Search Results (2,328)

Recently updated COVID-19 mRNA vaccines encode the spike protein of the omicron subvariant XBB.1.5 and are recommended for patients with inflammatory bowel disease (IBD) on immunosuppressive treatment. Nonetheless, their immunogenicity in patients with IBD against rapidly expanding virus variants remains unknown. This prospective multicenter cohort study is the first study to investigate the immunogenicity of XBB.1.5-adapted vaccines in patients with IBD. Systemic and mucosal antibodies targeting the receptor-binding domains (RBDs) of the omicron subvariants XBB.1.5, EG.5.1, and BA.2.86, as well as their neutralization were quantified before and two to four weeks after vaccination with monovalent XBB.1.5-adapted mRNA vaccines. Vaccination increased levels of serum anti-RBD IgG targeting XBB.1.5, EG.5.1, and BA.2.86 (1.9-fold, 1.8-fold, and 2.6-fold, respectively) and enhanced corresponding neutralization responses (2.3-fold, 3.1-fold, and 3.5-fold, respectively). Following vaccination, anti-TNF-treated patients had reduced virus neutralization compared to patients on treatments with other cellular targets. 11.1% and 16.7% of patients lacked EG.5.1 and BA.2.86 neutralization, respectively; all these patients received anti-TNF treatment. At mucosal sites, vaccination induced variant-specific anti-RBD IgG but failed to induce RBD-targeting IgA. Our findings provide a basis for future vaccine recommendations while highlighting the importance of frequent booster vaccine adaptation and the need for mucosal vaccination strategies in patients with IBD. Full article

To better understand the vulnerabilities of pregnant women during the COVID-19 pandemic, we conducted a comprehensive, retrospective cohort study to assess differences in immune responses to SARS-CoV-2 infection between pregnant and non-pregnant women. Nasopharyngeal swabs and serum specimens from 90 pregnant and 278 age-matched non-pregnant women were collected from 15 March 2020 to 23 July 2021 at NewYork-Presbyterian Queens Hospital in New York City. Multiplex reverse transcription polymerase chain reaction, neutralizing antibody, and cytokine array assays were used to assess the incidence, viral load, antibody titers and profiles, and examine cytokine expression patterns. Our results show a lower incidence of SARS-CoV-2 infection in pregnant women compared with non-pregnant women. Pregnant women infected with SARS-CoV-2 exhibited a substantially lower viral load. In addition, the levels of both anti-spike protein receptor-binding domain IgG neutralizing antibodies and anti-N Protein IgG were elevated in pregnant women. Finally, cytokine profiling revealed differential expression of leptin across cohorts. These findings suggest that pregnancy is associated with distinct immune and virological responses to SARS-CoV-2 infection, characterized by lower infection rates, substantially lower viral loads, and enhanced antibody production. Differential cytokine expression indicates unique immune modulation in pregnant women. Full article

Bats, with their virus tolerance, social behaviors, and mobility, are reservoirs for emerging viruses, including coronaviruses (CoVs) known for genetic flexibility. Studying the cophylogenetic link between bats and CoVs provides vital insights into transmission dynamics and host adaptation. Prior research has yielded valuable insights into phenomena such as host switching, cospeciation, and other dynamics concerning the interaction between CoVs and bats. Nonetheless, a distinct gap exists in the current literature concerning a comparative cophylogenetic analysis focused on elucidating the contributions of sequence fragments to the co-evolution between hosts and viruses. In this study, we analyzed the cophylogenetic patterns of 69 host–virus connections. Among the 69 host–virus links examined, 47 showed significant cophylogeny based on ParaFit and PACo analyses, affirming strong associations. Focusing on two proteins, ORF1ab and spike, we conducted a comparative analysis of host and CoV phylogenies. For ORF1ab, the specific window ranged in multiple sequence alignment (positions 520–680, 770–870, 2930–3070, and 4910–5080) exhibited the lowest Robinson–Foulds (RF) distance (i.e., 84.62%), emphasizing its higher contribution in the cophylogenetic association. Similarly, within the spike region, distinct window ranges (positions 0–140, 60–180, 100–410, 360–550, and 630–730) displayed the lowest RF distance at 88.46%. Our analysis identified six recombination regions within ORF1ab (positions 360–1390, 550–1610, 680–1680, 700–1710, 2060–3090, and 2130–3250), and four within the spike protein (positions 10–510, 50–560, 170–710, and 230–730). The convergence of minimal RF distance regions with combination regions robustly affirms the pivotal role of recombination in viral adaptation to host selection pressures. Furthermore, horizontal gene transfer reveals prominent instances of partial gene transfer events, occurring not only among variants within the same host species but also crossing host species boundaries. This suggests a more intricate pattern of genetic exchange. By employing a multifaceted approach, our comprehensive strategy offers a nuanced understanding of the intricate interactions that govern the co-evolutionary dynamics between bat hosts and CoVs. This deeper insight enhances our comprehension of viral evolution and adaptation mechanisms, shedding light on the broader dynamics that propel viral diversity. Full article

Grain size is one of the critical factors determining rice yield. Previous studies have found the grain-size-regulating function of Gα in rice. However, the regulatory mechanism underlying the development of rice grain mediated by Gα is still unclear. To reveal the functional mechanism of Gα in grain size regulation, a mutant of Gα (Gα-Cas9) was firstly constructed through a CRISPR/Cas9 strategy and was then grown in a greenhouse and field. The results showed that the seed length, plant height, 1000-grain weight, and spike length were significantly decreased in Gα-Cas9 compared to wild-type (WT) Pi-4b. During the grain filling stage, the increase in the grain dry weight of Pi-4b occurred earlier than that of Gα-Cas9. The total starch content and amylose content of matured grains of Pi-4b were higher than those of Gα-Cas9. Secondly, transcriptome sequencing analysis of Gα-Cas9 and Pi-4b during grain filling was performed to elucidate the functional pathways regulated by Gα. In total, 2867 and 4534 differentially expressed genes (DEGs) were discovered at 5 DAF and 10 DAF, and the starch and sucrose metabolism pathway enriched by DEGs was involved in grain size regulation mediated by Gα. Gα regulated the expression of starch-synthesis-related genes during grain filling, and the Gα protein interacted with OsNYC4 to trigger the sugar signaling pathway to promote starch accumulation in grain. Additionally, the GW2-WG1-OsbZIP47 pathway was switched off by Gα to relieve the inhibition of rice grain development. In this study, the results should provide new insights into the G protein signal transduction pathway. Full article

Abrin and ricin, both type II ribosome-inactivating proteins, are toxins of significant concern and are under international restriction by the Chemical Weapons Convention and the Biological and Toxin Weapons Convention. The development of a rapid and sensitive detection method for these toxins is of the utmost importance for the first emergency response. Emerging rapid detection techniques, such as surface-enhanced Raman spectroscopy (SERS) and lateral flow assay (LFA), have garnered attention due to their high sensitivity, good selectivity, ease of operation, low cost, and disposability. In this work, we generated stable and high-affinity nanotags, via an efficient freezing method, to serve as the capture module for SERS-LFA. We then constructed a sandwich-style lateral flow test strip using a pair of glycoproteins, asialofetuin and concanavalin A, as the core affinity recognition molecules, capable of trace measurement for both abrin and ricin. The limit of detection for abrin and ricin was 0.1 and 0.3 ng/mL, respectively. This method was applied to analyze eight spiked white powder samples, one juice sample, and three actual botanic samples, aligning well with cytotoxicity assay outcomes. It demonstrated good inter-batch and intra-batch reproducibility among the test strips, and the detection could be completed within 15 min, indicating the suitability of this SERS-LFA method for the on-site rapid detection of abrin and ricin toxins. Full article

The rapid spread of SARS-COV-2 and the millions of worldwide deaths and hospitalizations have prompted an urgent need for the development of screening tests capable of rapidly and accurately detecting the virus, even in asymptomatic people. The easy collection and the biomarker content of saliva, together with the label-free and informative power of surface-enhanced Raman spectroscopy (SERS) analysis have driven the creation of point-of-care platforms capable of identifying people with COVID-19. Indeed, different salivary fingerprints were observed between uninfected and infected people. Hence, we performed a retrospective analysis of SERS spectra from salivary samples of COVID-19-infected and -vaccinated subjects to understand if viral components and/or the immune response are implicated in spectral variations. The high sensitivity of the proposed SERS-based method highlighted the persistence of molecular alterations in saliva up to one month after the first positive swab, even when the subject tested negative for the rapid antigenic test. Nevertheless, no specific spectral patterns attributable to some viral proteins and immunoglobulins involved in COVID-19 infection and its progression were found, even if differences in peak intensity, presence, and position were observed in the salivary SERS fingerprint. Full article

Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin–kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin–angiotensin–aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled “Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions”, we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug. Full article

Antithrombin III (ATIII) is a potent endogenous anticoagulant that binds to heparan sulfate proteoglycans (HSPGs) on endothelial cells’ surfaces. Among these HSPGs, syndecans (SDCs) are crucial as transmembrane receptors bridging extracellular ligands with intracellular signaling pathways. Specifically, syndecan-4 (SDC4) has been identified as a key receptor on endothelial cells for transmitting the signaling effects of ATIII. Meanwhile, SDCs have been implicated in facilitating the cellular internalization of SARS-CoV-2. Given the complex interactions between ATIII and SDC4, our study analyzed the impact of ATIII on the virus entry into host cells. While ATIII binds to all SDC isoforms, it shows the strongest affinity for SDC4. SDCs’ heparan sulfate chains primarily influence ATIII’s SDC attachment, although other parts might also play a role in ATIII’s dominant affinity toward SDC4. ATIII significantly reduces SARS-CoV-2′s cellular entry into cell lines expressing SDCs, suggesting a competitive inhibition mechanism at the SDC binding sites, particularly SDC4. Conversely, the virus or its spike protein decreases the availability of SDCs on the cell surface, reducing ATIII’s cellular attachment and hence contributing to a procoagulant environment characteristic of COVID-19. Full article

In 2019, the emergence of the seventh known coronavirus to cause severe illness in humans triggered a global effort towards the development of new drugs and vaccines for the SARS-CoV-2 virus. These efforts are still ongoing in 2024, including the present work where we conducted a ligand-based virtual screening of terpenes with potential anti-SARS-CoV-2 activity. We constructed a Quantitative Structure–Activity Relationship (QSAR) model from compounds with known activity against SARS-CoV-2 with a model accuracy of 0.71. We utilized this model to predict the activity of a series of 217 terpenes isolated from the Fabaceae family. Four compounds, predominantly triterpenoids from the lupane series, were subjected to an in vitro phenotypic screening in Vero CCL-81 cells to assess their inhibitory activity against SARS-CoV-2. The compounds which showed high rates of SARS-CoV-2 inhibition along with substantial cell viability underwent molecular docking at the SARS-CoV-2 main protease, papain-like protease, spike protein and RNA-dependent RNA polymerase. Overall, virtual screening through our QSAR model successfully identified compounds with the highest probability of activity, as validated using the in vitro study. This confirms the potential of the identified triterpenoids as promising candidates for anti-SARS-CoV-2 therapeutics. Full article

Background: We aimed to identify the risk factors for impaired cellular and humoral immunity after three doses of the SARS-CoV-2 vaccine. Methods: Six months after the third vaccine dose, T-cell immunity was evaluated using interferon-gamma release assays (IGRAs) in 60 healthy and 139 immunocompromised (IC) individuals, including patients with hematologic malignancy (HM), solid malignancy (SM), rheumatic disease (RD), and kidney transplantation (KT). Neutralizing antibody titers were measured using the plaque reduction neutralization test (PRNT) and surrogate virus neutralization test (sVNT). Results: T-cell immunity results showed that the percentages of IGRA-positive results using wild-type/alpha spike protein (SP) and beta/gamma SP were 85% (51/60) and 75% (45/60), respectively, in healthy individuals and 45.6% (62/136) and 40.4% (55/136), respectively, in IC individuals. IC with SM or KT showed a high percentage of IGRA-negative results. The underlying disease poses a risk for impaired cellular immune response to wild-type SP. The risk was low when all doses were administered as mRNA vaccines. The risk factors for an impaired cellular immune response to beta/gamma SP were underlying disease and monocyte%. In the sVNT using wild-type SP, 12 of 191 (6.3%) individuals tested negative. In the PRNT of 46 random samples, 6 (13%) individuals tested negative for the wild-type virus, and 19 (41.3%) tested negative with omicrons. KT poses a risk for an impaired humoral immune response. Conclusions: Underlying disease poses a risk for impaired cellular immune response after the third dose of the SARS-CoV-2 vaccine; KT poses a risk for impaired humoral immune response, emphasizing the requirement of precautions in patients. Full article

The demand for accurate and efficient immunoassays calls for the development of precise, high-throughput analysis methods. This paper introduces a novel approach utilizing a weak measurement interface sensor for immunoassays, offering a solution for high throughput analysis. Weak measurement is a precise quantum measurement method that amplifies the weak value of a system in the weak interaction through appropriate pre- and post-selection states. To facilitate the simultaneous analysis of multiple samples, we have developed a chip with six flow channels capable of conducting six immunoassays concurrently. We can perform real-time immunoassay to determine the binding characteristics of spike protein and antibody through real-time analysis of the flow channel images and calculating the relative intensity. The proposed method boasts a simple structure, eliminating the need for intricate nano processes. The spike protein concentration and relative intensity curve were fitted using the Log-Log fitting regression equation, and R² was 0.91. Utilizing a pre-transformation approach to account for slight variations in detection sensitivity across different flow channels, the present method achieves an impressive limit of detection(LOD) of 0.85 ng/mL for the SARS-CoV-2 the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, with a system standard deviation of 5.61. Furthermore, this method has been successfully verified for monitoring molecular-specific binding processes and differentiating binding capacities. Full article

Smart Nano-enabled Antiviral Therapeutic (SNAT) is a promising nanodrug that previously demonstrated efficacy in preclinical studies to alleviate SARS-CoV-2 pathology in hamsters. SNAT comprises taxoid (Tx)-decorated amino (NH₂)-functionalized near-atomic size positively charged silver nanoparticles (Tx–[NH₂-AgNPs]). Herein, we aimed to elucidate the molecular mechanism of the viral inhibition and safety of aerosolized SNAT treatment in SARS-CoV-2-infected golden Syrian hamsters. High-resolution transmission electron microscopy (HR-TEM) coupled with energy dispersive spectroscopy (EDS) and ELISAs showed SNAT binds directly to the SARS-CoV-2 virus by interacting with intact spike (S) protein, specifically to S2 subunit. SNAT (≥1 µg/mL) treatment significantly lowered SARS-CoV-2 infections of Calu-3 cells. Extraction-free whole transcriptome assay was used to detect changes in circulatory micronome in hamsters treated intranasally with SNAT (two doses of 10 µg/mL of 2 mL each administered 24 h apart). Uninfected hamsters treated with SNAT had altered circulatory concentrations of 18 microRNAs (8 miRNAs upregulated, 10 downregulated) on day 3 post-treatment compared to uninfected controls. SNAT-induced downregulation of miR-141-3p and miR-200b-3p may reduce viral replication and inflammation by targeting Ythdf2 and Slit2, respectively. Further, SNAT treatment significantly lowered IL-6 expression in infected hamster lungs compared to untreated infected hamsters. Taken together, we demonstrate that SNAT binds directly to SARS-CoV-2 via the S protein to prevent viral entry and propose a model by which SNAT alters the cellular miRNA-directed milieu to promote antiviral cellular processes and neutralize infection. Our results provide insights into the use of low-dose intranasally delivered SNAT in treating SARS-CoV-2 infections in a hamster model. Full article

The appearance of new respiratory virus infections in humans with epidemic or pandemic potential has underscored the urgent need for effective broad-spectrum antivirals (BSAs). Bioactive compounds derived from plants may provide a natural source of new BSA candidates. Here, we investigated the novel phytocomplex formulation SP4™ as a candidate direct-acting BSA against major current human respiratory viruses, including coronaviruses and influenza viruses. SP4™ inhibited the in vitro replication of SARS-CoV-2, hCoV-OC43, hCoV-229E, Influenza A and B viruses, and respiratory syncytial virus in the low-microgram range. Using hCoV-OC43 as a representative respiratory virus, most of the antiviral activity of SP4™ was observed to stem primarily from its dimeric A-type proanthocyanidin (PAC-A) component. Further investigations of the mechanistic mode of action showed SP4™ and its PAC-A-rich fraction to prevent hCoV-OC43 from attaching to target cells and exert virucidal activity. This occurred through their interaction with the spike protein of hCoV-OC43 and SARS-CoV-2, thereby interfering with spike functions and leading to the loss of virion infectivity. Overall, these findings support the further development of SP4™ as a candidate BSA of a natural origin for the prevention of human respiratory virus infections. Full article

Genomic surveillance based on sequencing the entire genetic code of SARS-CoV-2 involves monitoring and studying genetic changes and variations in disease-causing organisms such as viruses and bacteria. By tracing the virus, it is possible to prevent epidemic spread in the community, ensuring a ‘precision public health’ strategy. A peptide-based design was applied to provide an efficacious strategy that is able to counteract any emerging viral variant of concern dynamically and promptly to affect the outcomes of a pandemic at an early stage while waiting for the production of the anti-variant-specific vaccine, which require longer times. The inhibition of the interaction between the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and one of the cellular receptors (DPP4) that its receptors routinely bind to infect human cells is an intriguing therapeutic approach to prevent the virus from entering human cells. Among the other modalities developed for this purpose, peptides surely offer unique advantages, including ease of synthesis, serum stability, low immunogenicity and toxicity, and small production and distribution chain costs. Here, we obtained a potent new inhibitor based on the rearrangement of a previously identified peptide that has been rationally designed on a cell dipeptidyl peptidase 4 (DPP4) sequence, a ubiquitous membrane protein known to bind the RBD-SPIKE domain of the virus. This novel peptide (named DPP4-derived), conceived as an endogenous “drug”, is capable of targeting the latest tested variants with a high affinity, reducing the VSV* DG-Fluc pseudovirus Omicron’s infection capacity by up to 14%, as revealed by in vitro testing in human Calu-3 cells. Surface plasmon resonance (SPR) confirmed the binding affinity of the new DPP4-derived peptide with Omicron variant RBD. Full article