Neuroimmune Mechanisms Underlying Post-acute Sequelae of SARS-CoV-2 (PASC) Pain, Predictions from a Ligand-Receptor Interactome.

PURPOSE OF REVIEW: Individuals with post-acute sequelae of SARS-CoV-2 (PASC) complain of persistent musculoskeletal pain. Determining how COVID-19 infection produces persistent pain would be valuable for the development of therapeutics aimed at alleviating these symptoms. RECENT FINDINGS: To generate hypotheses regarding neuroimmune interactions in PASC, we used a ligand-receptor interactome to make predictions about how ligands from PBMCs in individuals with COVID-19 communicate with dorsal root ganglia (DRG) neurons to induce persistent pain. In a structured literature review of -omics COVID-19 studies, we identified ligands capable of binding to receptors on DRG neurons, which stimulate signaling pathways including immune cell activation and chemotaxis, the complement system, and type I interferon signaling. The most consistent finding across immune cell types was an upregulation of genes encoding the alarmins S100A8/9 and MHC-I. This ligand-receptor interactome, from our hypothesis-generating literature review, can be used to guide future research surrounding mechanisms of PASC-induced pain.

COVID-19: A Possible Contribution of the MAPK Pathway.

BACKGROUND: COVID-19 is characterized by an uncontrolled inflammatory response with high pro-inflammatory cytokine production through the activation of intracellular pathways, such as mitogen-activated protein kinase (MAPK). Viruses are able to exploit the MAPK pathway to their advantage; this pathway relevance to severe COVID-19 is poorly described. The aim of this study was to quantify biomarkers involved in the MAPK pathway and to clarify its possible role in affecting some COVID-19-related clinical features. METHODS: H-RAS, C-RAF, MAPK1, MAPK2, and ERK were quantified through ELISA, and genetic polymorphisms were evaluated through real-time PCR. RESULTS: We prospectively recruited 201 individuals (158 positive and 43 negative for SARS-CoV-2): 35 were male, and their median age was 65 years. MAPK-related biomarker levels were increased in SARS-CoV-2-positive participants (n = 89) compared to negative ones (n = 29). Dyspnea was reported by 48%; this symptom was associated with PBMC C-RAF levels in positive participants (p = 0.022) and type of ventilation (p = 0.031). The highest degree of ventilation was used by 8% for invasive ventilation and 41% for continuous positive airway pressure (CPAP). CONCLUSIONS: This is the first study that showed a possible contribution of MAPK-related biomarkers in affecting COVID-19 clinical features, and this may be relevant for identifying COVID-19 positive participants at risk of serious complications.

Chemokines and chemokine receptors during COVID-19 infection.

Chemokines are crucial inflammatory mediators needed during an immune response to clear pathogens. However, their excessive release is the main cause of hyperinflammation. In the recent COVID-19 outbreak, chemokines may be the direct cause of acute respiratory disease syndrome, a major complication leading to death in about 40% of severe cases. Several clinical investigations revealed that chemokines are directly involved in the different stages of SARS-CoV-2 infection. Here, we review the role of chemokines and their receptors in COVID-19 pathogenesis to better understand the disease immunopathology which may aid in developing possible therapeutic targets for the infection.

Parallel Dysregulated Immune Response in Severe Forms of COVID-19 and Bacterial Sepsis via Single-Cell Transcriptome Sequencing.

Critically ill COVID-19 patients start developing single respiratory organ failure that often evolves into multiorgan failure. Understanding the immune mechanisms in severe forms of an infectious disease (either critical COVID-19 or bacterial septic shock) would help to achieve a better understanding of the patient's clinical trajectories and the success of potential therapies. We hypothesized that a dysregulated immune response manifested by the abnormal activation of innate and adaptive immunity might be present depending on the severity of the clinical presentation in both COVID-19 and bacterial sepsis. We found that critically ill COVID-19 patients demonstrated a different clinical endotype that resulted in an inflammatory dysregulation in mild forms of the disease. Mild cases (COVID-19 and bacterial non severe sepsis) showed significant differences in the expression levels of CD8 naïve T cells, CD4 naïve T cells, and CD4 memory T cells. On the other hand, in the severe forms of infection (critical COVID-19 and bacterial septic shock), patients shared immune patterns with upregulated single-cell transcriptome sequencing at the following levels: B cells, monocyte classical, CD4 and CD8 naïve T cells, and natural killers. In conclusion, we identified significant gene expression differences according to the etiology of the infection (COVID-19 or bacterial sepsis) in the mild forms; however, in the severe forms (critical COVID-19 and bacterial septic shock), patients tended to share some of the same immune profiles related to adaptive and innate immune response. Severe forms of the infections were similar independent of the etiology. Our findings might promote the implementation of co-adjuvant therapies and interventions to avoid the development of severe forms of disease that are associated with high mortality rates worldwide.

A Path-Based Analysis of Infected Cell Line and COVID-19 Patient Transcriptome Reveals Novel Potential Targets and Drugs Against SARS-CoV-2.

Most transcriptomic studies of SARS-CoV-2 infection have focused on differentially expressed genes, which do not necessarily reveal the genes mediating the transcriptomic changes. In contrast, exploiting curated biological network, our PathExt tool identifies central genes from the differentially active paths mediating global transcriptomic response. Here we apply PathExt to multiple cell line infection models of SARS-CoV-2 and other viruses, as well as to COVID-19 patient-derived PBMCs. The central genes mediating SARS-CoV-2 response in cell lines were uniquely enriched for ATP metabolic process, G1/S transition, leukocyte activation and migration. In contrast, PBMC response reveals dysregulated cell-cycle processes. In PBMC, the most frequently central genes are associated with COVID-19 severity. Importantly, relative to differential genes, PathExt-identified genes show greater concordance with several benchmark anti-COVID-19 target gene sets. We propose six novel anti-SARS-CoV-2 targets ADCY2, ADSL, OCRL, TIAM1, PBK, and BUB1, and potential drugs targeting these genes, such as Bemcentinib, Phthalocyanine, and Conivaptan.

New insights into extracellular and intracellular redox status in COVID-19 patients.

BACKGROUND: The imbalance of redox homeostasis induces hyper-inflammation in viral infections. In this study, we explored the redox system signature in response to SARS-COV-2 infection and examined the status of these extracellular and intracellular signatures in COVID-19 patients. METHOD: The multi-level network was constructed using multi-level data of oxidative stress-related biological processes, protein-protein interactions, transcription factors, and co-expression coefficients obtained from GSE164805, which included gene expression profiles of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and healthy controls. Top genes were designated based on the degree and closeness centralities. The expression of high-ranked genes was evaluated in PBMCs and nasopharyngeal (NP) samples of 30 COVID-19 patients and 30 healthy controls. The intracellular levels of GSH and ROS/O2• - and extracellular oxidative stress markers were assayed in PBMCs and plasma samples by flow cytometry and ELISA. ELISA results were applied to construct a classification model using logistic regression to differentiate COVID-19 patients from healthy controls. RESULTS: CAT, NFE2L2, SOD1, SOD2 and CYBB were 5 top genes in the network analysis. The expression of these genes and intracellular levels of ROS/O2• - were increased in PBMCs of COVID-19 patients while the GSH level decreased. The expression of high-ranked genes was lower in NP samples of COVID-19 patients compared to control group. The activity of extracellular enzymes CAT and SOD, and the total oxidant status (TOS) level were increased in plasma samples of COVID-19 patients. Also, the 2-marker panel of CAT and TOS and 3-marker panel showed the best performance. CONCLUSION: SARS-COV-2 disrupts the redox equilibrium in immune cells and the upper respiratory tract, leading to exacerbated inflammation and increased replication and entrance of SARS-COV-2 into host cells. Furthermore, utilizing markers of oxidative stress as a complementary validation to discriminate COVID-19 from healthy controls, seems promising.

Corrigendum: Identification of novel therapeutic candidates against SARS-CoV-2 infections: An application of RNA sequencing toward mRNA based nanotherapeutics.

[This corrects the article DOI: 10.3389/fmicb.2022.901848.].

Identification of Novel Therapeutic Candidates Against SARS-CoV-2 Infections: An Application of RNA Sequencing Toward mRNA Based Nanotherapeutics.

Due to fast transmission and various circulating SARS-CoV-2 variants, a significant increase of coronavirus 2019 infection cases with acute respiratory symptoms has prompted worries about the efficiency of current vaccines. The possible evasion from vaccine immunity urged scientists to identify novel therapeutic targets for developing improved vaccines to manage worldwide COVID-19 infections. Our study sequenced pooled peripheral blood mononuclear cells transcriptomes of SARS-CoV-2 patients with moderate and critical clinical outcomes to identify novel potential host receptors and biomarkers that can assist in developing new translational nanomedicines and vaccine therapies. The dysregulated signatures were associated with humoral immune responses in moderate and critical patients, including B-cell activation, cell cycle perturbations, plasmablast antibody processing, adaptive immune responses, cytokinesis, and interleukin signaling pathway. The comparative and longitudinal analysis of moderate and critically infected groups elucidated diversity in regulatory pathways and biological processes. Several immunoglobin genes (IGLV9-49, IGHV7-4, IGHV3-64, IGHV1-24, IGKV1D-12, and IGKV2-29), ribosomal proteins (RPL29, RPL4P2, RPL5, and RPL14), inflammatory response related cytokines including Tumor Necrosis Factor (TNF, TNFRSF17, and TNFRSF13B), C-C motif chemokine ligands (CCL3, CCL25, CCL4L2, CCL22, and CCL4), C-X-C motif chemokine ligands (CXCL2, CXCL10, and CXCL11) and genes related to cell cycle process and DNA proliferation (MYBL2, CDC20, KIFC1, and UHCL1) were significantly upregulated among SARS-CoV-2 infected patients. 60S Ribosomal protein L29 (RPL29) was a highly expressed gene among all COVID-19 infected groups. Our study suggested that identifying differentially expressed genes (DEGs) based on disease severity and onset can be a powerful approach for identifying potential therapeutic targets to develop effective drug delivery systems against SARS-CoV-2 infections. As a result, potential therapeutic targets, such as the RPL29 protein, can be tested in vivo and in vitro to develop future mRNA-based translational nanomedicines and therapies to combat SARS-CoV-2 infections.

Reconstructed Genome-Scale Metabolic Model Characterizes Adaptive Metabolic Flux Changes in Peripheral Blood Mononuclear Cells in Severe COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a mortal threat to human health. The elucidation of the relationship between peripheral immune cells and the development of inflammation is essential for revealing the pathogenic mechanism of COVID-19 and developing related antiviral drugs. The immune cell metabolism-targeting therapies exhibit a desirable anti-inflammatory effect in some treatment cases. In this study, based on differentially expressed gene (DEG) analysis, a genome-scale metabolic model (GSMM) was reconstructed by integrating transcriptome data to characterize the adaptive metabolic changes in peripheral blood mononuclear cells (PBMCs) in severe COVID-19 patients. Differential flux analysis revealed that metabolic changes such as enhanced aerobic glycolysis, impaired oxidative phosphorylation, fluctuating biogenesis of lipids, vitamins (folate and retinol), and nucleotides played important roles in the inflammation adaptation of PBMCs. Moreover, the main metabolic enzymes such as the solute carrier (SLC) family 2 member 3 (SLC2A3) and fatty acid synthase (FASN), responsible for the reactions with large differential fluxes, were identified as potential therapeutic targets. Our results revealed the inflammation regulation potentials of partial metabolic reactions with differential fluxes and their metabolites. This study provides a reference for developing potential PBMC metabolism-targeting therapy strategies against COVID-19.

Differential expression of carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and dipeptidyl peptidase-4 (DPP4) with detection of Middle East respiratory syndrome-coronavirus in peripheral blood.

BACKGROUND: Middle East respiratory syndrome-coronavirus (MERS-CoV) utilizes CD26 (dipeptidyl peptidase-4) and CD66e or CEACAM5 (carcinoembryonic antigen-related cell adhesion molecule 5) receptors for cell infection. Peripheral blood mononuclear cells (PBMCs) play a critical role in mounting adaptive immune response against the virus. This study was performed to assess the expression of CD26 and CD66e on PBMCs and their susceptibility to MERS-CoV infection. METHODS: Surface expression of CD26 and CD66e receptors on PBMCs from MERS-CoV patients (n = 20) and healthy controls (n = 20) was assessed by flow cytometry and the soluble forms were determined by enzyme-linked immunosorbent assay (ELISA). MERS-CoV UpE and Orf1a genes in PBMCs were detected by using Altona diagnostics reverse transcription polymerase chain reaction (RT-PCR) kit. RESULTS: Mean fluorescent intensity (MFI) of CD66e was significantly higher on CD4 + lymphocytes (462.4 ± 64.35 vs 325.1 ± 19.69; p < 0.05) and CD8 + lymphocytes (533.8 ± 55.32 vs 392.4 ± 37.73; p < 0.04) from patients with MERS-CoV infection compared to the normal controls. No difference in MFI for CD66e was observed on monocytes (381.8 ± 40.34 vs 266.8 ± 20.6; p = 0.3) between the patients and controls. Soluble form of CD66e among MERS-CoV patients was also higher than the normal controls (mean= 338.7 ± 58.75 vs 160.7 ± 29.49 ng/mL; p < 0.01). Surface expression of CD26 on PBMCs and its soluble form were no different between the groups. MERS-CoV was detected by RT-PCR in 16/20 (80%) patients from whole blood, among them 8 patients were tested in PBMCs, 4/8 (50%) patients were positive. CONCLUSION: Increased expression levels of CD66e (CEACAM5) may contribute to increased susceptibility of PBMCs to MERS-CoV infection and disease progression.

Nonproductive exposure of PBMCs to SARS-CoV-2 induces cell-intrinsic innate immune responses.

Cell-intrinsic responses mounted in PBMCs during mild and severe COVID-19 differ quantitatively and qualitatively. Whether they are triggered by signals emitted by productively infected cells of the respiratory tract or result from physical interaction with virus particles remains unclear. Here, we analyzed susceptibility and expression profiles of PBMCs from healthy donors upon ex vivo exposure to SARS-CoV and SARS-CoV-2. In line with the absence of detectable ACE2 receptor expression, human PBMCs were refractory to productive infection. RT-PCR experiments and single-cell RNA sequencing revealed JAK/STAT-dependent induction of interferon-stimulated genes (ISGs) but not proinflammatory cytokines. This SARS-CoV-2-specific response was most pronounced in monocytes. SARS-CoV-2-RNA-positive monocytes displayed a lower ISG signature as compared to bystander cells of the identical culture. This suggests a preferential invasion of cells with a low ISG baseline profile or delivery of a SARS-CoV-2-specific sensing antagonist upon efficient particle internalization. Together, nonproductive physical interaction of PBMCs with SARS-CoV-2- and, to a much lesser extent, SARS-CoV particles stimulate JAK/STAT-dependent, monocyte-accentuated innate immune responses that resemble those detected in vivo in patients with mild COVID-19.

Severe COVID-19 correlates with lower mitochondrial cristae density in PBMCs and greater sitting time in humans.

An interaction between mitochondrial dynamics, physical activity levels, and COVID-19 severity has been previously hypothesized. However, this has not been tested. We aimed to compare mitochondrial morphology and cristae density of PBMCs between subjects with non-severe COVID-19, subjects with severe COVID-19, and healthy controls. Additionally, we compared the level of moderate-vigorous physical activity (MVPA) and sitting time between groups. Blood samples were taken to obtain PBMCs. Mitochondrial dynamics were assessed by electron microscopy images and western blot of protein that regulate mitochondrial dynamics. The International Physical Activity Questionnaire (IPAQ; short version) was used to estimate the level of MVPA and the sitting time The patients who develop severe COVID-19 (COVID-19++) not present alterations of mitochondrial size neither mitochondrial density in comparison to non-severe patients COVID-19 (COVID-19) and control subjects (CTRL). However, compared to CTRL, COVID-19 and COVID-19++ groups have lower mitochondrial cristae length, a higher proportion of abnormal mitochondrial cristae. The COVID-19++ group has lower number (trend) and length of mitochondrial cristae in comparison to COVID-19 group. COVID-19, but not COVID-19++ group had lower Opa 1, Mfn 2 and SDHB (Complex II) proteins than CTRL group. Besides, COVID-19++ group has a higher time sitting. Our results show that low mitochondrial cristae density, potentially due to physical inactivity, is associated with COVID-19 severity.

Measurement of Mitochondrial Respiration in Cryopreserved Human Peripheral Blood Mononuclear Cells (PBMCs).

Inflammatory diseases caused by infectious agents such as the SARS-CoV-2 virus can lead to impaired reductive-oxidative (REDOX) balance and disrupted mitochondrial function. Peripheral blood mononuclear cells (PBMCs) provide a useful model for studying the effects of inflammatory diseases on mitochondrial function but can be limited by the need to store these cells by cryopreservation prior to assay. Here, we describe a method for improving and determining PBMC viability with normalization of values to number of living cells. The approach can be applied not only to PBMC samples derived from patients with diseases marked by an altered inflammatory response such as viral infections.

ISGylation is increased in the peripheral blood mononuclear cells derived from symptomatic COVID-19 patients.

Cytokine-driven hyper inflammation has been identified as a critical factor behind poor outcomes in patients severely infected with SARS-CoV-2 virus. Notably, protein ISGylation, a protein conjugated form of Type 1 IFN-inducible ubiquitin-like protein ISG15 (Interferon-Stimulated Gene 15), induces cytokine storm (CS) and augments colonic inflammation in colitis-associated colon cancers in mouse models. However, whether ISGylation is increased and causally responsible for CS and hyper inflammation in symptomatic COVID-19 patients is unknown. Here, we measured ISGylation levels in peripheral blood mononuclear cells (PBMCs) from 10 symptomatic (SARS-CoV-2-positive with symptoms) and asymptomatic (SARS-CoV-2-positive with no symptoms) COVID-19 patients, and 4 uninfected individuals (SARS-CoV-2-negative), using WesTm assay. Strikingly, we note significant increases in protein ISGylation and MX-1 (myxovirus-resistance protein-1) protein levels, both induced by type-I IFN, in symptomatic but not in asymptomatic patients and uninfected individuals. Knowing that ISGylation augments CS and intestinal inflammation in colon cancers, we propose that increased ISGylation may be an underlying cause of CS and inflammation in symptomatic patients.

Serum levels of vitamin D and immune system function in patients with COVID-19 admitted to intensive care unit.

OBJECTIVE: Vitamin D is believed to affect the functionality of the immune system for the prevention of coronavirus disease. To investigate the role of this vitamin against the Coronavirus, this study analyzed the serum levels of vitamin D, the transcription pattern of inflammatory cytokines, and the frequency of total lymphocytes, TCD4+, TCD8+, and NK cells in 50 COVID-19-affected subjects in comparison to 50 healthy participants. MATERIALS AND METHODS: This study diagnosed and evaluated 100 patients. Frequency of lymphocytes was determined using flow cytometry. Cytokine expression levels were measured using Real-Time PCR. Serum levels of vitamin D and cytokines levels in cultured cell supernatant were measured by ELISA. RESULTS: Patients with COVID-19 exhibited decreased serum levels of vitamin D versus the healthy participants (p = 0.0024). The total number of lymphocytes, TCD4+, TCD8+, and NK cells was significantly reduced in patients with COVID-19 (p < 0.0001). Considerable upregulation of IL-12, IFN-γ, and TNF-α was seen in COVID-19 patients compared to the control group, whereas IFN-α was downregulated in COVID-19 patients. ELISA results also had increased levels of IL-12, TNF-α, and IFN-γ (p = 0.0014, 0.0012, and p < 0.0001, respectively), and decreased level of IFN-α (p = 0.0021) in patients with COVID-19 compared to the control group. CONCLUSION: These findings suggest a probable association among vitamin D concentrations, immune system function, and risk of COVID-19 infection. As a result, it is recommended that vitamin D be considered as a candidate for handling and controlling COVID-19 because of its ability to target the cytokine storm and its antiviral effects.

Time-Resolved Gene Expression Analysis Monitors the Regulation of Inflammatory Mediators and Attenuation of Adaptive Immune Response by Vitamin D.

Peripheral blood mononuclear cells (PBMCs) belong to the innate and adaptive immune system and are highly sensitive and responsive to changes in their systemic environment. In this study, we focused on the time course of transcriptional changes in freshly isolated human PBMCs 4, 8, 24 and 48 h after onset of stimulation with the active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Taking all four time points together, 662 target genes were identified and segregated either by time of differential gene expression into 179 primary and 483 secondary targets or by driver of expression change into 293 direct and 369 indirect targets. The latter classification revealed that more than 50% of target genes were primarily driven by the cells' response to ex vivo exposure than by the nuclear hormone and largely explained its down-regulatory effect. Functional analysis indicated vitamin D's role in the suppression of the inflammatory and adaptive immune response by down-regulating ten major histocompatibility complex class II genes, five alarmins of the S100 calcium binding protein A family and by affecting six chemokines of the C-X-C motif ligand family. Taken together, studying time-resolved responses allows to better contextualize the effects of vitamin D on the immune system.

Systems Biology and Bioinformatics approach to Identify blood based signatures molecules and drug targets of patient with COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection results in the development of a highly contagious respiratory ailment known as new coronavirus disease (COVID-19). Despite the fact that the prevalence of COVID-19 continues to rise, it is still unclear how people become infected with SARS-CoV-2 and how patients with COVID-19 become so unwell. Detecting biomarkers for COVID-19 using peripheral blood mononuclear cells (PBMCs) may aid in drug development and treatment. This research aimed to find blood cell transcripts that represent levels of gene expression associated with COVID-19 progression. Through the development of a bioinformatics pipeline, two RNA-Seq transcriptomic datasets and one microarray dataset were studied and discovered 102 significant differentially expressed genes (DEGs) that were shared by three datasets derived from PBMCs. To identify the roles of these DEGs, we discovered disease-gene association networks and signaling pathways, as well as we performed gene ontology (GO) studies and identified hub protein. Identified significant gene ontology and molecular pathways improved our understanding of the pathophysiology of COVID-19, and our identified blood-based hub proteins TPX2, DLGAP5, NCAPG, CCNB1, KIF11, HJURP, AURKB, BUB1B, TTK, and TOP2A could be used for the development of therapeutic intervention. In COVID-19 subjects, we discovered effective putative connections between pathological processes in the transcripts blood cells, suggesting that blood cells could be used to diagnose and monitor the disease's initiation and progression as well as developing drug therapeutics.

Boosted Pro-Inflammatory Activity in Human PBMCs by Lipopolysaccharide and SARS-CoV-2 Spike Protein Is Regulated by α-1 Antitrypsin.

For the treatment of severe COVID-19, supplementation with human plasma-purified α-1 antitrypsin (AAT) to patients is currently considered. AAT inhibits host proteases that facilitate viral entry and possesses broad anti-inflammatory and immunomodulatory activities. Researchers have demonstrated that an interaction between SARS-CoV-2 spike protein (S) and lipopolysaccharides (LPS) enhances pro-inflammatory responses in vitro and in vivo. Hence, we wanted to understand the potential anti-inflammatory activities of plasma-derived and recombinant AAT (recAAT) in a model of human total peripheral blood mononuclear cells (PBMCs) exposed to a combination of CHO expressed trimeric spike protein and LPS, ex vivo. We confirmed that cytokine production was enhanced in PBMCs within six hours when low levels of LPS were combined with purified spike proteins ("spike"). In the presence of 0.5 mg/mL recAAT, however, LPS/spike-induced TNF-α and IL-1ß mRNA expression and protein release were significantly inhibited (by about 46-50%) relative to LPS/spike alone. Although without statistical significance, recAAT also reduced production of IL-6 and IL-8. Notably, under the same experimental conditions, the plasma-derived AAT preparation Respreeza (used in native and oxidized forms) did not show significant effects. Our findings imply that an early pro-inflammatory activation of human PBMCs is better controlled by the recombinant version of AAT than the human plasma-derived AAT used here. Considering the increasing clinical interest in AAT therapy as useful to ameliorate the hyper-inflammation seen during COVID-19 infection, different AAT preparations require careful evaluation.

Previously published ethno-pharmacological reports reveal the potentiality of plants and plant-derived products used as traditional home remedies by Bangladeshi COVID-19 patients to combat SARS-CoV-2.

Several plants have traditionally been used since antiquity to treat various gastroenteritis and respiratory symptoms similar to COVID-19 outcomes. The common symptoms of COVID-19 include fever or chills, cold, cough, flu, headache, diarrhoea, tiredness/fatigue, sore throat, loss of taste or smell, asthma, shortness of breath, or difficulty breathing, etc. This study aims to find out the plants and plant-derived products which are being used by the COVID-19 infected patients in Bangladesh and how those plants are being used for the management of COVID-19 symptoms. In this study, online and partially in-person survey interviews were carried out among Bangladeshi respondents. We selected Bangladeshi COVID-19 patients who were detected Coronavirus positive (+) by RT-PCR nucleic acid test and later recovered. Furthermore, identified plant species from the surveys were thoroughly investigated for safety and efficacy based on the previous ethnomedicinal usage reports. Based on the published data, they were also reviewed for their significant potentialities as antiviral, anti-inflammatory, and immunomodulatory agents. We explored comprehensive information about a total of 26 plant species, belonging to 23 genera and 17 different botanical families, used in COVID-19 treatment as home remedies by the respondents. Most of the plants and plant-derived products were collected directly from the local marketplace. According to our survey results, greatly top 5 cited plant species measured as per the highest RFC value are Camellia sinensis (1.0) > Allium sativum (0.984) > Azadirachta indica (0.966) > Zingiber officinale (0.966) > Syzygium aromaticum (0.943). Previously published ethnomedicinal usage reports, antiviral, anti-inflammatory, and immunomodulatory activity of the concerned plant species also support our results. Thus, the survey and review analysis simultaneously reveals that these reported plants and plant-derived products might be promising candidates for the treatment of COVID-19. Moreover, this study clarifies the reported plants for their safety during COVID-19 management and thereby supporting them to include in any future pre-clinical and clinical investigation for developing herbal COVID-19 therapeutics.

Identification of PBMC-based molecular signature associational with COVID-19 disease severity.

The longevity of COVID-19 as a global pandemic, and the devastating effects it has had on certain subsets of individuals thus far has highlighted the importance of identifying blood-based biomarkers associated with disease severity. We employed computational and transcriptome analyses of publicly available datasets from PBMCs from 126 patients with COVID-19 admitted to ICU (n = 50), COVID-19 not admitted to ICU (n = 50), non-COVID-19 admitted to ICU (n = 16) and non-COVID-19 not admitted to ICU (n = 10), and utilized the Gencode V33 assembly to analyze protein coding mRNA and long noncoding RNA (lncRNA) transcriptomes in the context of disease severity. Our data identified several aberrantly expressed mRNA and lncRNA based biomarkers associated with SARS-CoV-2 severity, which in turn significantly affected canonical, upstream, and disease functions in each group of patients. Immune, interferon, and antiviral responses were severely suppressed in COVID-19 patients admitted to ICU versus those who were not admitted to ICU. Our data suggests a possible therapeutic approach for severe COVID-19 through administration of interferon therapy. Delving further into these biomarkers, roles and their implications on the onset and disease severity of COVID-19 could play a crucial role in patient stratification and identifying varied therapeutic options with diverse clinical implications.