This study investigated the role of protein disulphide isomerase A4 (PDIA4) in the pathogenesis of coronavirus disease 2019 (COVID-19), focusing on its relationship with disease severity and potential as a biomarker. We analysed a cohort of adult COVID-19 patients with varying disease severity, grouped by vaccination status. Serum levels of PDIA4 and cytokines (interleukin [IL]-6, interferon gamma inducible protein-10 [IP-10], IL-16, monocyte chemoattractant protein-1 [MCP-1], and platelet-derived growth factor-BB [PDGF-BB]) were measured using enzyme-linked immunosorbent assay and compared among patients with different disease severities. Statistical analyses were performed to assess the correlation between PDIA4 levels, disease severity, and inflammatory markers. Unvaccinated COVID-19 patients with pneumonia had significantly higher PDIA4 levels than those without pneumonia (517.94 ± 264 vs. 284.86 ± 2.24; p = 0.0022). Although unvaccinated patients requiring oxygen support exhibited higher PDIA4 levels than those not requiring oxygen (519.30 ± 269.67 vs. 420.89 ± 240.49; p = 0.4825), the difference was not statistically significant. No significant difference was observed in the PDIA4 levels between unvaccinated patients with and without respiratory failure. Levels of PDIA4 were positively correlated with the levels of IL-16, MCP-1, IP-10, and IL-6 (correlation coefficients: 0.28-0.62), although this correlation was weaker or absent in vaccinated patients. Our findings suggest that PDIA4 is associated with COVID-19 severity and may serve as a potential biomarker of disease progression. Further studies are needed to elucidate the mechanisms by which PDIA4 influences the immune response and assess its potential for therapeutic exploration in COVID-19.

The COVID-19 pandemic has posed significant challenges to global health, with type 2 diabetes mellitus (T2DM) emerging as a key risk factor for adverse outcomes. This study systematically reviews and quantifies the association between T2DM and COVID-19 outcomes, including mortality, severity, and need for mechanical ventilation.

A systematic review and meta-analysis were conducted that adhered to PRISMA guidelines. We searched PubMed, Scopus, Web of Science and Embase for studies published from december 2019 to march 2024. Eligible studies reported on the impact of T2DM on COVID-19 outcomes in the adult population. Data were extracted and analyzed using a random-effects model, and heterogeneity was assessed using the I2 statistic. Publication bias was assessed using Egger regression, Kendall's Tau, and the Fail-safe N calculation.

Eighteen studies were included in the meta-analysis for mortality, six for severity and five for mechanical ventilation. T2DM was significantly associated with higher mortality (OR = 3.66, 95% CI: 2.20-5.11, p < 0.001), higher severity (OR = 1.97, 95% CI: 1.02-2.92, p < 0.001), and higher need for mechanical ventilation (OR = 2.34, 95% CI: 1.18-3.49, p < 0.001). Heterogeneity was high for mortality (I2 = 83.83%) but low for severity and mechanical ventilation (I2 = 0%). No significant publication bias was found.

T2DM is associated with significantly worse outcomes in COVID-19 patients, including higher mortality, higher severity and a greater likelihood of needing mechanical ventilation. These findings emphasize the need for targeted interventions and management strategies for individuals with T2DM during the ongoing pandemic. Future research should focus on understanding the underlying mechanisms and exploring strategies to mitigate these risks.

Although much is known about the pathophysiology of severe COVID-19, there are still areas that remain to be determined. It is well established that the pivotal molecular event is a hyperinflammatory response also referred to as a cytokine storm. The aim of this retrospective cohort study was to determine miRNAs which might be predictive for the admission to the intensive care unit (ICU). We analyzed blood samples from 210 COVID-19 patients and the control group consisted of 80 healthy individuals. Results revealed the miRNA expression pattern has the potential to predict the severity of COVID-19, reflecting the clinical symptoms of the infection, such as the need for oxygen therapy and concomitant pneumonia. In particular, low expression of miRNAs miR106a-5p, miR17-5p, miR181a-5p, miR191-5p, miR20a-5p and miR451a, especially in the initial phase of the disease, is associated with an unfavorable clinical course of SARS-CoV-2 infection (admission to the ICU).

Many questions remain unanswered regarding the implication of genetics and lipid metabolites with severe SARS-CoV-2 infections. We performed bulk RNA-seq and a total fatty acid panel analysis on PBMCs and plasma collected from 10 infected and 10 uninfected patients. Univariate comparison of lipid metabolites using the Mann-Whitney U-test revealed that six lipid metabolites were significantly increased in COVID-19 patients, including the lipid mediators arachidonic acid (AA) and eicosapentaenoic acid (EPA), which both give rise to eicosanoids. Key lipids implicated in inflammation, including AA and EPA, along with the fatty acids DHA and DPA, were significantly and positively correlated to the WHO disease severity score. Analysis of our bulk RNA-seq dataset demonstrated distinct transcriptional profiles leading to a segregation of COVID-19 patients based on the WHO score. Ontology, KEGG, and Reactome analysis identified several key pathways and nodes that were enriched for genes related to innate immunity, interactions between lymphoid and nonlymphoid cells, interleukin signaling, and subsequent DNA damage pathways. EPA levels correlated with heightened cell cycling and DNA damage pathways observed in patients with a high WHO score. We studied gene expression in nasopharyngeal swabs from 58 healthy and COVID-19 participants and identified that genes implicated in eicosanoid synthesis, such as alox5, alox12, and alox15B, were specifically up-regulated in high WHO score patients in several cell types of the nasopharynx, especially goblet cells across different viral variants (Deta and Omicron). Using published nasal scRNA-seq datasets from COVID-19 patients, we evaluated the expression of genes implicated in eicosanoid synthesis, such as ALOX5, ALOX15, and ALOX15B, across nasal cell types and COVID-19 severity groups. Altogether, our study highlights the fact that the increase in specific lipids implicated in inflammation and the genes required for their synthesis correlated with the severity of the SARS-CoV-2 infection.

The immune system employs innate and adaptive immunity to combat pathogens and stress stimuli. Innate immunity rapidly detects pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) via pattern recognition receptors (PRRs), whereas adaptive immunity mediates antigen-specific T/B cell responses. The NLRP3 inflammasome, a key cytoplasmic PRR, consists of leucine-rich repeat, nucleotide-binding, and pyrin domains. Its activation requires priming (signal 1: Toll-like receptors/NOD-like receptors/cytokine receptors) and activation (signal 2: PAMPs/DAMPs/particulates). NLRP3 triggers cytokine storms and neuroinflammation, contributing to inflammatory diseases. Emerging therapies target NLRP3 via nuclear receptors (transcriptional regulation), adeno-associated virus (AAV) vectors (gene delivery), and microRNAs (post-transcriptional modulation). This review highlights NLRP3's signaling cascade, pathological roles, and combinatorial treatments leveraging nuclear receptors, AAVs, and microRNAs for immunomodulation.

Ras homolog gene family-guanosine triphosphatases (Rho-GTPases), key molecular switches regulating cytoskeletal dynamics and cellular signaling, play a pivotal role in viral infections by modulating critical processes such as viral entry, replication, and release. This review elucidates the intricate mechanisms through which Rho-GTPases, via interactions with guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and other signaling pathways, including the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), rat sarcoma (Ras), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, facilitate viral pathogenesis. Specific viruses, such as influenza A virus (IAV), herpesviruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV), exploit Rho-GTPase-mediated cytoskeletal reorganization to enhance infectivity. For example, Rho-GTPases promote actin remodeling and membrane fusion, which are essential for viral entry and intracellular transport. Furthermore, Rho-GTPases modulate immune responses, often suppressing antiviral defenses to favor viral replication. Despite these insights, the molecular mechanisms underlying Rho-GTPase regulation during viral infections remain incompletely understood. Future research should focus on delineating the precise roles of Rho-GTPases in distinct viral life cycles, uncovering novel regulatory mechanisms, and developing targeted antiviral therapies that selectively inhibit Rho-GTPase signaling without compromising host cell functions. Such advancements could pave the way for broad-spectrum antiviral strategies, particularly against viruses that heavily rely on cytoskeletal manipulation for infection.

Porcine reproductive and respiratory syndrome virus (PRRSV) infects pulmonary alveolar macrophages and induces inflammation in the respiratory system. In swine farms, coinfection with PRRSV and bacterial pathogens is common and can result in clinically complicated outcomes, including porcine respiratory disease complex. Coinfection can cause excessive expressions of proinflammatory mediators and may lead to cytokine-storm-like syndrome. An immunological hallmark of PRRSV-2 is the bidirectional regulation of NF-κB with the nucleocapsid (N) protein identified as the NF-κB activator. We generated an NF-κB-silencing mutant PRRSV-2 by mutating the N gene to block its binding to PIAS1 [protein inhibitor of activated STAT-1 (signal transducer and activator of transcription 1)]. PIAS1 functions as an NF-κB repressor, and thus, the PIAS1-binding modified N-mutant PRRSV-2 became NF-κB activation-resistant in its phenotype. During coinfection of pigs with PRRSV-2 and Streptococcus suis, the N-mutant PRRSV-2 decreased the expression of proinflammatory cytokines and showed clinical attenuation. This review describes the coinfection of pigs with various pathogens, the generation of mutant PRRSV for NF-κB suppression, inflammatory profiles during bacterial coinfection, and the potential application of these findings to designing a new vaccine candidate for PRRSV-2.

Background: Current therapies for severe COVID-19, such as steroids and immunomodulators are associated with various side effects. N-acetylcysteine (NAC) has emerged as a potential adjunctive therapy with minimal side effects for patients with cytokine storm due to COVID-19. However, evidence supporting high-dose intravenous NAC in severe COVID-19 pneumonia requiring mechanical ventilation is limited. Methods: We conducted a retrospective analysis of consecutive patients aged ≥ 18 who were admitted for acute respiratory failure (PaO2/FiO2 ratio <300) with SARS-CoV-2 infection to the Intensive Care Unit (ICU) of Queen Elizabeth Hospital from fifth July 2020 to 31st October 2022. Inclusion was limited to patients who required mechanical ventilation. High-dose NAC refers to a dosage of 10 g per day. The primary outcome was all-cause mortality within 28 days. Propensity-score matched analysis using logistic regression was performed. Results: Among the 136 patients analyzed, 42 (40.3%) patients received NAC. The unmatched NAC patients displayed a higher day-28 mortality (12 (28.6%) versus 4 (6.5%), p = 0.005) and fewer ventilator-free days (18.5 (0-23.0) versus 22.0 (18.3-24.0), p = 0.015). No significant differences were observed in ICU and hospital length of stays among survivors. In patients who were not treated with tocilizumab, those receiving NAC exhibited a trend toward a quicker reduction in C-reactive protein compared to those who did not receive NAC.After propensity score matching which included 64 patients with 33 (51.6%) receiving NAC, no significant differences were found in 28-day mortality, ventilator-free days, or ICU and hospital length of stay. After adjusting for potential confounders, logistic regression of the propensity score-matched population did not demonstrate that the use of NAC independently affected 28-day mortality. Conclusions: In patients with COVID-19 pneumonia requiring mechanical ventilation and receiving standard COVID-19 treatment, the addition of high-dose NAC did not lead to improved clinical outcomes.

The people living with HIV with abnormal immune responses have been identified as a population that is particularly susceptibility to contracting COVID-19. We explored the correlation between gene polymorphisms of IL-17A, IL-17F, and IL-6, and the susceptibility to COVID-19 in individuals with HIV infection.

In this cross-sectional study, 337 HIV-positive patients were included. Serological and molecular tests were done using ELISA and PCR-RFLP methods. Allelic frequency, haplotype analyses, linkage disequilibrium were calculated. A linear regression model was used to analyze the interleukin SNP genotypes in HIV patients with and without COVID-19.

A total of 337 PLWH were recruited for this study, with 170 having COVID-19 and 167 not having it. The mean age and laboratory indicators showed no significant differences between the two groups (P > 0.05). The allele frequency analysis found no significant difference in the IL-17A rs2275913 polymorphism between case and control groups. However, the IL-17F rs763780 and IL-6 rs1800795 had significantly greater frequencies of specific alleles in the case group compared to the control group. The A-A haplotype of IL-17 in SNPs-rs 2,275,913 and rs763780 rising the risk of COVID-19 infection in PLWH by up to 2.398 times compared with the other haplotypes, and the A-G and G-A haplotypes have a protective role against the incidence of COVID-19 infection.

This study is the first to show a significant correlation between the prevalence of COVID-19 and variety polymorphism at IL-17 and IL-6, which suggests that genetic changes in interleukin genes may relate to COVID-19 distribution.

Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using 18F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.

We report that the recombinantly produced galectin-3 (Gal-3) not only reduces the infectivity of a pseudotyped lentivirus expressing SARS-CoV2-S protein i.e., LV(CoV2-S) in the susceptible cells but also dampens the inflammatory response of innate immune cells. Glycan moieties of the CoV2-S protein promote cellular infectivity of LV(CoV2-S). Exogenously added Gal-3, acting via its carbohydrate recognition domain (CRD), prevents LV(CoV2-S) infection of the susceptible cells. Accordingly, Gal-3 mediated LV(CoV2-S) neutralization is inhibited when Gal-3 is pre-incubated with either α-lactose or a single domain antibody specific to the CRD of Gal-3. BMDCs from Gal-3KO as compared to those from WT mice generate significantly higher cytokine response and the exogenously added Gal-3 reduces cytokine levels following stimulation with the derivates of CoV2-S protein. Therefore, modifying the interaction of Gal-3 and glycans of the viral CoV2-S protein might represent a strategy that reduces the infectivity of SARS-CoV2 and mitigates immunopathology caused by the virus infection.

Given the recurrent waves of COVID-19 and the emergence of new viral infections, optimizing the potential of remdesivir as an antiviral agent is critical. While several reviews have explored the efficacy of remdesivir, few have comprehensively addressed its challenges, such as the necessity for intravenous infusion, suboptimal lung accumulation, and safety concerns related to its formulation. This review critically examines these challenges while proposing innovative solutions and effective combinations with other antiviral agents and repurposed drugs. By highlighting the role of complex generics, we aim to enhance therapeutic efficacy in ways not previously discussed in existing literature. Furthermore, we address the development of novel drug delivery systems which specifically aim to improve remdesivir's pharmacological profile. By analyzing recent findings, we assess both the successes and limitations of current approaches, providing insights into ongoing challenges and strategies for further optimization. This review uniquely focuses on targeted drug delivery systems and innovative formulations, thereby maximizing remdesivir's therapeutic benefits and broadening its application in combating emerging viral threats. In doing so, we fill a critical gap in literature, offering a comprehensive overview that informs future research and clinical strategies.

The BBB is created by a special system of brain microvascular endothelial cells (BMECs), pericytes (PCs), the capillary basement membrane, and the terminal branches ("end-feet") of astrocytes (ACs). The key function of the BBB is to protect the central nervous system (CNS) from potentially harmful/toxic substances in the bloodstream by selectively controlling the entry of cells and molecules, including nutrients and components of the immune system. The loss of BBB integrity in response to neuroinflammation, as manifested by an increase in permeability, depends predominantly on the activity of proinflammatory cytokines. However, the pathomechanism of structural and functional changes in the BBB under the influence of individual cytokines is still poorly understood. This review summarizes the current state of knowledge on this topic, which is important from both pathophysiological and therapeutic points of view. The structures and functions of all components of the BBB are reviewed, with emphasis given to differences between this and other locations of the circulatory system. The protein composition of the interendothelial tight junctions in the context of regulating BBB permeability is presented, as is the role of pericyte-BMEC interactions in the exchange of metabolites, ions, and nucleic acids. Finally, the documented actions of proinflammatory cytokines within the BBB are discussed.

Spores of the bacterium Bacillus subtilis (B. subtilis) have been shown to carry a number of properties potentially beneficial for vaccination. Firstly, as vehicles enabling mucosal delivery of heterologous antigens and secondly, as stimulators of innate immunity. Here, we have examined the specificity of protection conferred by the spore-induced innate response, focusing on influenza H1N1, respiratory syncytial virus (RSV), and coronavirus-2 (SARS-CoV-2) infections.

In vivo viral challenge murine models were used to assess the prophylactic anti-viral effects of B. subtilis spores delivered by intranasal instilling, using an optimised three-dose regimen. Multiple nasal boosting doses following intramuscular priming with SARS-CoV-2 spike protein was also tested for the capability of spores on enhancing the efficacy of parenteral vaccination. To determine the impact of spores on immune cell trafficking to lungs, we used intravascular staining to characterise cellular participants in spore-dosed pulmonary compartments (airway and lung parenchyma) before and after viral challenge.

We found that mice pre-treated with spores developed resistance to all three pathogens and, in each case, exhibited a significant improvement in both survival rate and disease severity. Intranasal spore dosing expanded alveolar macrophages and induced recruitment of leukocyte populations, providing a cellular mechanism for the protection. Most importantly, virus-induced inflammatory leukocyte infiltration was attenuated in spore-treated lungs, which may alleviate the associated collateral tissue damage that leads to the development of severe conditions. Remarkably, spores were able to promote the induction of tissue-resident memory T cells, and, when administered following an intramuscular prime with SARS-CoV-2 spike protein, increased the levels of anti-spike IgA and IgG in the lung and serum.

Taken together, our results show that Bacillus spores are able to regulate both innate and adaptive immunity, providing heterologous protection against a variety of important respiratory viruses of high global disease burden.

The antibody-mediated immune response is crucial for the development of protective immunity against SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Understanding the interaction between SARS-CoV-2 and the immune system is critical because new variants emerge as a result of the virus's ongoing evolution. Understanding the function of B cells in the SARS-CoV-2 infection process is critical for developing effective and long-lasting vaccines against this virus. Triggered by the innate immune response, B cells transform into memory B cells (MBCs). It is fascinating to observe how MBCs provide enduring immune defence, not only eradicating the infection but also safeguarding against future reinfection. If there is a lack of B cell activation or if the B cells are not functioning properly, it can lead to a serious manifestation of the disease and make immunisation less effective. Individuals with disruptions in the B cells have shown increased production of cytokines and chemokines, resulting in a poor prognosis for the disease. Therefore, we have developed an updated review article to gain insight into the involvement of B cells in SARS-CoV-2 infection. The discussion has covered the generation, functioning, and dynamics of neutralising antibodies (nAbs). Furthermore, we have emphasised immunotherapeutics that rely on nAbs.

Hyperinflammation is a significant factor in long COVID, impacting over 65 million post-COVID-19 individuals globally. Herbal remedies, including propolis, show promise in reducing severity and pro-inflammatory cytokines. However, the natural pharmacological role of propolis in COVID-19 management remains underexplored. Employing network pharmacology and in silico techniques, we assessed propolis extract's potential in countering SARS-CoV-2-induced inflammation. We identified 80 flavonoids via LC-MS/MS QTOF and employed 11 anti-inflammatory drugs as references for inflammation target fishing. Utilizing in silico techniques encompassing target fishing, molecular docking, and dynamics, we examined propolis' effects. We identified 1105 gene targets connected to inflammation through multiple validated target predictors. By integrating SARS-CoV-2 DEGs from GSE147507 with these targets, we identify 25 inflammation-COVID-19-associated propolis targets, including STAT1, NOS2, CFB, EIF2K2, NPY5R, and BTK. Enrichment analyses highlighted primary pharmacological pathways related to Epstein-Barr virus infection and COVID-19. Molecular docking validated isokaempferide, iristectorigenin B, 3'-methoxypuerarin, cosmosiin, and baicalein-7-O-β-d-glucopyranoside, which exhibited strong binding affinity and stability with relevant genes. Moreover, our findings indicate that propolis ligands could potentially suppress reactivation of Epstein-Barr Virus infections in post-COVID-19 cases. However, this study has a limitation in that the concentration of each propolis compound has not been quantified. Therefore, further exploration of propolis compounds quantification and experimental validation are needed to support these findings.

Papaverine (PV) has been previously identified as a promising candidate in SARS-CoV-2 repurposing screens. In this study, we further investigated both its antiviral and immunomodulatory properties. PV displayed antiviral efficacy against SARS-CoV-2 and influenza A viruses H1N1 and H5N1 in single infection as well as in co-infection. We demonstrated PV's activity against various SARS-CoV-2 variants and identified its action at the post-entry stage of the viral life cycle. Notably, treatment of air-liquid interface (ALI) cultures of primary bronchial epithelial cells with PV significantly inhibited SARS-CoV-2 levels. Additionally, PV was found to attenuate interferon (IFN) signaling independently of viral infection. Mechanistically, PV decreased the activation of the IFN-stimulated response element following stimulation with all three IFN types by suppressing STAT1 and STAT2 phosphorylation and nuclear translocation. Furthermore, the combination of PV with approved COVID-19 therapeutics molnupiravir and remdesivir demonstrated synergistic effects. Given its immunomodulatory effects and clinical availability, PV shows promising potential as a component for combination therapy against COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in high mortality among hospitalized patients; thus, identifying mortality markers in treating these patients is essential. To evaluate the association between viral load and serum biomarkers with mortality among hospitalized patients with COVID-19.

A retrospective cohort study was conducted among 198 inpatient records from a tertiary hospital in Mexico City between January and April 2021. The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and serum biomarkers with death due to COVID-19 was assessed using Cox regression models.

The median age was 54.9 years, and 61.6% were males. The mortality rate was 43.4%. After adjusting for potential confounders, patients with higher viral load [adjusted hazard ratio (aHR) = 1.56; 95% confidence interval (95% CI) = 1.01, 2.42; P value = 0.041]; and higher concentrations of BUN (aHR = 4.87;95% CI = 2.70, 8.79; P value = 0.001), creatinine (aHR = 1.60;95% CI = 1.01, 2.54; P value = 0.043), osmolality (aHR = 4.37;95% CI = 2.34, 8.14; P value = 0.001), and glucose (aHR = 2.41;95% CI = 1.40, 4.18; P value = 0.001) were more likely to have a fatal prognosis. Conversely, mortality risk was lower among patients with high concentrations of lymphocytes (aHR = 0.47;95% CI = 0.30, 0.72; P value = 0.001).

SARS-CoV-2 viral load and serum biomarkers such as BUN, creatinine, glucose, osmolarity, and lymphocytes could help physicians identify individuals who require closer monitoring.

The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial type 2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that IGFBP2 mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of Igfbp2 significantly reduced mRNA expression of proinflammatory cytokines-Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors-Ccr2 and Ccr5-in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500 ng/mL). Finally, we demonstrated higher levels of cytokines-TNF-α; IL-6 and chemokine receptor-CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19.

Our research is driven by the need to design an advanced multi-epitope vaccine construct (MEVC) using the S-protein of SARS-CoV-2 to combat the emergence of new variants. Through rigorous computational screening, we have identified linear and discontinuous B-cell epitopes, CD8 + and CD4 + T-cell epitopes, ensuring extensive MEVC coverage across 90.03% of the global population. The MEVC, featuring four CD4 + and four CD8 + T-cell epitopes connected linearly with two adjuvant proteins on both ends, has been carefully designed to elicit robust immune response. Our in-silico analysis has confirmed the construct's antigenicity, non-allergenicity, and non-toxicity with optimized codon sequences for enhanced expression in E. coli K12. Furthermore, molecular docking and dynamics analyses have demonstrated its strong binding affinity with TLR-3 and TLR 4, and in-silico immune simulation yielded promising results on heightened B-cell and T-cell-mediated immunity. However, wet lab experiments are essential to validate computational findings to revolutionize the development of vaccines against SARS-CoV-2.

Much remains to be understood about COVID-19, but the protective role of antibodies (Igs) is widely accepted in SARS-CoV-2 infection. Igs' functions are mainly carried out by receptors that bind to their Fc portion (FcR), and less attention has been dedicated to the cytoplasmic members of this family. In this work, we used single-cell RNA sequencing (scRNA-seq) data to discern cell populations in bronchoalveolar lavage fluid obtained from healthy individuals and patients with mild or severe COVID-19. Then, we evaluated the transcription of neonatal FcR (FcRn, FCGRT gene) and tripartite motif-containing protein 21 (TRIM21) and its downstream signaling components. The TRIM21 pathway is vital for virus infections as it has a dual function, leading opsonized viruses to degradation by proteasomes and the activation of innate inflammatory anti-virus response. The transcriptional level of FCGRT showed no statistical differences in any cell population comparing the three groups of patients. On the other hand, TRIM21 transcription was significantly higher in myeloid cells collected from patients with mild COVID-19. When comparing mild with severe cases, there was no statistical difference in TRIM21 transcription in lung adaptive lymphoid cells and innate lymphoid cells (ILC). Yet, we analyzed the transcription of all downstream signaling molecules in myeloid and, as most cells expressed the receptor, in adaptive lymphoid cells. Moreover, ILCs from mild cases and all cell populations from severe cases were missing most downstream components of the pathway. We observed that members of the ubiquitin-proteasome system (UPS) and other components associated with TRIM21 proteasomal degradation were transcribed in mild cases. Despite the transcription of the danger sensors DDX58 and IFIH1, the transcriptional level of inflammatory IL1B and IL18 was generally very low, along with the NLRP3 danger sensor, members of the NF-κB pathway, and TNF. Therefore, our data suggest that TRIM21 may contribute to SARS-CoV-2 protection by reducing the viral load, while the inflammatory branch of the pathway would be silenced, leading to no pathogenic cytokine production.

Background: Timely and accurate identification of bloodstream infections (BSIs) in intensive care unit (ICU) patients remains a key challenge, particularly in COVID-19 settings, where immune dysregulation can obscure early clinical signs. Methods: Cytokine profiling was evaluated to discriminate between ICU patients with and without BSIs, and, among those with confirmed BSIs, to further stratify bacterial infections by Gram type. Serum samples from 45 ICU COVID-19 patients were analyzed using a 21-cytokine panel, with feature selection applied to identify candidate markers. Results: A machine learning workflow identified key features, achieving robust performance metrics with AUC values up to 0.97 for BSI classification and 0.98 for Gram typing. Conclusions: In contrast to traditional approaches that focus on individual cytokines or simple ratios, the present analysis employed programmatically generated ratios between pro-inflammatory and anti-inflammatory cytokines, refined through feature selection. Although further validation in larger and more diverse cohorts is warranted, these findings underscore the potential of advanced cytokine-based diagnostics to enhance precision medicine in infection management.

COVID-19, caused by SARS-CoV-2, has become a global public health threat. Although no replication-competent virus has been found in breast milk samples, breastfeeding practices during the pandemic were impacted. It is well known that breast milk is adapted to meet the needs of infants, providing the appropriate amounts of nutrients and various bioactive compounds that contribute to the maturation of the immune system and antioxidant protection, safeguarding infants against diseases. While its composition is variable, breast milk contains immune cells, antibodies, and cytokines, which have anti-inflammatory, pro-inflammatory, antiviral, and antibacterial properties that strengthen infant immunity. Since COVID-19 vaccines have not yet been approved for infants under six months of age, newborns rely on the passive transfer of antibodies via the placenta and breast milk to protect them against severe SARS-CoV-2 infection. Several studies that analyzed breast milk samples in the context of COVID-19 have demonstrated that a strong antibody response is induced following maternal infection with SARS-CoV-2. Therefore, this review aims to provide a comprehensive overview of the impact of maternal exposure to SARS-CoV-2 through natural infection and/or vaccination on the immunological composition of breast milk based on the studies conducted on this topic.

Pulmonary homeostasis can be agitated either by external environmental insults or endogenous factors produced during respiratory/pulmonary diseases. The lungs counter these insults by initiating mechanisms of inflammation as a localized, non-specific first-line defense response. Cytokines are small signaling glycoprotein molecules that control the immune response. They are formed by numerous categories of cell types and induce the movement, growth, differentiation, and death of cells. During respiratory diseases, multiple proinflammatory cytokines play a crucial role in orchestrating chronic inflammation and structural changes in the respiratory tract by recruiting inflammatory cells and maintaining the release of growth factors to maintain inflammation. The issue aggravates when the inflammatory response is exaggerated and/or cytokine production becomes dysregulated. In such instances, unresolving and chronic inflammatory reactions and cytokine production accelerate airway remodeling and maladaptive outcomes. Pro-inflammatory cytokines generate these deleterious consequences through interactions with receptors, which in turn initiate a signal in the cell, triggering a response. The cytokine profile and inflammatory cascade seen in different pulmonary diseases vary and have become fundamental targets for advancement in new therapeutic strategies for lung diseases. There are considerable therapeutic approaches that target cytokine-mediated inflammation in pulmonary diseases; however, blocking specific cytokines may not contribute to clinical benefit. Alternatively, broad-spectrum anti-inflammatory approaches are more likely to be clinically effective. Herein, this comprehensive review of the literature identifies various cytokines (e.g., interleukins, chemokines, and growth factors) involved in pulmonary inflammation and the pathogenesis of respiratory diseases (e.g., asthma, chronic obstructive pulmonary, lung cancer, pneumonia, and pulmonary fibrosis) and investigates targeted therapeutic treatment approaches.

Considering the potential antiviral and immunomodulatory properties of imatinib, this drug has been investigated in several studies as a potential treatment option for severe cases of COVID-19, given that treatment modalities available remain limited.

To evaluate the benefits or otherwise of imatinib for COVID-19 in severely ill patients, we performed a systematic review of studies that tested the efficacy and the safety of imatinib for COVID-19 and executed a meta-analysis.

We searched Medline, Embase and Cochrane with the following search terms: 'coronavirus', 'SARS-Cov2', 'covid', 'covid-19' and 'imatinib'. The latest search date was November 2023. We used Cochrane Collaboration's tool to assess bias in randomized trials.

We included three randomized controlled trials with 561 participants. A total of 276 patients received imatinib and 285 received placebo. The mortality results showed no statistically significant differences between imatinib and controls (RR 0.61; 95% CI 0.37 to 1.01; p=0.06). There was no significant difference in length of hospital stay or severe adverse events occurring between groups.

Current evidence suggests that the potential benefits of imatinib should be further evaluated in randomized controlled trials in patients hospitalized for COVID-19.

Particulate matter 2.5 (PM2.5) pollution and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are the greatest environmental health issues worldwide. Several statistics revealed the significant positive correlation between the morbidity of coronavirus disease-19 (COVID-19) and the levels of air pollution. Nevertheless, there is no direct experimental evidence to indicate the effect of PM2.5 exposure on SARS-CoV-2 infection. The objective of this study was to evaluate whether the infection of SARS-CoV-2 affected by PM2.5 through angiotensin-converting enzyme II (ACE2) expression enhances and investigate the function of ACE2 in lung injury induced by PM2.5. An animal model of PM2.5-induced lung injury was established using wild-type (WT, C57BL/6), human ACE2 transgenic (K18-hACE2 TG), and murine ACE2 gene knockout (mACE2 KO) mice. The results indicate that PM2.5 exposure facilitates SARS-CoV-2 infection through inducing ACE2 expression in vitro (10 μg/mL) and in vivo (6.25 mg/kg/day in 50 μL saline). The levels of ACE, inflammatory cytokines, and mitogen-activated protein kinase (MAPK) proteins in WT, K18-hACE TG and mACE2 KO mice were significantly increased after PM2.5 instillation. The severest PM2.5-induced lung damage was observed in mACE2 KO mice. In summary, ACE2 plays a double-edged sword role in lung injury, PM2.5 exposure contributed to SARS-CoV-2 infection through inducing ACE2 expression, but ACE2 also protected pulmonary inflammation from PM2.5 challenge.

COVID-19 appears to have a progression of three stages. The latter stage is characterized by a high level of cytokine release, which in turn triggers an uncontrolled reaction known as cytokine storm where mast cells are involved. The presence of anti-IgE antibodies against SARS-CoV-2 in this phase has been previously reported, suggesting an association with the severity of the disease. Our study aims to assess the prognostic significance of IgE antibodies against SARS-CoV-2 across a spectrum of clinical presentations, including individual with mild symptoms, hospitalized patients, and those who presented a critical progression.

The study included 64 patients distributed into the following groups: 22 critically ill hospitalized individuals (Critical); 21 non-critical hospitalized patients (Severe); 21 mild symptomatic non-hospitalized cases (Mild); and 22 healthy blood donors with samples collected in October 2019. Anti-IgE antibodies against Spike (S) protein were detected using a homemade ELISA, where the plate was sensitized with the RBD of recombinant S protein.

Among 64 SARS-CoV-2 infected patients, 28.1% tested positive for IgE isotype antibodies against S protein RBD, whose prevalence was similar across severity groups: Mild 23.8%, Severe 28.6%, and Critical 31.8% (p = 0.842). Patients with IgE response exhibited higher levels of LDH compared to non-IgE responders, with a 40% increase (p = 0.037), and a non-significantly higher tendency in other inflammatory markers.

In SARS-CoV-2 infection, roughly a fourth of patients presented an IgE isotype response, regardless of disease severity, which is associated with higher levels of LDH.

An excessively reactive immune system results in the cytokine storm COVID-19. A healthy diet is essential to maintain the balance between the immune system and inflammatory and oxidative stress. Associations between single foods and nutrients and COVID-19 have been examined. However, no prior study has examined associations between nutrient patterns and COVID-19. This study assessed the link between nutrient patterns and the COVID-19 severity and length of hospital stay in Iranian adults.

This cross-sectional study included 107 Iranian adults aged 20-60 years, who were admitted to Amir Alam Hospital in Tehran, Iran, due to COVID-19. Data on their symptoms were collected through a demographic questionnaire and verified against their hospital records. Three non-consecutive 24-h dietary recalls were used to collect participants' food and beverage intake. Principal component analysis (PCA) was used to derive nutrient patterns.

A total of 95 Covid patients with a mean age of 46.2 years were included. Four major dietary patterns were identified using the Scree Plot chart, including high carbohydrate and high minerals pattern; high protein and high vitamins pattern; high fat pattern; and poor nutrient pattern. Adherence to the poor nutrient patterns was associated with a higher number of hospitalization days and lower appetite (p < 0.05). The poor dietary patterns were associated with an increased likelihood of headache, fever, and respiratory distress syndrome (RDS). Also, headaches were more common with adherence to the high-fat pattern (p < 0.05).

The findings of this study show that a poor nutrient pattern is related to longer hospital stays and reduced appetite. It also connected to an increased likelihood of symptoms including headaches, fever, and respiratory distress syndrome. A strong association was found between respiratory distress syndrome, headaches, and a high-fat diet was found. Further studies with prospective designs are needed to better understand and validate these findings.

This study aimed to determine the maximum daily insulin dose (MDI) and associated factors in critically ill patients with coronavirus disease 2019 (COVID-19) receiving insulin therapy, under ventilator and/or extracorporeal membrane oxygenation (ECMO) management.

This cross-sectional analysis used the Cross ICU Searchable Information System data from a Japanese multicenter retrospective observational cohort study of critically ill patients with COVID-19 receiving ventilation and/or ECMO, from February 2020 to March 2022. Maximum daily insulin dose was determined, and factors associated with it and maximum daily insulin dose per body weight were assessed using linear regression analysis.

The analysis included 788 patients. Their mean age, glycated hemoglobin level, maximum daily insulin dose, and time from admission to the maximum daily insulin dose were 65.2 ± 13.0 years, 7.0 ± 1.5% (53.0 ± 7.1 mmol/mol), 46.0 ± 43.6 U/day, and 7.3 ± 7.0 days, respectively. Male sex (β = 6.902, P = 0.034), body mass index (β = 1.020, P = 0.001), glycated hemoglobin (β = 12.272, P < 0.001), and having renal failure (β = 20.637, P = 0.003) were independent determinants of maximum daily insulin dose. Age (β = 0.004, P = 0.035), glycated hemoglobin (β = 0.154, P < 0.001), and having renal failure (β = 0.282, P = 0.004) were independent determinants of maximum daily insulin dose per body weight.

In patients with COVID-19 on ventilator and/or ECMO management, the maximum daily insulin dose reached after about 1 week of hospitalization was approximately 46.0 U/day. Glycated hemoglobin and renal failure were both associated with the maximum daily insulin dose and maximum daily insulin dose per body weight.

Understanding the immunopathogenesis of COVID-19 has yielded valuable insights into predicting adverse outcomes-particularly mortality. However, significant gaps persist in our comprehension of the complex interplay among the proposed pathophysiological mechanisms. Here, we aim to investigate the immunological factors associated with mortality in critically ill, unvaccinated COVID-19 patients admitted to the intensive care unit (ICU).

We conducted a single-center, prospective study involving 56 unvaccinated COVID-19 patients admitted to the ICU. Plasma cytokine levels at admission were quantified using enzyme-linked immunosorbent assay (ELISA). Continuous variables were presented as median (IQR), and categorical variables as frequencies and percentages. Non-parametric tests assessed group differences. Logistic regression and receiver operating characteristic (ROC) curve analyses identified predictors of mortality, with bootstrapping (1000 re-samplings; 95 % BCa CI) applied for model validation.

Deceased patients exhibited significantly higher levels of interleukin (IL)-1β, IL-2, IL-6, transforming growth factor (TGF)-β, and interferon (IFN)-γ compared to survivors. Conversely, IL-10 and IL-27 were associated with favorable outcomes. Logistic regression modeling identified elevated IL-2 and IFN-γ levels as significant predictors of mortality. Notably, individual ROC curve analyses demonstrated that IL-1β and TGF-β had excellent discriminatory ability for mortality, while IFN-γ, IL-2, and IL-27 showed very good to excellent discriminatory capacity.

Our results indicate that distinct cytokine profiles differentiate survivors from non-survivors in critically ill, unvaccinated COVID-19 patients. These findings highlight the importance of cytokine dysregulation in severe COVID-19 cases and suggest potential targets for prognostic approaches. Further research is warranted to validate these results and translate them into effective clinical management strategies.

COVID-19 exhibits not only respiratory symptoms but also neurological/psychiatric symptoms rarely including delirium/psychosis. Pathological studies on COVID-19 provide evidence that the cytokine storm, in particular (epidermal growth factor) EGF receptor (EGFR, ErbB1, Her1) activation, plays a central role in the progression of viral replication and lung fibrosis. Of note, SARS-CoV-2 virus (specifically, S1 spike domain) mimics EGF and directly transactivates EGFR, preceding the inflammatory process. In agreement, the anticancer drugs targeting EGFR such as Nimotuzumab and tyrosine kinase inhibitors are markedly effective on COVID-19. However, these data might raise a provisional caution regarding implication of psychiatric disorder such as schizophrenia. The author's group has been investigating the etiologic and neuropathologic associations of EGFR signaling with schizophrenia. There are significant molecular associations between schizophrenia and EGFR ligand levels in blood as well as in the brain. In addition, perinatal challenges of EGFR ligands and intraventricular administration of EGF to rodents and monkeys both resulted in severe behavioral and/or electroencephalographic endophenotypes relevant to this disorder. These animal models also display postpubertal abnormality in soliloquy-like self-vocalization as well as in intercortical functional connectivity. Here, we discuss neuropsychiatric implication of coronavirus infection and its interaction with the EGFR system, by searching related literatures in PubMed database as of the end of 2023.

Severe acute respiratory syndrome coronavirus (SARS-CoV), the virus responsible for COVID-19, interacts with the host immune system through complex mechanisms that significantly influence disease outcomes, affecting both innate and adaptive immunity. These interactions are crucial in determining the disease's severity and the host's ability to clear the virus. Given the virus's substantial socioeconomic impact, high morbidity and mortality rates, and public health importance, understanding these mechanisms is essential. This article examines the diverse innate immune responses triggered by SARS-CoV-2's structural proteins, including the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins, along with nonstructural proteins (NSPs) and open reading frames. These proteins play pivotal roles in immune modulation, facilitating viral replication, evading immune detection, and contributing to severe inflammatory responses such as cytokine storms and acute respiratory distress syndrome (ARDS). The virus employs strategies like suppressing type I interferon production and disrupting key antiviral pathways, including MAVS, OAS-RNase-L, and PKR. This study also explores the immune pathways that govern the activation and suppression of immune responses throughout COVID-19. By analyzing immune sensing receptors and the responses initiated upon recognizing SARS-CoV-2 structural proteins, this review elucidates the complex pathways associated with the innate immune response in COVID-19. Understanding these mechanisms offers valuable insights for therapeutic interventions and informs public health strategies, contributing to a deeper understanding of COVID-19 immunopathogenesis.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, presents with varying severity among individuals. Both viral and host factors can influence the severity of acute and chronic COVID-19, with chronic COVID-19 commonly referred to as long COVID. SARS-CoV-2 infection can be properly diagnosed by performing real-time reverse transcription polymerase chain reaction analysis of nasal swab samples. Pulse oximetry, chest X-ray, and complete blood count (CBC) analysis can be used to assess the condition of the patient to ensure that the appropriate medical care is delivered. This study aimed to develop biosignatures that can be used to distinguish between patients who are likely to develop severe disease and require hospitalization from patients who can be safely monitored in less intensive settings.

A retrospective investigation was conducted on 7897 adult patients with virologically confirmed SARS-CoV-2 infection between January 26, 2020, and November 30, 2023; all patients underwent comprehensive CBC testing at Taipei Veterans General Hospital. Among them, 1867 patients were independently recruited for a population study involving genome-wide genotyping of approximately 424 000 genomic variants. Therefore, the participants were divided into two patient cohorts, one with genomic data (n = 1867) and one without (n = 6030) for model validation and training, respectively.

We constructed and validated a biosignature model by using a combination of CBC measurements to predict subsequent hospitalization events (hazard ratio = 3.38, 95% confidence interval: 3.07-3.73 for the training cohort and 3.03 [2.46-3.73] for the validation cohort; both p < 10 -8 ). The obtained scores were used to identify the top quartile of patients, who formed the "very high risk" group with a significantly higher cumulative incidence of hospitalization (log-rank p < 10 -8 in both the training and validation cohorts). The "very high risk" group exhibited a cumulative hospitalization rate of >60%, whereas the rate for the other patients was approximately 30% over a 1.5-year period, providing a binary classification of patients with distinct hospitalization risks. To investigate the genetic factors mediating this risk, we conducted a genome-wide association study. Specific regions in chromosomes 7 and 10 and the mitochondrial chromosome (M), harboring IKAROS family zinc finger 1 ( IKZF1 ), actin binding LIM protein 1 ( ABLIM1 ), and mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 3 ( MT-ND3 ), exhibited prominent associations with binary risk classification. The identified exonic variants of IKZF1 are linked to several autoimmune diseases. Notably, people with different genotypes of the leading variants (rs4132601, rs141492519, and Affx-120744614) exhibited varying cumulative hospitalization rates after infection.

We successfully developed and validated a biosignature model of COVID-19 severe disease in virologically confirmed patients. The identified genomic variants provide new insights for infectious disease research and medical care.

This review explores the synergistic potential of natural products and nanotechnology for viral infections, highlighting key antiviral, immunomodulatory, and antioxidant properties to combat pandemics caused by highly infectious viruses. These pandemics often result in severe public health crises, particularly affecting vulnerable populations due to respiratory complications and increased mortality rates. A cytokine storm is initiated when an overload of pro-inflammatory cytokines and chemokines is released, leading to a systemic inflammatory response. Viral mutations and the limited availability of effective drugs, vaccines, and therapies contribute to the continuous transmission of the virus. The coronavirus disease-19 (COVID-19) pandemic has sparked renewed interest in natural product-derived antivirals. The efficacy of traditional medicines against pandemic viral infections is examined. Their antiviral, immunomodulatory, anti-inflammatory, and antioxidant properties are highlighted. This review discusses how nanotechnology enhances the efficacy of herbal medicines in combating viral infections.

Prevention and/or management of the dysregulated immune response in patients with COVID-19 is expected to help in the treatment of COVID-19. Boswellic acids (BAs) have great therapeutic potential because they have anti-inflammatory and immunomodulatory effects. Here, we aimed to investigate the mechanism of action of a BA formulation, Inflawell syrup, which was previously shown to be effective in reducing disease symptoms in patients who suffer from mild to moderate COVID-19. Patients with mild to moderate COVID-19 were treated with either Inflawell containing boswellic acids or a placebo for 14 days. The serum levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8, IL-1α, IL-17, IL-1Ra, and Monocyte Chemoattractant Protein-1 (MCP-1), were measured both at study onset and on day 14 after treatment started. In addition, to further investigate the signaling pathway(s) underlying the changes in cytokine levels, we evaluated the expression of tumor necrosis factor receptor 1 (TNFR1), tumor necrosis factor receptor 2 (TNFR2), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 mRNAs and phospho-inhibitor of nuclear factor kappa B (IκB) and IκB proteins. In our study, a significant decrease in the serum levels of IL-1α (p < .009), IL-8 (p < .04), TNF-α (p < .0001), and MCP-1 (p < .007) was detected in patients treated with Inflawell. Additionally, our data revealed a decrease in phospho-IκB protein levels (p < .02) and NF-κB p65 mRNA levels (p < .002), whereas the amount of IκB protein (p < .01) in the Inflawell group was significantly greater than that in the placebo group. Furthermore, despite the decreasing trend in the expression of TNFR1 and TNFR2 in the Inflawell group, there was no statistically significant difference compared with that in the placebo group. In general, treatment with Inflawell syrup led to a lower level of proinflammatory cytokines and a decrease in the activity of the TNF-α/NF-κB signaling pathway.