcriptional reprogramming, marked by a switch to a pro-inflammatory gene expression profile, including transcriptional upregulation of the chemokines CXCL9, CXCL10, and CXCL11. Proteomic analysis of organoid-conditioned medium post-treatment confirmed chemokine secretion. IFNγ-treatment of organoids led to enhanced T cell migration in a CXCL11-dependent manner without affecting T cell activation status. Taken together, our results suggest a specific role for CXCL11 in T cell recruitment that could be targeted to prevent T cell trafficking to the inflamed intestine.

Tuberculosis in kidney transplant candidates and recipients.

Tuberculosis (TB) is the leading cause of infectious mortality and morbidity in the world, second only to coronavirus disease 2019. Patients with chronic kidney disease and kidney transplant recipients are at a higher risk of developing TB than the general population. Active TB is difficult to diagnose in this population due to close mimics. All transplant candidates should be screened for latent TB infection and given TB prophylaxis. Patients who develop active TB pre- or post-transplantation should receive multidrug combination therapy of antitubercular therapy for the recommended duration with optimal dose modification as per glomerular filtration rate.

Regular cold shower exposure modulates humoral and cell-mediated immunity in healthy individuals.

BACKGROUND: Cold hydrotherapy is an ancient practice that has recently gained scientific interest for its potential health benefits. This study explored the effects of regular cold shower exposure on immune cell function. METHODS: Sixty healthy Egyptian adults were randomized to take cold or hot showers daily for 90 days. Levels of immunoglobulins, cytokines, and interferon-gamma were measured in blood samples at baseline, 30, 60, and 90 days. RESULTS: The cold shower group exhibited significant increases in immunoglobulin levels. Conversely, the hot shower group showed a significant decrease in IgM levels at 60 and 90 days compared to baseline, alongside nonsignificant decrease of IgG and IgA. the cold shower group demonstrated elevated levels of IL-2 and IL-4 at 90 days, indicating enhanced T-cell proliferation and humoral immunity, respectively. In contrast, the hot shower group did not exhibit significant changes in cytokine levels. There were no significant differences in IFN-γ and TNF-α levels between the groups. CONCLUSIONS: Regular cold shower exposure appears to enhance humoral and cell-mediated immunity through the upregulation of antibodies, interleukin-2, and interleukin-4. Brief cold stressors may induce physiological adaptations that prime the immune response. This accessible, sustainable lifestyle modification could potentially serve as an alternative therapy to boost immunity. Further research on larger populations is warranted to better understand the physiological effects of cold temperatures on immunity.

Evaluating TRAIL and IP-10 alterations in vaccinated pregnant women after COVID-19 diagnosis and their correlation with neutralizing antibodies.

Background: This study evaluates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon-γ-induced protein-10 (IP-10) in pregnant women with COVID-19 and their newborns, exploring the effects of antiviral treatments and vaccine-induced neutralizing antibody (Nab) inhibition on these key viral infection biomarkers. Methods: We studied 61 pregnant women with past COVID-19 and either three (n=56) or four (n=5) doses of vaccination, and 46 without COVID-19 but vaccinated. We analyzed them and their newborns' blood for TRAIL, IP-10, and Nab levels using enzyme-linked immunosorbent assays (ELISA), correlating these with other clinical factors. Results: Our study found lower TRAIL but higher IP-10 levels in maternal blood than neonatal cord blood, irrespective of past COVID-19 diagnosis. Cases diagnosed with COVID-19 < 4 weeks previously had higher maternal blood TRAIL levels (16.49 vs. 40.81 pg/mL, p=0.0064) and IP-10 (154.68 vs. 225.81 pg/mL, p=0.0170) than those never diagnosed. Antiviral medication lowered TRAIL and IP-10 in maternal blood without affecting Nab inhibition (TRAIL: 19.24 vs. 54.53 pg/mL, p=0.028; IP-10: 158.36 vs. 255.47 pg/mL, p=0.0089). TRAIL and IP-10 levels were similar with three or four vaccine doses, but four doses increased Nab inhibition (p=0.0363). Previously COVID-19 exposed pregnant women had higher Nab inhibition (p < 0.0001). No obvious correlation was found among TRAIL, IP-10, and Nab inhibition level. Conclusions: Our study suggests that lower maternal TRAIL and higher IP-10 levels compared to neonatal cord blood coupled with a rise in both markers following COVID-19 diagnosis that could be reduced by antivirals indicates a correlation to infection severity. Higher vaccine doses enhance Nab inhibition, irrespective of antiviral medication use and independent of TRAIL or IP-10 levels, highlighting the significance and safety of adequate vaccination and antiviral use post-diagnosis in pregnant women.

Latent tuberculosis infection and diagnostic performance of the tuberculin skin test among type 2 diabetics in Sana'a city, Yemen.

BACKGROUND: Tuberculosis (TB) is one of the most widespread infectious diseases worldwide, typically persisting in the body as a latent TB infection (LTBI). Patients with type 2 diabetes have an increased risk of LTBI progressing to active TB. Therefore, this study determined the prevalence and predictors of LTBI and assessed the agreement between tuberculin skin test (TST) and interferon-gamma release assay (IGRA) in diagnosing LTBI among type 2 diabetics in Sana'a city, Yemen. METHODS: A cross-sectional study was conducted among 150 type 2 diabetics in private health facilities in Sana'a in 2023. Data about demographics, diabetes-related characteristics, and potential risk factors for LTBI were collected using a structured questionnaire. Patients were then screened for LTBI using TST and IGRA. Univariate analysis was used to identify LTBI-associated risk factors, and multivariable binary logistic regression was used to identify independent predictors of LTBI. The agreement between TST and IGRA for diagnosing LTBI was assessed using Cohen's kappa coefficient (κ). RESULTS: LTBI was prevalent among 29.3% of type 2 diabetics using both types of tests (25.3% with IGRA and 21.3% with TST). Male gender was an independent predictor of LTBI (AOR = 4.4, 95% confidence interval: 1.30-15.08; P = 0.018). However, being employed (AOR = 0.3, 95% CI: 0.09-0.75; P = 0.013) and longer duration since diabetes diagnosis (AOR = 0.3, 95% CI: 0.12-0.98; P = 0.046) were identified as predictors of lower LTBI risk. The agreement between TST and IGRA for the diagnosis of LTBI was 88%, with a good and statistically significant agreement between the two test types (κ = 0.670; P < 0.001). CONCLUSIONS: LTBI is common among type 2 diabetics seeking medical care in Sana'a city, with about one-third of them possibly being latently infected. A higher LTBI risk can be predicted among males, while a lower risk can be predicted among those employed or being diagnosed with diabetes for at least five years. The TST shows good agreement with IGRA in diagnosing LTBI among type 2 diabetics, supporting its continued use as a cost-effective and easily accessible test for diagnosing LTBI in the country.

Comparative Evaluation of Diagnostic Performance: Standard E TB Feron ELISA vs QuantiFERON-TB Gold Plus for Latent Tuberculosis Infection Detection in Diverse Risk Groups in Bangladesh.

Background: Around one-quarter of the global population has latent tuberculosis infection (LTBI). If left untreated, LTBI has 5-10% lifetime risk of developing into TB. Interferon-gamma release Assays (IGRAs) are more sensitive than the tuberculin skin test for LTBI detection. However, the high cost and complexity of IGRAs are barriers to adoption in resource-constrained settings. This study evaluated the diagnostic performance of a more affordable IGRA, Standard E TB-Feron (TBE), among different risk groups in Bangladesh. Methods: 532 participants of all age groups were enrolled from the TB Screening and Treatment Centers and Dhaka Hospital of icddr,b between June and September 2023. The participants were categorized into four risk groups: healthy people, healthcare workers/ attendants of TB patients, patients with microbiologically confirmed TB, and people with a history of TB. The diagnostic performance of TBE was compared to QuantiFERON-TB Gold Plus (QFT-Plus) for all groups. GeneXpert, culture, and microscopy were used to confirm TB microbiologically. Results: TBE had an overall agreement of 85.9% (95% CI, 82.5% to 88.7%), positive percent agreement of 86.1% (95% CI, 80.6% to 90.5%), and negative percent agreement of 85.7% (95% CI, 81.3% -89.4%) with QFT-Plus. Among 81 culture-positive patients, TBE and QFT-Plus were positive for 60 (74.1%) and 62 (76.5%) respectively. Among healthy people, TBE and QFT results were positive for 49 (24.5%) and 59 (29.5%) respectively. Among health workers and contacts, TBE and QFT-Plus were positive for 79 (39.5%) and 73 (35.5%) respectively. Conclusion: We found a substantial agreement (Cohen's kappa of 0.71) between TBE and QFT-Plus in detecting LTBI across different groups, suggesting its potential as a cost-effective diagnostic tool. Implementation of TBE in routine clinical practice could increase accessibility to LTBI diagnosis, facilitating the timely initiation of preventative therapy, and leading to a reduction of active TB incidence.

Interferon-Induced Transmembrane Protein 1 (IFITM1) Is Downregulated in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors.

Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.

IL-6 Blockade in Cytokine Storm Syndromes.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine elevated in cytokine storm syndromes, including hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). It is also elevated in cytokine release syndrome (CRS) after immune activating cancer therapies such as chimeric antigen receptor (CAR) T-cells or bispecific T-cell engagers (BITEs) and in some patients after infection with SARS-CoV-2. The interaction of IL-6 with its receptor complex can happen in several forms, making effectively blocking this cytokine's effects clinically challenging. Fortunately, effective clinical agents targeting the IL-6 receptor (tocilizumab) and IL-6 directly (siltuximab) have been developed and are approved for use in humans. IL-6 blockade has now been used to safely and effectively treat several cytokine storm syndromes (CSS). Other methods of investigation in effective IL-6 blockade are underway.