Severe Acute Respiratory Syndrome Coronavirus Research Articles

Surfaces environmental monitoring of SARS-CoV-2: Loop mediated isothermal amplification (LAMP) and droplet digital PCR (ddPCR) in comparison with standard Reverse-Transcription quantitative polymerase chain reaction (RT-qPCR) techniques.

The persistence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) on substrates, and the impact of fomites on Coronavirus Disease 19 (COVID-19) transmission, is until now, widely discussed. Consequently, further investigations are required for a correct risk assessment in high-risk facilities such as hospitals, healthcare facilities (HCFs), and long-term care facilities (LTCFs). Therefore, appropriate surveillance and disinfection programs represent the best approach to guarantee the safety of these communities. This study proposes an environmental SARS-CoV-2 surfaces routine monitoring approach in HCF and communities' settings, to provide rapid and effective evaluation of surface hygienic conditions and the effectiveness of applied sanitization measures. Surfaces samples (n = 118) were collected using the SRK® kit (Copan Italia) from 2020 to 2023. Three molecular techniques were compared: Reverse Transcription Loop mediated isothermal AMPlification (RT-LAMP, Enbiotech), Reverse-Transcription quantitative polymerase chain reaction (RT-qPCR) (RT-qPCR, Seegene) and droplet digital PCR (ddPCR, Bio-Rad). For ddPCR, two RNA extraction methods were compared: TRIzol LS (Invitrogen) versus QIAmp Viral Mini kit (QIAGEN), showing how the latter is more suitable for surfaces. Regarding the quantitative ddPCR results, the ROC analysis allowed to reduce the manufacturer cut-off for droplets number (from 3 to 1) for the positive samples. Moreover, a new cut-off for the viral RNA copies' number/μL for each target (N1 and N2) on environmental monitoring was fixed at 2,82. The results obtained using the QIAmp kit, suggested that the N2 target is more stable in the environment and could be most suitable for the virus environmental detection. The percentage of positive samples was similar among the techniques (26% for RT-LAMP, 36% for ddPCR and 23% for RT-qPCR). Using RT-qPCR as reference method, a sensitivity (SE) of 30% for RT-LAMP and 41% for ddPCR was observed. By contrast, specificity (SP) was higher for RT-LAMP (75%) respect to ddPCR (66%). Comparing the faster RT-LAMP with the sensitive ddPCR the 26% and 74% of SE and SP for RT-LAMP, were reported. The low sensitivity for RT-LAMP and ddPCR could be explained with the use of clinical rather than environmental kits, other than the changing in the virus prevalence during the sampling campaign. Although the RT-LAMP requires improvements in term of SE and SP, this research presents an innovative environmental monitoring and prevention method for SARS-CoV-2, that could be extended to other pathogens that are under environmental surveillance.

Design, synthesis, and biological evaluation of novel 2'-deoxy-2'-spirooxetane-7-deazapurine nucleoside analogs as anti-SARS-CoV-2 agents.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global public health crisis and continues to pose grave threats to human health. The efficacy of current vaccines and therapeutics is likely limited for future emerging strains due to the highly mutative nature of the virus, underscoring an urgent need for the development of new, potent antiviral agents. In this study, we report the design and synthesis of a series of novel 2'-deoxy-2'-spirooxetane-7-deazapurine nucleoside analogs as potential inhibitors of SARS-CoV-2 replication. Some of these compounds demonstrate potent antiviral activity, offering a potential new weapon for therapeutic intervention against the ever-evolving SARS-CoV-2 virus. Among the tested compounds, nucleoside analog 11q exhibited the most potent antiviral activity against SARS-CoV-2 in Vero E6 cells, with IC50 values of 0.14 μM for the wild-type strain and 0.36 μM for the BA.5 strain. Notably, compound 11q exhibits up to nine times greater inhibitory activity against wild-type SARS-CoV-2 compared to Remdesivir and also possesses a superior selectivity index. These findings suggest that compound 11q is a highly promising lead candidate for future drug development aimed at combating SARS-CoV-2.

Anti-inflammatory Alkaloids Targeting IL-1 against Respiratory Viral Infections: A Special Insight into Drug Development against SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the deadliest viruses among respiratory viruses which resulted in COVID-19 pandemic. The virus gets transmitted by the nasal route and moves down to the trachea, bronchi, and then to the lungs. Once replicated inside the alveolar cells, the SARS-CoV-2 makes the membrane of the alveolar sac porous, which causes the leaking of plasma from surrounding blood vessels into the alveolar sac leading to its buildup. This process results in the production of pro-inflammatory cytokines like interleukin-1β (IL-1β) and Tumor necrosis factor-α (TNF-α) by the helper T-cells at the site of the infection, causing difficulty in breathing. Plant-based alkaloids can be promising to treat viral infections. Plants have contributed to drug development against viruses like Herpes simplex virus (HSV), Human immunodeficiency virus (HIV), Hepatitis B virus (HBV), and viruses that cause respiratory diseases in humans. Plant alkaloids, either in the form of extract, infusion, or powder, have shown potential in treating viral diseases mainly by targeting the replication of viruses. Alkaloids like Tetrandrine, Oxymatrine, and Berberine have been shown to have a positive role in mediating pro-inflammatory cytokines like IL-1. These alkaloids thus inactivate the nuclear factor kappa-B (NF-kB) pathway, inhibiting the expression of its targeted genes, IL-1β and TNF-α. This inactivation of NF-kB results in reduced levels of IL-1 and TNF-α, and consequently reduced inflammation, decreasing the stress on the immune cells and increasing the ability of the patient to fight the infection. Despite vaccine development for SARS-CoV-2, the virus is continuously evolving into new varieties, posing a threat to humans and it is necessary to develop effective drug discovery programs. Natural products can pave the way in this regard. This review can contribute towards safer drug development against SARS-CoV-2, combating the threat of the ever-emerging variants of this virus.

Ethnic and racial differences in children and young people withrespiratory and neurological post-acute sequelae of SARS-CoV-2: an electronic health record-based cohort study from the RECOVER Initiative.

Children from racial and ethnic minority groups are at greater risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether they have increased risk for post-acute sequelae of SARS-CoV-2 (PASC). Our objectives were to assess whether the risk of respiratory and neurologic PASC differs by race/ethnicity and social drivers of health. We conducted a retrospective cohort study of individuals <21 years seeking care at 24 health systems across the U.S, using electronic health record (EHR) data. Our cohort included those with a positive SARS-CoV-2 molecular, serology or antigen test, or with a COVID-19, multisystem inflammatory disease in children, or PASC diagnosis from February 29, 2020 to August 1, 2022. We identified children/youth with at least 2 codes associated with respiratory and neurologic PASC. We measured associations between sociodemographic and clinical characteristics and respiratory and neurologic PASC using odds ratios and 95% confidence intervals estimated from multivariable logistic regression models adjusted for other sociodemographic characteristics, social vulnerability index or area deprivation index, time period of cohort entry, presence and complexity of chronic respiratory (respectively, neurologic) condition and healthcare utilization. Among 771,725 children in the cohort, 203,365 (26.3%) had SARS-CoV-2 infection. Among children with documented infection, 3217 children had respiratory PASC and 2009 children/youth had neurologic PASC. In logistic regression models, children <5 years (Odds Ratio [OR] 1.78, 95% CI 1.62-1.97), and of Hispanic White descent (OR 1.19, 95% CI 1.05-1.35) had higher odds of having respiratory PASC. Children/youth living in regions with higher area deprivation indices (OR 1.25, 95% CI 1.10-1.420 for 60-79th percentile) and with chronic complex respiratory conditions (OR 3.28, 95% CI 2.91-3.70) also had higher odds of respiratory PASC. In contrast, older (OR 1.57, 95% CI 1.40-1.77 for those aged 12-17 years), non-Hispanic White individuals and those with chronic pre-existing neurologic conditions (OR 2.04, 95% CI 1.78-2.35) were more likely to have a neurologic PASC diagnosis. Racial and ethnic differences in healthcare utilization for neurologic and respiratory PASC may reflect social drivers of health and inequities in access to care. National Institutes of Health.

Epidemiology and treatment trends for acute encephalopathy under the impact of SARS-CoV-2 pandemic based on a prospective multicenter consecutive case registry.

Acute encephalopathy is a severe condition predominantly affecting children with viral infections. The purpose of this study was to elucidate the epidemiology, treatment, and management of acute encephalopathy. The study also aimed to understand how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has affected epidemiological trends. This retrospective study used the database of the Febrile Acute Convulsion and Encephalopathy registry, a prospective multicenter consecutive case registry for acute encephalopathy and febrile convulsive status epilepticus. Pediatric patients aged 0-18years hospitalized and diagnosed with acute encephalopathy between January 2020 and August 2023 were included in this study. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was the most common syndrome (36 cases, 27.5%). SARS-CoV-2 was the most common pathogen (19 cases, 14.5%), followed by influenza virus type A (15 cases, 11.5%). Targeted temperature management was performed for 25 (69.4%) of 36 patients with AESD; 5 (50.0%) of 10 patients with hemorrhagic shock and encephalopathy; and only 1 (5.9%) of 17 patients with mild encephalitis or encephalopathy with a reversible splenial lesion (MERS). High-dose corticosteroids were administered to 9 (90.0%) of 10 patients with hemorrhagic shock and encephalopathy and 11 (30.6%) of 36 patients with AESD. The primary causative pathogen of acute encephalopathy has changed to SARS-CoV-2. AESD remains the most common syndrome. Targeted temperature management is more, whereas high-dose corticosteroid therapy is less, frequently used. No specific treatment for mild encephalitis or encephalopathy with a reversible splenial lesion has been established.

Profiling epithelial viral receptor expression in amniotic membrane and nasal epithelial cells at birth.

Children with wheeze and asthma present with airway epithelial vulnerabilities, such as impaired responses to viral infection. It is postulated that the in utero environment may contribute to the development of airway epithelial vulnerabilities. The aims of the study were to establish whether the receptors for rhinovirus (RV), respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are expressed in the amniotic membrane and whether the pattern of expression is similar to newborn nasal epithelium. Placenta were collected (n=33) from newborns in AERIAL, a sub-study nested under the ORIGINS birth cohort. Using purified RNA from amniotic samples (n=33), along with previously extracted RNA from nasal epithelial cells from newborns (n=20), real-time quantitative polymerase chain reaction (qPCR) was performed to determine gene expression of viral receptors for RV, RSV and SARS-CoV-2 in both amniotic and newborn nasal epithelial samples. In addition, receptor protein expression was quantified through Western blot and localised using immunohistochemical staining in amniotic samples. Amniotic and newborn nasal samples expressed various receptors for RV (ICAM-1, LDLR, CDHR3), RSV (NCL, CX3CR1) and SARS-CoV-2 (ACE2, TMPRSS2) at the gene level, although the magnitude of expression varied. In addition, protein expression of these receptors was confirmed in the amniotic samples. These proteins were localised to the epithelial layer of the amniotic membrane. This proof-of-concept study indicates the potential of amniotic samples to facilitate investigation into the interactions between the in utero environment and prenatal programming of epithelial innate immune responses to viruses.

A label-free gold nanoparticles functionalized peptide dendrimer biosensor for visual detection of breakthrough infections in COVID-19 vaccinated patients

Given the global implementation of effective COVID-19 vaccines, which do not confer complete immunity, it is crucial to monitor the occurrence of breakthrough infections, particularly against newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Hence, we developed a label-free colorimetric assay using gold nanoparticles (GNPs) functionalized with a peptide dendrimer incorporating highly reactive epitopes of the nucleocapsid (N) protein. This assay relies on the tween-20 induced colorimetric changes caused by the aggregation of peptide dendrimer-coated GNPs in the absence of anti- SARS-CoV-2 N antibodies, and vice versa. Transmission electron microscopy, dynamic light scattering, and circular dichroism spectroscopy analyses all showed the formation of a uniform and highly stable coating of the peptide dendrimer over GNPs. Surface plasmon resonance experiments have demonstrated a strong binding affinity for the peptide dendrimer and anti- SARS-CoV-2 N antibodies, with a KD value of 525 nM. To validate the proof-of-concept, we have tested this assay on seventy human serum samples, and receiver operating characteristic curve analysis demonstrated high diagnostic sensitivity (88.89 %) and specificity (100 %). This approach opens up new avenues for the development of simple and rapid diagnostic assays for identifying antibodies against viral infections and other pathogens.

Post-COVID-19 sequelae are associated with sustained SARS-CoV-2-specific CD4+ immune responses.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to widespread post-acute sequelae of COVID-19 (PASC), affecting multiple body systems. Despite its prevalence, PASC's pathogenesis remains unclear, with hypotheses suggesting viral persistence, immune activation, and autoimmune responses among the pathogenetic mechanism. This study aimed to evaluate T cell memory response in PASC patients, one year post-hospital discharge and correlate it with clinical parameters to identify a potential PASC-associated fingerprint. Peripheral blood mononuclear cells (PBMCs) from PASC patients and healthy controls (HC) were stimulated with a pool of spike peptides. CD4+ and CD8+ T cell responses were evaluated by flow cytometry using the activation-induced markers assay (AIM). Findings showed significant activation of the CD4+ T cell compartment, with a higher proportion of responders among PASC patients. Central memory (CM) T cells expressing pro-inflammatory cytokines were more prevalent in responders. Clinical correlations revealed higher SARS-CoV-2-specific T cell responses in patients with reduced diffuse lung capacity for carbon monoxide (DLCO) and residual symptoms. These immune changes, especially in CM T cells, could play a pivotal role in PASC's development and persistence, impacting patients' daily lives.

Enhanced Macrophage Uptake of Spray-Dried Phosphatidylserine-Loaded Microparticles for Pulmonary Drug Delivery Applications.

Macrophages are an integral part of the innate immune system and act as a first line of defense to pathogens; however, macrophages can be reservoirs for pathogens to hide and replicate. Tuberculosis, influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are common diseases whose pathogens are uptaken into macrophages. Current treatments for diseases such as these are limited by the therapeutic delivery method, which typically involves systemic delivery in large, frequent doses. This study aims to overcome this limitation via the development of an inhalable dry powder microparticle (MP) formulation capable of targeted drug delivery to alveolar macrophages in addition to controlled release of a therapeutic. A simple one-step spray drying method was used to synthesize acetalated dextran (Ac-Dex) MP loaded with the model therapeutic, curcumin, and 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), which is a phospholipid that induces ligand-receptor mediated macrophage phagocytosis. The resulting MP exhibited significantly more uptake by RAW 264.7 macrophages in comparison to MP without DPPS, and it was shown that DPPS-mediated uptake was macrophage specific. The particles exhibited pH-responsive release and in vitro aerosol dispersion analysis confirmed the MP can be effectively aerosolized for pulmonary delivery. Overall, the described MP has the potential to improve treatment efficacy for macrophage-associated diseases.

Practical SERS Substrates by Spray Coating of Silver Solutions for Deep Learning-Assisted Sensitive Antigen Identification

Surface-enhanced Raman spectroscopy (SERS) has long been recognized for its rapid and sensitive detection capabilities; however, challenges persist in practical fabrication of the substrates and interpreting complex data. Herein, we propose a deep learning (DL) assisted SERS approach to enable rapid and sensitive detection of analytes on a practical yet highly effective substrates prepared by direct spray-coating of a nanoparticle-free true solution of a reactive Ag ink and on-site thermal annealing mediated generation of nanostructures. This design ensured homogeneous distribution of Ag nanostructures throughout the entire substrate, significantly increasing the number of hotspots and enhancing the Raman signals, thereby achieving an impressive analytical enhancement factor of ~1010 in a reproducible and consistent manner. The diagnostic utility of this platform was demonstrated by detecting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein in both buffer and saliva, with detection limits of 74.3pg/mL and 7.43ng/mL, respectively. The DL-assisted SERS not only accurately identified the presence or absence of viral antigen, but also automatically quantified the viral load. This automatic identification achieved an outstanding accuracy of ~99.9%, highlighting the exceptional performance of the proposed platform. This simple, cost-effective, scalable, and ultra-sensitive DL-assisted SERS platform offers significant opportunities for early and precise detection in a range of analytical scenarios.

On the importance of data curation for knowledge mining in antiviral research.

The recent severe acute respiratory syndrome coronavirus 2 pandemic has clearly exemplified the need for broad-spectrum antiviral (BSA) medications. However, previous outbreaks show that about one year after an outbreak, interest in antiviral research diminishes and the work toward an effective medication is left unfinished. Martin et al. endeavored to support the early stages of focused BSA development by creating the Small Molecule Antiviral Compound Collection (SMACC), which is publicly available online at https://smacc.mml.unc.edu. SMACC is a highly curated database with over 32,500 entries of chemical compounds tested in both phenotypic and target-based assays across 13 viruses from the NIAID's list of emerging infectious diseases/pathogens. The authors advise judicious use of knowledge collections such as SMACC and recommend users critically evaluate retrieved data and resulting hypotheses prior to experimental testing. When used correctly, SMACC-like databases may serve as a reference for medicinal chemists and virologists working to develop novel BSA medications. To summarize, we emphasize the importance of data curation for both novel outbreak prediction and development of BSAs against these outbreaks.

Targeting SIRT1 by Scopoletin to Inhibit XBB.1.5 COVID-19 Life Cycle.

Natural products have historically driven pharmaceutical discovery, but their reliance has diminished with synthetic drugs. Approximately 35% of medicines originate from natural products. Scopoletin, a natural coumarin compound found in herbs, exhibits antioxidant, hepatoprotective, antiviral, and antimicrobial properties through diverse intracellular signaling mechanisms. Furthermore, it also enhances the activity of antioxidants. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes viral pneumonia through cytokine storms and systemic inflammation. Cellular autophagy pathways play a role in coronavirus replication and inflammation. The Silent Information Regulator 1 (SIRT1) pathway, linked to autophagy, protects cells via FOXO3, inhibits apoptosis, and modulates SIRT1 in type-II epithelial cells. SIRT1 activation by adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) enhances the autophagy cascade. This pathway holds therapeutic potential for alveolar and pulmonary diseases and is crucial in lung inflammation. Angiotensin-converting enzyme 2 (ACE-2) activation, inhibited by reduced expression, prevents COVID-19 virus entry into type-II epithelial cells. The coronavirus disease 2019 (COVID-19) virus binds ACE-2 to enter into the host cells, and XBB.1.5 COVID-19 displays high ACE-2-binding affinity. ACE-2 expression in pneumocytes is regulated by signal transducers and activators of transcription-3 (STAT3), which can increase COVID-19 virus replication. SIRT1 regulates STAT3, and the SIRT1/STAT3 pathway is involved in lung diseases. Therapeutic regulation of SIRT1 protects the lungs from inflammation caused by viral-mediated oxidative stress. Scopoletin, as a modulator of the SIRT1 cascade, can regulate autophagy and inhibit the entry and life cycle of XBB.1.5 COVID-19 in host cells.

Severe acute respiratory syndrome coronavirus 2 variants in patients with coronavirus disease 2019 and environmental sampling from the hospital and market during the coronavirus disease 2019 pandemic in Thailand

Limited genomic surveillance data is available for SARS-CoV-2 in Thailand during the second and third wave outbreaks, including both patient and environmental samples. This study investigated the presence of SARS-CoV-2 RNA in patient samples, on frequently touched surfaces, and in environmental swab samples (EVSs) collected from urban markets in Bangkok between April 2021 and August 2022. A total of 78,159 nasopharyngeal swab samples from patients and 327 environmental swab samples from hospital and market settings were collected. SARS-CoV-2 RNA was detected in 3,706 of 78,159 patient samples and one of 327 environmental samples using real-time RT-PCR. In total, 54 patient samples and an environmental sample were subjected to whole-genome sequencing and mass array genotyping, respectively. Only 46 samples passed the quality assessment based on the analysis criteria. The lineages detected included B.1.1.529 (2 samples), B.1.1.7 (15 samples), B.1.351 (3 samples), B.1.36.16(6 samples), B.1.617.2 (1 sample), AY.102 (1 sample), AY.4 (11 samples), AY.25 (1 sample), BA.1 (1 sample), BA.1.1 (3 samples), and BA.2 (2 samples). The phylogenetic analysis of the viral genome sequences revealed similar lineages during this study period.

Replication-incompetent VSV-based vaccine elicits protective responses against SARS-CoV-2 and influenza virus.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses lead to severe respiratory illnesses and death in humans, exacerbated in individuals with underlying health conditions, remaining substantial global public health concerns. Here, we developed a bivalent replication-incompetent single-cycle pseudotyped vesicular stomatitis virus vaccine that incorporates both a prefusion-stabilized SARS-CoV-2 spike protein lacking a furin cleavage site and a full-length influenza A virus neuraminidase protein. Vaccination of K18-hACE2 or C57BL/6J mouse models generated durable levels of neutralizing antibodies, T cell responses, and protection from morbidity and mortality upon challenge with either virus. Furthermore, the vaccine provided heterologous protection upon challenge with a different influenza virus strain, supporting the advantage of using NA to increase the breadth of vaccine protection. Now, no bivalent vaccine is approved for use against both SARS-CoV-2 and influenza virus. Our study supports using this platform to develop safe and efficient vaccines against multiple viruses.

Single- and multiple-dose pharmacokinetics and safety of the SARS-CoV-2 3CL protease inhibitor RAY1216: a phase 1 study in healthy participants.

Coronavirus disease 2019, which leads to pneumonia, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAY1216 is a 3C-like protease inhibitor that targets SARS-CoV-2. The aim of our study was to assess the pharmacokinetics (PK) and safety of RAY1216 in healthy volunteers. This was a randomized, placebo-controlled, double-blind study consisting of four components: a single ascending dose study, a drug-drug interaction study, a multiple ascending dose study, and a food-effect study. All participants were randomly assigned to receive either a single dose or multiple doses of RAY1216 or placebo. A total of 88 healthy adult participants (male-to-female ratio of 1:1) aged 18-50 years were enrolled. A total of 37 participants (42%) experienced at least one adverse event (AE). All AEs were mild or moderate and were resolved without additional treatment. The most commonly reported adverse drug reactions were hypertriglyceridemia, hyperuricemia, and elevated serum creatinine levels. RAY1216 was well-absorbed after administration with exposure increasing in a dose-dependent manner. Food appeared to increase exposure and delay the absorption of RAY1216. Ritonavir significantly inhibited drug metabolism, and increased drug exposure increased the associated safety risks. RAY1216 was found to be well tolerated and safe in healthy participants. On the basis of preclinical results, PK characteristics, and the safety profile of RAY1216, a dosage of 400 mg three times daily was selected, thereby establishing a foundation for future research and for the clinical application of RAY1216.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05829551.

In Silico Discovery of SARS-CoV-2 Main Protease Inhibitors Using Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations.

The 3C-like protease of severe acute respiratory syndrome coronavirus 2, known as the main protease (Mpro), is an attractive drug target for the treatment of coronavirus disease 2019. This study reports the discovery of novel Mpro inhibitors using several in silico techniques, including docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. We performed docking calculations on 5950 compounds with bioactivity, and 12 compounds were selected. An enzymatic assay was conducted, revealing that BP-1-102 exhibits significant Mpro inhibitory activity with an IC50 of 11.1 μM. The identification of seed compounds from the experiments on a few compounds demonstrates the effectiveness of our docking calculations. Furthermore, the detailed analyses using MD and FMO calculations suggested an interaction mechanism in which the hydroxyl group of BP-1-102 forms a hydrogen bond with E166 of Mpro. The Mpro inhibitory activity of SH-4-54, a derivative without the aforementioned hydroxyl group, was investigated and observed to be significantly reduced, with an IC50 of 81.5 μM. This result strongly supports the suggested interaction mechanism.

MRNA vaccine-induced SARS-CoV-2 spike-specific IFN-γ and IL-2 T-cell responses are predictive of serological neutralization and are transiently enhanced by pre-existing cross-reactive immunity.

Our findings provide valuable insights into the potential contributions of mRNA vaccine-induced spike-specific T-cell responses to the durability of neutralizing antibody levels in both uninfected and hybrid immune recipients. Our study additionally sheds light on the precise impacts of pre-existing cross-reactive T-cell immunity to severe acute respiratory syndrome coronavirus 2 on the magnitude and kinetics of cellular and humoral responses to vaccination. Accordingly, our data will help optimize the development of next-generation T cell-based coronavirus vaccines and vaccine regimens to maximize efficacy and durability.

Temporal profiling of human lymphoid tissues reveals coordinated defense against viral challenge

Adaptive immunity is generated in lymphoid organs, but how these structures defend themselves during infection in humans is unknown. The nasal epithelium is a major site of viral entry, with adenoid nasal-associated lymphoid tissue (NALT) generating early adaptive responses. In the present study, using a nasopharyngeal biopsy technique, we investigated longitudinal immune responses in NALT after a viral challenge, using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as a natural experimental model. In acute infection, infiltrating monocytes formed a subepithelial and perifollicular shield, recruiting neutrophil extracellular trap-forming neutrophils, whereas tissue macrophages expressed pro-repair molecules during convalescence to promote the restoration of tissue integrity. Germinal center B cells expressed antiviral transcripts that inversely correlated with fate-defining transcription factors. Among T cells, tissue-resident memory CD8 T cells alone showed clonal expansion and maintained cytotoxic transcriptional programs into convalescence. Together, our study provides unique insights into how human nasal adaptive immune responses are generated and sustained in the face of viral challenge.

Plasma proteomic evidence for increased β-amyloid pathology after SARS-CoV-2 infection.

Previous studies have suggested that systemic viral infections may increase risks of dementia. Whether this holds true for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections is unknown. Determining this is important for anticipating the potential future incidence of dementia. To begin to do this, we measured plasma biomarkers linked to Alzheimer's disease pathology in the UK Biobank before and after serology-confirmed SARS-CoV-2 infections. SARS-CoV-2 infection was associated with biomarkers associated with β-amyloid pathology: reduced plasma Aβ42:Aβ40 ratio and, in more vulnerable participants, lower plasma Aβ42 and higher plasma pTau-181. The plasma biomarker changes were greater in participants who had been hospitalized with COVID-19 or had reported hypertension previously. We showed that the changes in biomarkers were linked to brain structural imaging patterns associated with Alzheimer's disease, lower cognitive test scores and poorer overall health evaluations. Our data from this post hoc case-control matched study thus provide observational biomarker evidence that SARS-CoV-2 infection can be associated with greater brain β-amyloid pathology in older adults. While these results do not establish causality, they suggest that SARS-CoV-2 (and possibly other systemic inflammatory diseases) may increase the risk of future Alzheimer's disease.

A transient reduction of the varicella-zoster virus-specific immunoglobulin G level after vaccination against severe acute respiratory syndrome coronavirus 2 with an mRNA vaccine in nursing home residents, but not staff.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines are highly effective in protecting against severe disease and hospitalization. However, a potential risk of herpes zoster (HZ) has been identified after vaccination against SARS-CoV-2 mRNA vaccine. To evaluate the effect of the vaccination on immune response against varicella-zoster virus (VZV), the immunoglobulin G (IgG) titers against VZV and measles virus (MV) as a control, before and after the vaccination in residents and staff of two nursing homes. The geometric mean VZV IgG titer in 24 residents (range, 74-100 years) at two months after the second dose of vaccine decreased significantly from that before the vaccine; however, it recovered to the same level as before vaccination at five months after the second dose and decreased again at two months after the third dose. In contrast, the geometric mean VZV IgG and MV IgG titers in 22 staff (range, 20-69 years) were not significantly different than before vaccination, two, and five months after the second dose of vaccine, and two and five months after the third dose. This study has revealed that VZV IgG and MV IgG titers were temporarily reduced in nursing home residents, but not in staff, after immunization against SARS-CoV-2, suggesting an effect on antibody production.