Sunday, January 8, 2023

Upregulation of PD‐L1 by SARS‐CoV‐2 promotes immune evasion

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Abstract

Patients with severe COVID-19 often suffer from lymphopenia, which is linked to T cell sequestration, cytokine storm and mortality. However, it remains largely unknown how SARS-CoV-2 induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS-CoV-2-infected cells. We adopted a reverse time-order gene coexpression network (TO-GCN) approach to analyze time-series RNA-sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS-CoV-2-activated NF-κB and IRF1 pathways contributing to viral infection and COVID-19 severity through epigenetic analysis of H3K4me3 ChIP-sequencing. Cross-referencing our transcriptomic and epigenomic datasets revealed that coupling NF-κB and IRF1 pathways mediate PD-L1 immunosuppressive programs. Interestingly, we observed higher PD-L1 expression in Omicron-infected cells than SARS-CoV-2 infected cells. Blocking PD-L1 at an earl y stage of virally-infected AAV-hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS-CoV-2-mediated NF-κB and IRF1-PD-L1 axis may represent an alternative strategy to reduce COVID-19 severity.

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The third vaccine dose significantly reduces susceptibility to the B.1.1.529 (Ômicron) SARS‐CoV‐2 variant

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Abstract

The main COVID-19 vaccine formulations used today are mainly based on the wild-type SARS-CoV-2 spike glycoprotein as an antigen. However, new virus variants capable of escaping neutralization activity of serum antibodies elicited in vaccinated individuals have emerged. The Omicron (B.1.1.529) variant caused epidemics in regions of the world in which most of the population has been vaccinated. In this study, we aimed to understand what determines individual's susceptibility to Omicron in a scenario of extensive vaccination. For that purpose, we collected nasopharynx swab (n = 286) and blood samples (n = 239) from flu-like symptomatic patients, as well as their vaccination history against COVID-19. We computed the data regarding vaccine history, COVID-19 diagnosis, COVID-19 serology and viral genome sequencing to evaluate their impact on the number of infections. As main results, we showed that vaccination in general did not reduce the number of individuals infected by Omicron, even with an increased immune response found among vaccinated non-infected individuals. Nonetheless, we found that individuals who received the third vaccine dose showed significantly reduced susceptibility to Omicron infections. A relevant evidence that support this finding was the higher virus neutralization capacity of serum samples of most patients who received the third vaccine dose. In summary, this study shows that boosting immune responses after a third vaccine dose reduces susceptibility to COVID-19 caused by the Omicron variant. Results presented in this study are useful for future formulations of COVID-19 vaccination policies.

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Rapid Detection of Monkeypox Virus by Multiple Cross Displacement Amplification Combined with Nanoparticle‐based Biosensor platform

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Abstract

The current outbreak of monkeypox virus (MPXV) has become a public health emergency of international concern that highlights the need for rapid, sensitive MPXV diagnostic assays. Here, we combined isothermal multiple cross displacement amplification (MCDA) with nanoparticle-based lateral flow biosensor (LFB) to devise a diagnostic test for the diagnosis of MPXV infection (called MPXV-MCDA-LFB) and differentiation of West and Central African MPXV isolates. The MPXV-MCDA-LFB protocol conducts isothermal MCDA reaction for DNA templates followed by LFB detection of preamplification target sequences. Two MCDA primer sets were designed targeting the D41L and ATI genes of Central and West African MPXV isolates, respectively, and the optimal condition of two MCDA reactions was 64 ºC for 30 min. The two MCDA reactions were decoded by LFB, which was devised for detecting three targets, including two amplicons yielded from two MCDA reactions and a chromatography contr ol. Thus, the MPXV-MCDA-LFB assay could be completed within 50 min including rapid template preparation (15 min), MCDA reaction (30 min) and reporting of result (< 5 min). The MPXV-MCDA-LFB method is very sensitive and can detect the target genes (D14L and ATI) with as low as five copies of plasmid template per reaction and 12.5 copies of pseudovirus in human blood samples. MPXV-MCDA-LFB assay does not cross-react with non-MPXV templates, validating its specificity. Therefore, the MPXV-MCDA-LFB assay developed here is a useful tool for rapid and reliable diagnosis of MPXV infection.

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Single‐cell transcriptomics dissects epithelial heterogeneity in HPV+ cervical adenocarcinoma

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Abstract

The intra- and inter-tumoral heterogeneity of epithelial cells in human papillomavirus (HPV)+ cervical adenocarcinoma (CEAD) remains largely unknown. To investigate this issue, we performed single-cell RNA sequencing on 19,229 epithelial cells sorted from three tumor samples of three patients with HPV+ CEAD. Six epithelial subclusters (Epi1 to Epi6) were identified that showed distinct gene expression. Among these, Epi1 and Epi4 had apparent tumor hallmarks and metabolic activities. Epi1 was highly enriched in hallmarks of hypoxia, IL2/STAT5 signaling, retinol metabolism, glycolysis, and arachidonic acid metabolism, while Epi4 was highly enriched in hallmarks of G2M checkpoint, E2F targets, DNA repair, PI3K/AKT/MTOR signaling, glycolysis, fatty acid degradation, TCA cycle, and glutathione metabolism. We also investigated inter-tumoral epithelial heterogeneity and found that Patient 1 was highly enriched for KRAS signaling and angiogenesis, while Patient 2 was highly enriched for epithelial-mesenchymal transition and TGF-β signaling, and Patient 3 was highly enriched for hypoxia, DNA repair, G2M checkpoint, and E2F targets. Using single-cell RNA sequencing, we revealed the intra- and inter-tumoral heterogeneity of epithelial cells in HPV+ CEAD, providing insights into the importance of personalized treatment for patients with HPV+ CEAD.

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Wednesday, January 4, 2023

Effectiveness and pharmacokinetic exposures of first-line drugs used to treat drug-susceptible tuberculosis in children: a systematic review and meta-analysis

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Abstract
Background
Optimal doses of first line drugs for drug-susceptible tuberculosis (DS-TB) treatment in children and young adolescents remain uncertain. We aimed to determine if children treated using WHO-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic exposures.
Methods
Titles, abstracts, and full-text articles were screened. We searched Pubmed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children <18 years, being treated for DS-TB with rifampicin, pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO, CRD42021274222.
Results
Of 304 studies identified, 46 studies were eligible for full-text review and 12 and 18 articles were included for the efficacy and pharmacokinetic analysis, respectively. Of 1,830 children in cluded in the efficacy analysis, 82% had favourable outcomes (range 25%-95%). At WHO-recommended doses, exposures to rifampicin, pyrazinamide, and ethambutol were lower in children as compared to adults. Children ≤6 years have 35% lower AUC than older children (14.4 (9.9-18.8) vs 22.0 (13.8-30.1) μg.h/mL) and children with HIV (CWHIV) had 35% lower rifampicin AUC than HIV negative children (17.3 (11.4-23.2) vs 26.5 (21.3-31.7) μg.h/mL). Heterogeneity and small sample sizes were major limitations.
Conclusion
There is large variability in outcomes with an average 82% favourable outcomes. Drug exposures are lower in children than in adults. Younger children and CWHIV are underexposed to rifampicin. Standardization of pharmacokinetic paediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.
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Are psychedelics the answer to chronic pain: a review of current literature

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Abstract

Chronic pain is a common and complex problem, with an unknown etiology. Psychedelics like lysergic acid diethylamide (LSD) and psilocybin, may play a role in the management of chronic pain. Through activation of the serotonin-2A (5-HT2A) receptor, several neurophysiological responses result in the disruption of functional connections in brain regions associated with chronic pain. Healthy reconnections can be made through neuroplastic effects, resulting in sustained pain relief. However, this process is not fully understood and evidence of efficacy is limited and of low quality. In cancer and palliative related pain, the analgesic potential of psychedelics was established decades ago, and the current literature shows promising results on efficacy and safety in patients with cancer-related psychological distress. In other areas, patients suffering from severe headache disorders like migraine and cluster headache who have self-medicated with psychedelics report both acute and prophylactic efficacy of LSD and psilocybin. Randomized control trials are now being conducted to study the effects in cluster headache Furthermore, psychedelics have a generally favorable safety profile especially when compared to other analgesics like opioids. In addition, psychedelics do not have the addictive potential of opioids. Given the current epidemic use of opioids, and that patients are in desperate need of an alternative treatment, it is important that further research is conducted on the efficacy of psychedelics in chronic pain conditions.
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Antibodies to varicella-zoster virus and three other herpesviruses and survival in adults with glioma

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Abstract
Background
Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed survival of adults with glioma in relation to their antibody measurements to 4 common herpes viral infections, including VZV, measured post-diagnosis.
Materials and Methods
We analyzed IgG antibody measurements to VZV, cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and Epstein-Barr virus (EBV) collected from 1378 adults with glioma diagnosed between 1991 and 2010. Blood was obtained a median of 3 months after surgery. Associations of patient IgG levels with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw, and tumor grade. Models were stratified by recruitment series and meta-analyzed to account for time-dependent treatment effects.
Results
VZV antibody seropositivity was associated with improved survival outcomes in adults with glioma (Hazard ratio, HR=0.70, 95% Confidence Interval 0.54-0.90, p=0.006). Amongst cases who were seropositive for VZV antibodies, survival was significantly improved for those above the 25th percentile of continuous reactivity measurements versus those below (HR=0.76, 0.66-0.88, p=0.0003). Antibody seropositivity to EBV was separately associated with improved survival (HR=0.71, 0.53-0.96, p=0.028). Antibody positivity to two other common viruses (CMV, HSV) was not associated with altered survival.
Conclusions
Low levels of VZV or EBV antibodies are associated with poorer survival outcomes for adults with glioma. Differential immune response rather than viral exposure may explain these findings.
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Contribution of genotypes in Prothrombin and Factor V Leiden to COVID‐19 and disease severity in patients at high risk for hereditary thrombophilia

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abstract

Aim

Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis.

Methods

This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a subset of cases (n=4092). This subgroup was age and gender matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank.

Results

The ratio of males (31.08%; 27.01%) and the mean age (36.85 ±15.20; 33.89±14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p<0.05). FVL prevalence, CT positivity rate, history of thrombosis, and Pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p<0.05). Disease severity was mainly affected by Factor V Leiden and not related to genotypes at the Prothrombin mutations.

Conclusion

Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients.

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Integrative systems immunology uncovers molecular networks of the cell cycle that stratify COVID‐19 severity

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Abstract

Several perturbations in the number of peripheral blood leukocytes, such as neutrophilia and lymphopenia associated with Coronavirus disease 2019 (COVID-19) severity, point to systemic molecular cell cycle alterations during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, the landscape of cell cycle alterations in COVID-19 remains primarily unexplored. Here, we performed an integrative systems immunology analysis of publicly available proteome and transcriptome data to characterize global changes in the cell cycle signature of COVID-19 patients. We found significantly enriched cell cycle-associated gene co-expression modules and an interconnected network of cell cycle-associated differentially expressed proteins (DEPs) and genes (DEGs) by integrating the molecular data of 1,469 individuals (981 SARS-CoV-2 infected patients and 488 controls [either healthy controls or individuals with other respiratory illnesses]). Among these DEPs and DEGs are seve ral cyclins (CCNs), cell division cycles (CDCs), cyclin-dependent kinases (CDKs), and mini-chromosome maintenance (MCMs) proteins. COVID-19 patients partially shared the expression pattern of some cell cycle-associated genes with other respiratory illnesses but exhibited some specific differential features. Notably, the cell cycle signature predominated in the patients' blood leukocytes (B, T, and NK cells) and was associated with COVID-19 severity and disease trajectories. These results provide a unique global understanding of distinct alterations in cell cycle-associated molecules in COVID-19 patients, suggesting new putative pathways for therapeutic intervention.

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Birth weight, gestational age and risk of cardiovascular disease in early adulthood: Influence of familial factors

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Abstract
The association between intrauterine growth restriction (IUGR) and cardiovascular disease (CVD) later in life might be confounded by familial factors. We conducted a bi-national register-based cohort study to assess associations of birthweight for gestational age (GA), a proxy for IUGR, and GA with CVD risk in early adulthood, before and after addressing familial factors via sibling comparison. We included 3,410,334 live non-malformed singleton births in Sweden (1973-1996) and Denmark (1978-1998). During a median follow-up of 10 years from age 18 onwards, 29,742 individuals developed incident CVD (hypertensive, ischemic heart, and cerebrovascular diseases). Compared with individuals born with appropriate birthweight for GA (AGA, 10th-90th percentiles) or full term (39-40 gestational weeks), individuals born severely small for GA (SGA, <3rd percentile) or preterm (22-36 weeks) were at increased risk of CVD [HRs (95% CIs): 1.38 (1.32-1.45) and 1 .31 (1.25-1.38), respectively]. The association was attenuated when comparing individuals born SGA with their AGA siblings (1.11, 0.99-1.25), but remained robust when comparing individuals born preterm with their term siblings (1.21, 1.07-1.37). Our findings suggest that both SGA and preterm birth are associated with CVD risk in early adulthood, with greater familial confounding noted for SGA.
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