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1.
medrxiv; 2024.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2024.02.26.24302674

ABSTRACT

To elucidate the important cellular and molecular drivers of pulmonary long COVID, we generated a single-cell transcriptomic map of the airway mucosa using bronchial brushings from patients with long COVID who reported persistent pulmonary symptoms. Adults with and without long COVID were recruited from the general community in greater Vancouver, Canada. The cohort was divided into those with pulmonary long COVID (PLC), which was defined as persons with new or worsening respiratory symptoms following at least one year from their initial acute SARS-CoV-2 infection (N=9); and control subjects defined as SARS-CoV-2 infected persons whose acute respiratory symptoms had fully resolved or individuals who had not experienced acute COVID-19 (N=9). These participants underwent bronchoscopy from which a single cell suspension was created from bronchial brush samples and then sequenced. A total of 56,906 cells were recovered for the downstream analysis, with 34,840 cells belonging to the PLC group. A dimensionality reduction plot shows a unique cluster of neutrophils in the PLC group (p<.05). Ingenuity Pathway Analysis revealed that neutrophil degranulation pathway was enriched across epithelial cells. Differential gene expression analysis between the PLC and control groups demonstrated upregulation of mucin genes in secretory cell clusters. A single-cell transcriptomic landscape of the small airways shows that the PLC airways harbors a dominant neutrophil cluster and an upregulation in the neutrophil-associated activation signature with increased expression of MUC genes in the secretory cells. Together, they suggest that pulmonary symptoms of long COVID may be driven by chronic small airway inflammation.


Subject(s)
Severe Acute Respiratory Syndrome , COVID-19 , Inflammation
2.
biorxiv; 2024.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2024.02.25.581989

ABSTRACT

Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between organs and specific SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed increased viremia in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection.


Subject(s)
Inflammation , Hepatitis D , Viremia , Chronobiology Disorders , Coronavirus Infections , Acute Disease , Dysbiosis , Central Nervous System Diseases
3.
biorxiv; 2024.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2024.02.09.579589

ABSTRACT

The coronavirus disease of 2019 (COVID-19) pandemic that has led to more than 700 million confirmed cases and near 7 million deaths. Although Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains as an important question, which is also centered on the mystery whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to the neurological complications both acutely and in long COVID.


Subject(s)
Inflammation , Severe Acute Respiratory Syndrome , COVID-19 , Microvascular Angina , Papilloma, Choroid Plexus , Acute Disease , Infections , Central Nervous System Diseases
4.
medrxiv; 2024.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2024.02.05.24301794

ABSTRACT

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8+ T cells, and the enhanced expression of T cell exhaustion markers, such as programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-3 (Tim-3), in pregnant women. We identified additional evidence of immune dysfunction in severely and critically ill pregnant women, including a lack of expected elevation in regulatory T cell (Treg) levels, diminished interferon responses, and profound suppression of monocyte function. Consistent with earlier data, we found maternal obesity was also associated with altered immune responses to SARS-CoV-2 infection, including enhanced production of inflammatory cytokines by T cells. Certain gut bacterial species were altered in pregnancy and upon SARS-CoV-2 infection in pregnant individuals compared to non-pregnant women. Shifts in cytokine and chemokine levels were also identified in the sera of pregnant individuals, most notably a robust increase of interleukin-27 (IL-27), a cytokine known to drive T cell exhaustion, in the pregnant uninfected control group compared to all non-pregnant groups. IL-27 levels were also significantly higher in uninfected pregnant controls compared to pregnant SARS-CoV-2-infected individuals. Using two different preclinical mouse models of inflammation-induced fetal demise and respiratory influenza viral infection, we found that enhanced IL-27 protects developing fetuses from maternal inflammation but renders adult female mice vulnerable to viral infection. These combined findings from human and murine studies reveal nuanced pregnancy-associated immune responses, suggesting mechanisms underlying the increased susceptibility of pregnant individuals to viral respiratory infections.


Subject(s)
Inflammation , Obesity , Severe Acute Respiratory Syndrome , COVID-19 , Virus Diseases , Respiratory Tract Infections , Immune System Diseases , Fetal Death
5.
researchsquare; 2024.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3935003.v1

ABSTRACT

Interleukin-6 (IL-6) is a pleiotropic cytokine that has many biological activities, including inflammation, hematopoiesis, bone metabolism, embryonic development, and other fundamental processes. Recently, IL-6 has been widely recognized as an important pro-inflammatory cytokine involved in cytokine storm pathogenesis during severe inflammatory diseases, such as coronavirus disease 2019 (COVID-19). Therefore, IL-6 is considered to be a therapeutic target for inhibiting cytokine storm. In the present study, we investigated the suppressive effect of isofraxidin, a major coumarin compound of Acanthopanax senticosus, on the overexpression of IL-6 and its molecular mechanism. When human hepatocellular carcinoma cell lines, HuH-7 and HepG2, were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA), a marked induction of IL-6 mRNA expression was observed in HuH-7 cells compared with HepG2 cells. Isofraxidin significantly suppressed TPA-induced IL-6 mRNA expression in HuH-7 cells in a dose-dependent manner. Furthermore, isofraxidin inhibited TPA-induced phosphorylation of ERK1/2 in a dose dependent manner. Similarly, the MAPK/ERK inhibitor U0126 suppressed TPA-induced IL-6 mRNA expression. However, isofraxidin had no effects on TPA-induced phosphorylation of SAPK/JNK, Akt (Ser473), and STAT3 (Tyr705), nuclear translocation of NF-κB p65, and degradation of IκB. Taken together, isofraxidin suppresses TPA-induced overexpression of IL-6 mRNA by selectively inhibiting the activation of the MAPK/ERK pathway in HuH-7 cells, indicating that isofraxidin may be an effective anti-inflammatory agent for treating cytokine storm.


Subject(s)
Inflammation , COVID-19 , Adenoma, Liver Cell , Bone Diseases, Metabolic
6.
researchsquare; 2024.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3930462.v1

ABSTRACT

Unpredictable fatal outcome of COVID-19 is attributed to dysregulated inflammation. Impaired early adaptive immune response leads to late stage inflammatory outcome. The purpose of this study was to develop biomarkers for early detection of host immune impairment at first diagnosis from leftover RNA samples, which may in turn identify high risk patients. Leftover RNA samples of COVID-19 patients at first diagnosis were stored. Following prospective follow-up, the samples were shorted and categorized into outcome groups. Impaired adaptive T cell response (severity score) and Impaired IL-10 response (undetectable IL-10 in the presence of high expression of a representative interferon response gene) were determined by RT-PCR based assay. We demonstrate that a T cell response based ‘severity score’ comprising rational combination of Ct values of a target genes’ signature can predict high risk noncomorbid potentially critical COVID-19 patients with a sensitivity of 91% (95%CI:58.7–99.8) and specificity of 92.6% (95% CI:75.7–99)(AUC:0.88). Although inclusion of comorbid patients reduced sensitivity to 77% (95%CI:54.6–92.2), the specificity was still 94% (95%CI:79.8–99.3)(AUC:0.82). The same for ‘impaired IL-10 response’ were little lower to predict high risk noncomorbid patients 64.2% (95%CI:35.1–87.2) and 82% (95%CI:65.5–93.2) respectively. Inclusion of comorbid patients drastically reduce sensitivity and specificity51.6% (95%CI:33.1–69.8) and 80.5% (95%CI:64.0-91.8) respectively. As best of our knowledge this is the first demonstration of a metric based approach showing the ‘severity score’ as an indicator of early adoptive immune response, could be used as predictor of severe COVID-19 outcome at the time of first diagnosis using the same leftover swab RNA. The work flow could reduce expenditure and reporting time of the prognostic test for an earliest clinical decision ensuring possibility of early rational management.


Subject(s)
COVID-19 , Space Motion Sickness , Inflammation
7.
preprints.org; 2024.
Preprint in English | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202402.0212.v1

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause potentially life-threatening coronavirus disease (COVID-19). COVID-19 is a multisystem disease and is associated with significant respiratory distress, systemic hyper inflammation, vasculitis and multi-organ failures. SARS-CoV-2 causes deterioration of numerous systems with increasing evidence implying that COVID-19 affects endothelium and vascular function. The endothelium is important for preserving vascular tone and homeostasis. The overactivation and dysfunction of endothelial cells are significant outcomes of severity in patients with COVID-19. The Angiopoietin 1/Tie 2 pathway plays an important role in endothelium quiescence and vessel stability. The disruption of Angiopoietins/Tie balance affects vessel contact barrier and leads to vessel leakage, and this in turn causes endothelial dysfunction. Although vascular instability through SARS-CoV-2 is associated with endothelial dysfunction, it is still not understood if the virus affects Angiopoietin/Tie axis directly or via other mechanisms such as cytokine storm and/or immune response associated with the infection. This review provides an overview of the impact SARS-CoV-2 has on endothelial function and more specifically the Angiopoietin/Tie pathway.


Subject(s)
Inflammation , Disease , COVID-19 , Coronavirus Infections , Vasculitis
8.
preprints.org; 2024.
Preprint in English | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202401.2238.v1

ABSTRACT

Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations, characterized by distinct interactomes – namely protein assemblies - under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation's influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly and disease.


Subject(s)
Neoplasms , Inflammation , Congenital, Hereditary, and Neonatal Diseases and Abnormalities , Neurodegenerative Diseases
9.
authorea preprints; 2024.
Preprint in English | PREPRINT-AUTHOREA PREPRINTS | ID: ppzbmed-10.22541.au.170667194.40245825.v1

ABSTRACT

Background: In the SARS-CoV-2/COVID-19 pandemic, we need to understand the impact of immunomodulatory medications on COVID-19 symptom severity in patients with inflammatory diseases, including the Type 2/Th2 polarized skin disease, atopic dermatitis/AD. Since it is believed that Type 1/Th1immunity controls viral infections, and that there is a Th1/Th2 counter-regulation, we hypothesized that Th2 targeting with the IL-4Rα-antagonist, dupilumab, in patients with moderate-to-severe AD rebalances Th1/Th2 axis, potentially leading to attenuated COVID-19 symptoms. Methods: : 1,237 moderate-to-severe AD patients in the Icahn School of Medicine at Mount Sinai Department of Dermatology were enrolled in a registry. Patients were screened for COVID-19-related symptoms and assigned a severity score (asymptomatic[0]-fatal[5]). Scores were compared among 3 treatment groups: dupilumab (n=632), other systemic treatments (n=107), and limited/no treatment (n=498). Demographic and comorbid covariates were adjusted by multivariate logistic regression models. Results: : The dupilumab-treated group showed reduced incidence and severity of COVID-19 symptoms versus other treatment groups. Dupilumab-treated patients were less likely to experience moderate-to-severe symptoms versus patients on other systemics (p=0.01) and on limited/no treatment (p=0.04), and less likely to experience any symptoms versus patients on other systemics (p=0.01). This effect was seen in our entire cohort and in the subgroup of patients with verified COVID-19 or high-risk exposure. Conclusions: : Patients on dupilumab experienced less severe COVID-19 manifestations and lesser symptoms compared to patients on other systemics and on limited/no treatment. These results suggest that Th2 modulation with dupilumab may have a protective effect on anti-viral immune response in AD patients.


Subject(s)
Inflammation , Alzheimer Disease , Dermatitis, Atopic , COVID-19 , Skin Diseases
10.
authorea preprints; 2024.
Preprint in English | PREPRINT-AUTHOREA PREPRINTS | ID: ppzbmed-10.22541.au.170667185.58147011.v1

ABSTRACT

Introduction: Nitazoxanide is a broad-spectrum antiparasitic that has been tested for COVID-19 due to the anti-inflammatory effects and in vitro anti-viral activity and promising clinical benefits against influenza and other viruses. The aim of this study was to synthesize the best evidence on the efficacy and safety of nitazoxanide as treatment for patients with COVID-19. Methods Searches for studies were performed in peer-reviewed and gray literature. The following elements were used to define eligibility criteria: (1) Population, individuals with laboratory-confirmed SARS-CoV-2 infection; (2) Intervention, nitazoxanide; (3) Comparison, placebo; (4) Outcomes: positive RT-PCR status, composite measure of disease progression (severe COVID-19, ICU admission or invasive mechanical ventilation), death, serum biomarkers of inflammation (C-reactive protein, IL-6, and IL-8), and any adverse events; (5) Study type: blinded, placebo-controlled, randomized clinical trials (RCT). Treatment effects were reported as relative risk (RR) and mean difference (MD) with 95% confidence intervals (CI). Results Four blinded, placebo-controlled RCT were included in the meta-analysis and enrolled individuals with mild or moderate SARS-CoV-2 infection. We found no difference between nitazoxanide and placebo in the frequency of positive RTP-PCR results (RR = 0.83; 95% CI 0.58 to 1.17) and there was no decreased risk for disease progression (severe COVID-19, ICU admission or invasive mechanical ventilation) (RR = 0.40; 95% CI 0.08 to 2.13) and deaths (RR = 0.55; 95% CI 0.18 to 1.68) among patients receiving nitazoxanide. There were no differences for patients treated with nitazoxanide and placebo in the levels of inflammatory markers. Conclusions In this study, we found no current evidence from blinded, placebo-controlled, RCT on the efficacy of nitazoxanide in treating patients with COVID-19. This living systematic review should be updated as soon as the results of ongoing RCT are published.


Subject(s)
Inflammation , Death , COVID-19
11.
authorea preprints; 2024.
Preprint in English | PREPRINT-AUTHOREA PREPRINTS | ID: ppzbmed-10.22541.au.170667676.60180250.v1

ABSTRACT

Extensive immune response associated inflammation is the major reason for the pathological outcome of COVID-19 infection. Infliximab is an anti tumor necrosis factor (anti-TNF) drug that is used to reduce inflammation through TNF-α inhibition. Inhibition of main inflammatory cytokine such as TNF-α may has a potential effect in COVID-19 treatment. Here, we report the clinical outcome associated with Infliximab treatment in a 65-year-old woman with confirmed COVID-19 infection. Infliximab therapy was started on day 9th, patient demonstrated clinical improvement and recovery from COVID-19. Our findings suggest that the association of TNF-α inhibition and clinical management together contributes to COVID-19 patient survival.


Subject(s)
Inflammation , Necrosis , COVID-19 , Coronavirus Infections
12.
researchsquare; 2024.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3913399.v1

ABSTRACT

Background: The SARS-CoV-2 Omicron pandemic had a global impact on individuals with cancers. This study aimed to investigate the effect of Omicron infection on cancer patients in China. Methods: A retrospective study was conducted, including 347 patients with cancer who received radiotherapy or chemoradiotherapy between July 2022 and March 2023. The patients were divided into three groups: those without SARS-CoV-2 infection during treatment (Non-COVID-19 group), those who began treatment at least 10 days after first testing positive for SARS-CoV-2 (≥10-d COVID-19 group), and those who began treatment less than 10 days after first testing positive for SARS-CoV-2 (<10-d COVID-19 group). The serum levels of SAA, hsCRP, ALT, etc, were used to assess the severity of inflammation, liver damage, and cardiovascular injury. Results: The proportion of moderate and severe infected cases was higher in ≥10-d COVID-19 group compared with <10-d COVID-19 group (p=0.0446). Additionally, the serum levels of SAA, hsCRP, IL-6 and PCT, were significantly higher in ≥10-d COVID-19 group (p<0.05). Serum ALT, LDH and HBDH levels were also elevated in ≥10-d COVID-19 group (p<0.05). However, no significant differences were observed in frequency of neutropenia, thrombocytopenia and completion rates among three groups. Conclusion: Omicron infection leads to inflammation, liver damage and cardiovascular injury in cancer patients. Surprisingly, the duration of delay in radiotherapy or chemoradiotherapy after Omicron infection did not affect completion rates of current therapy, which was not consistent with the recommendations of NCCN guidelines. Moreover, the severity of Omicron infection was worse among cancer patients who received delayed treatment.


Subject(s)
Neoplasms , Inflammation , Chemical and Drug Induced Liver Injury , Thrombocytopenia , COVID-19 , Cardiovascular Diseases , Neutropenia , Infections
13.
researchsquare; 2024.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3914352.v2

ABSTRACT

The vasculature is heavily impacted by SARS-CoV-2 infection. Conflicting results exist concerningthe mechanisms by which the SARS-CoV-2 virus acts on the vasculature. The presence of the virus within endothelial cells has been reported in patient samples. However, the ACE2 receptor wasnot detected in endothelial cells when analyzed by RNAseq analysis. Thus, how SARS-CoV-2 contributes to vascular inflammation and whether cross-talk between epithelial cells and endothelial cells is involvedare unclear. Therefore, we investigated the interaction between SARS-CoV-2 and the vasculature using 2D and 3D in vitro models, as well asour previously developed 3D vesseloid model. We first determined the suitability of the 3D vesseloid model for our study and then assessed whether SARS-CoV-2 is able to directly infect endothelial cells. In the absence of ACE2 in endothelial cells, no infection was detected. When ACE2 was overexpressed in endothelial cells, low uptake of viral particles by endothelial cells was observed without efficient viral production. We then explored the possibility that an indirect effect of SARS-CoV-2 infection involvesepithelial-endothelial cellcross-talk. After infection of the epithelial cells, a significant inflammatory response was detected in the endothelial cells. Furthermore, we investigated the cytokines possibly implicated and identified CXCL10 as the most highly expressed proinflammatorycytokine and explored its function in this context. Finally, the clinical relevance of our findings was confirmed by evaluating CXCL10 and alternative cytokine dosages in blood samples fromSARS-CoV-2-infected patients, which were validated in silico in an independent patient cohort.


Subject(s)
Inflammation , COVID-19 , Infections
14.
preprints.org; 2024.
Preprint in English | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202401.1910.v1

ABSTRACT

Acute kidney infection (AKI) occurred by tubular necrosis and glomerular dysfunction caused by many factors. SARS CoV-2 infection identified to cause fatal AKI. This paper aims to review the effect of covid-19 infection on the failure of the kidney and its mechanism. It identified that the SARS-CoV-2 received by the targeted cell by Angiotensin-converting enzyme 2 (ACE2). After the virus received by the target cells, it induces the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, and interferons (IFN) by immune cells and causes cytokine storm. The pro-inflammatory cytokines are again responsible to induce the secretion of cyclooxygenase‑2 (COX‑2), which causes inflammation and pain as well it stimulates the iNOS enzyme to produce NO which allows the vasodilation of renal arteries. The increased production of NO by iNO enhanced the vasodilation of arteries, and allows the adhesion of neutrophils to the artery, and causes damage to glomerulus and tubules. Hence, the most likely sustainable intervention could be the application of angiotensin-converting enzyme 2 (ACE2) inhibition by the receptors of the target cells in these vital organs to reduce sever destruction during treatment at the early stage of infection.


Subject(s)
Inflammation , Kidney Diseases , Severe Acute Respiratory Syndrome , COVID-19 , Pain , Necrosis , Acute Kidney Injury
15.
preprints.org; 2024.
Preprint in English | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202401.2016.v1

ABSTRACT

Viruses continue to provide vital insights into the field of control of gene expression. Viral transactivators, in concert with other viral and cellular proteins, regulate expression of self, other viruses, and host genes with profound effects on infected cells, underlying inflammation, control of immune responses, and pathogenesis. The multifunctional Tat proteins of lentiviruses (HIV-1, HIV-2, and SIV) transactivate gene expression by recruiting host proteins and binding to trans-acting responsive regions (TARs) in viral and host RNAs. SARS-CoV-2 nucleocapsid participates in early viral transcription, recruits similar cellular proteins, and shares intracellular, surface, and extracellular distribution with Tat. SARS-CoV-2 nucleocapsid interacting with the Replication-Transcription complex might, therefore, transactivate viral and cellular RNAs in transcription and reactivation of self and other viruses, acute and chronic pathogenesis, immune evasion, and viral evolution, constituting a potential pan-coronaviral therapeutic target. Here, we show by using primary and secondary structural comparisons that the leaders of SARS-CoV-2 and other coronaviruses contain TAR-like sequences in stem-loops 2 and 3, the coronaviral nucleocapsid C-terminal domains (N-CTDs) harbor a region of similarity to TAR-binding regions of lentiviral Tat proteins, and the coronaviral nonstructural protein 12 has a cysteine-rich metal binding, dimerization domain similar to that in lentiviral Tat proteins.


Subject(s)
Severe Acute Respiratory Syndrome , HIV Infections , Inflammation
16.
researchsquare; 2024.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3903857.v1

ABSTRACT

The ongoing COVID-19 pandemic necessitates the identification of effective biomarkers to gauge disease severity. C-reactive protein (CRP), D-Dimer, and White Blood Cell counts (WBCs) have emerged as potential indicators of COVID-19 severity and prognosis. This research, conducted at Qalla Hospital, enrolled 112 confirmed COVID-19 patients and 35 healthy controls, employing comprehensive clinical and laboratory evaluations that included CRP, D-Dimer, and WBC measurements. The diagnosis of COVID-19 adhered to established clinical criteria and was confirmed through SARS-CoV-2 testing, with stringent assessments to ensure precise participant classification. The results unveiled significantly elevated CRP (p-value=0.0001), D-Dimer (p-value=0.0001), and WBCs in COVID-19 patients compared to healthy controls. Elevated CRP levels, indicative of inflammation, increased D-Dimer levels associated with coagulation abnormalities, and raised WBCs within the CRP level (0.943), indicative of an immune response, were prevalent in COVID-19 patients. Gender distribution was balanced, while comorbidities such as diabetes mellitus (25%), hypertension (34.8%), kidney disease (6.2%), and multiple concurrent diseases (34%) were prevalent in the COVID-19 cohort. The discussion underscores the substantial differences in CRP, D-Dimer, and WBCs, emphasizing their potential as valuable biomarkers for diagnosing and monitoring COVID-19 severity. These biomarkers could serve as critical tools in evaluating disease progression, predicting complications, and guiding tailored therapeutic interventions. In conclusion, CRP, D-Dimer, and WBCs exhibited marked disparities between healthy individuals and COVID-19 patients, indicating their potential as diagnostic and prognostic indicators. Continued investigation into the utility of these biomarkers may refine risk stratification and treatment strategies, ultimately enhancing patient outcomes in COVID-19 management. A deeper understanding of the clinical implications of CRP, D-Dimer, and WBC levels could profoundly impact disease management and patient care strategies.


Subject(s)
Diabetes Mellitus , Inflammation , Kidney Diseases , COVID-19 , Coagulation Protein Disorders , Hypertension
17.
researchsquare; 2024.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3904203.v1

ABSTRACT

Background: The Coronavirus Disease 2019 (COVID-19) pandemic has had a significant global impact, particularly on the older adult population. To address concerns regarding the emergence and persistence of cognitive impairment and its potential risk factors, this study aimed to investigate cognitive function and its relationship with inflammation in older COVID-19 survivors during a three-month follow-up. Methods: In this descriptive-analytical study, 177 hospitalized patients with COVID-19 aged >60 years were examined between July 2021 and February 2022.Psychiatric and cognitive assessments were conducted at discharge and at one month and three months post-discharge. All the statistical analyses were conducted using a Statistical Package for the Social Sciences (SPSS) version 24 (P<0.05). Cognitive status was analyzed with the Repeated Measures Test, and relationships between inflammatory indices and cognitive function were explored via the Pearson correlation test and Mann‒Whitney U test. The normality of the data was examined using the Kolmogorov‒Smirnov test. Results:A cognitive assessment of patients indicated lower scores onthe informant subscales of the General Practitioner Assessment of Cognition (GPCOG) during the time of discharge, as well as at the 1-and 3-month follow-up intervals. Negative correlations were found between cognitive function and depression/anxiety. Elevated C-reactive protein (CRP), D-dimer, and Lactate dehydrogenase (LDH) levels were linked to lower cognitive scores, while the Erythrocyte sedimentation rate (ESR) and Creatine phosphokinase (CPK) were not significantly correlated. Over time, cognitive function and anxiety improved, while depression and daily activity challenges persisted. Conclusions: This study highlights the lingering impact of inflammation on cognition among older COVID-19 survivors. Moreover, these findings underscore the urgent need for focused interventions and rehabilitation efforts to foster sustained cognitive recovery in this population.


Subject(s)
Inflammation , Depressive Disorder , COVID-19 , Mental Disorders , Anxiety Disorders , Cognition Disorders
18.
researchsquare; 2024.
Preprint in English | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-3891055.v1

ABSTRACT

Background and aim: Millions of people worldwide have suffered from coronavirus disease 2019 (COVID-19). COVID-19 can lead to coagulopathy and thrombosis, presenting as pulmonary artery thromboembolism, deep vein thrombosis, and thrombotic microangiopathy (TMA), the latter being a rare finding in affected patients’ kidneys. Prior reports have rarely addressed the pathophysiology, clinical presentations, and therapeutic options in patients with COVID-19-associated TMA. Case presentation: We herein described a case of renal biopsy-proven TMA after COVID-19 in a 36-year-old woman. Initial examination revealed inflammation, acute kidney injury (AKI), anemia, and thrombocytopenia. She was diagnosed with hemolytic uremic syndrome, pulmonary infection, and COVID-19. After treatment, her condition stabilized but remained hemodialysis-dependent after discharge. One week later, she was re-hospitalized, and physical examination showed anemia and bilateral lower extremity edema. Abdominal ultrasound showed increased bilateral kidney echogenicity. Whole-exome sequencing detected an unknown variant of the C3 gene associated with hemolytic uremic syndrome susceptibility type 5/complement C3 deficiency. Kidney biopsy showed renal artery lesions, including small arteriole endothelial swelling, intimal thickening, mucinous degeneration, luminal occlusion, and small arterial wall necrosis. She received plasma exchange and steroids with significant renal function recovery. Conclusion: TMA likely contributed to AKI after COVID-19,thus supporting the notion that TMA plays an important role in the pathogenesis of COVID-19-related kidney injury. When diagnosing and treating COVID-19 patients with abnormal renal function, clinicians should incorporate kidney biopsy and genetic testing for the complement system, identify renal-limited and systemic TMA, and treat accordingly, which can improve patient outcomes.


Subject(s)
Edema , Thrombotic Microangiopathies , Thrombocytopenia , Pulmonary Embolism , Inflammation , Kidney Diseases , COVID-19 , Hemolytic-Uremic Syndrome , Anemia , Coronary Occlusion , Adenocarcinoma, Mucinous , Necrosis , Venous Thrombosis , Thrombosis , Acute Kidney Injury
19.
biorxiv; 2024.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2024.01.10.575114

ABSTRACT

SARS-CoV-2, the virus responsible for COVID-19, triggers symptoms such as sneezing, aches and pain.1 These symptoms are mediated by a subset of sensory neurons, known as nociceptors, that detect noxious stimuli, densely innervate the airway epithelium, and interact with airway resident epithelial and immune cells.2-6 However, the mechanisms by which viral infection activates these neurons to trigger pain and airway reflexes are unknown. Here, we show that the coronavirus papain-like protease (PLpro) directly activates airway-innervating trigeminal and vagal nociceptors in mice and human iPSC-derived nociceptors. PLpro elicits sneezing and acute pain in mice and triggers the release of neuropeptide calcitonin gene-related peptide (CGRP) from airway afferents. We find that PLpro-induced sneeze and pain requires the host TRPA1 ion channel that has been previously demonstrated to mediate pain, cough, and airway inflammation.7-9 Our findings are the first demonstration of a viral product that directly activates sensory neurons to trigger pain and airway reflexes and highlight a new role for PLpro and nociceptors in COVID-19.


Subject(s)
Acute Pain , Inflammation , Pain , Severe Acute Respiratory Syndrome , COVID-19
20.
medrxiv; 2024.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2024.01.11.24301000

ABSTRACT

Pre-existing anti-interferon alpha (anti-IFN-) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti-IFN- autoantibodies in the airways - the initial site of infection - can also determine disease outcomes. In this study, we developed a new multiparameter technology, flowBEAT, to quantify and profile the isotypes of anti-IFN- and anti-SARS-CoV-2 antibodies in longitudinal samples collected over 20 months from the airway and matching blood of 129 donors with mild, moderate, and severe COVID-19. We found unexpectedly that nasal anti-IFN- autoantibodies were induced post-infection onset in more than 70% of mild to moderate COVID-19 cases and associated with robust anti-SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti-IFN- autoantibodies followed the peak of host IFN- production and waned with disease recovery, revealing a regulated balance between IFN- and anti-IFN- response. Notably, only a subset of mild to moderate patients progressed to develop systemic anti-IFN-, which correlated with systemic inflammation and worsened symptoms. In contrast, patients with life-threatening COVID-19 sustained elevated anti-IFN- in both airways and blood, coupled with uncontrolled viral load and IFN- production. Our studies thereby reveal a novel protective role for nasal anti-IFN- autoantibodies in the immunopathology of COVID-19 and, more broadly, suggest that anti-IFN- may serve an important regulatory function to restore homeostasis following viral invasion of the respiratory mucosa.


Subject(s)
COVID-19 , Inflammation
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