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1.
Viruses ; 14(3)2022 03 05.
Article in English | MEDLINE | ID: covidwho-1732241

ABSTRACT

Profound clinical differences between the first and second waves of COVID-19 were observed in Europe. Nitric oxide (NO) may positively impact patients with Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection. It is mainly generated by inducible nitric oxide synthase (iNOS). We studied serum iNOS levels together with serum interleukin (IL)-6 and IL-10 in patients with SARS-CoV-2 infection in the first wave (n = 35) and second wave (n = 153). In the first wave, serum iNOS, IL-6, IL-10 levels increased significantly, in line with the World Health Organization (WHO) score severity, while in the second wave, iNOS did not change with the severity. The patients of the second wave showed lower levels of iNOS, IL-6, and IL-10, as compared to the corresponding subgroup of the first wave, suggesting a less severe outcome of COVID-19 in these patients. However, in the severe patients of the second wave, iNOS levels were significantly lower in patients treated with steroids or azithromycin before the hospitalization, as compared to the untreated patients. This suggests an impairment of the defense mechanism against the virus and NO-based therapies as a potential therapy in patients with low iNOS levels.


Subject(s)
COVID-19 , Humans , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II , SARS-CoV-2
2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-307685

ABSTRACT

Importance: Clinical severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seems to be lower in children compared to that in adults. Defining the pathophysiological mechanisms of such disease patterns maybe relevant for development of effective public health strategies. It has been hypothesised that the lower severity of SARS-CoV-2 infection in children could be due to the differential expression of angiotensin-converting enzyme 2 (ACE2), which serves as a virus receptor.Objective: To evaluate the expression of ACE2, ACE1, and TMPRSS2 genes at the level of the two most relevant entry sites for SARS-CoV-2, the upper respiratory tract and small intestine, in healthy children and adult subjects.Design, Setting, and Participants: This prospective study included healthy individuals of both sexes, aged 1-10 years in the paediatric population (n=30) and 20-80 years in the adult population (n=30). The participants were consecutively evaluated at two tertiary centres for paediatrics, gastroenterology, and otolaryngology.Main Measures: Expression of ACE2, ACE1, and TMPRSS2 genes in samples collected from the upper respiratory tract and small intestine.Results: We found no difference in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium between children and adult subjects. ACE2 expression was more abundant in the small intestine of children compared to that in adults. ACE1 expression was higher in the small intestine of adults compared to that in children. Intestinal TMPRSS2 expression was similar in the two study populations.Conclusions and Relevance: The general lower severity of SARS-CoV-2 infection in children does not seem to be related to a lower expression of ACE2 and/or TMPRSS2 in the respiratory tract or in the gastrointestinal tract. Other co-factors may confer protection against SARS-CoV-2 in children. The exploration of such factors is of pivotal importance for development of innovative protective strategies against SARS-CoV-2.Funding Statement: This work was supported in part by a grant of Regione Campania POR FESR 2014/2020, Task Force Covid-19 DGR 140 – 17 March 2020.Declaration of Interests: The authors have no other conflict of interests that are directly relevant to the content of this manuscript, which remains their sole responsibility.Ethics Approval Statement: The study was approved by the Ethics Committee of the University Federico II of Naples, Italy. Written informed consent was obtained from the adult participants and from the parents/tutors of minors.

3.
Sci Rep ; 12(1): 1212, 2022 01 24.
Article in English | MEDLINE | ID: covidwho-1649849

ABSTRACT

The molecular basis of the wide clinical heterogeneity of Coronavirus disease 2019 (COVID-19) is still unknown. Matrix metalloproteinases (MMPs) may have a role in the lung damage and regeneration that occur in severe patients. We studied serum MMP3 and MMP9 as potential biomarkers of COVID-19 severity, in 108 hospitalized patients with different World Health Organization (WHO) severity stage and in 48 controls. At hospital admission, serum MMP3 was increased in COVID-19 patients with a significant trend along the progression of the WHO stage, while serum levels of MMP9 were significantly increased in COVID-19 patients with no correlation with disease severity. At 1 week from hospitalization, MMP3 was reduced, suggesting an early pathogenic role of the protein in lung inflammation, while MMP9 levels were further increased, indicating a late role of the protein in the inflammatory process, specifically during the repairing phase. Furthermore, serum MMP9 was positively correlated with serum interleukin-6, myeloperoxidase, and circulating neutrophils and monocytes number. In conclusion, serum MMP3 may help to early predict the severity of COVID-19 and both proteins, MMP3 and MMP9, may contribute to define severe COVID-19 patients that may benefit from a targeted therapy on MMPs.


Subject(s)
COVID-19/blood , Matrix Metalloproteinase 3/blood , Matrix Metalloproteinase 9/blood , Patient Acuity , SARS-CoV-2/metabolism , Adult , Aged , Biomarkers/blood , Female , Humans , Male , Middle Aged
6.
Biomolecules ; 11(9)2021 09 16.
Article in English | MEDLINE | ID: covidwho-1408458

ABSTRACT

Systemic vascular damage with micro/macro-thrombosis is a typical feature of severe COVID-19. However, the pathogenesis of this damage and its predictive biomarkers remain poorly defined. For this reason, in this study, serum monocyte chemotactic protein (MCP)-2 and P- and E-selectin levels were analyzed in 204 patients with COVID-19. Serum MCP-2 and P-selectin were significantly higher in hospitalized patients compared with asymptomatic patients. Furthermore, MCP-2 increased with the WHO stage in hospitalized patients. After 1 week of hospitalization, MCP-2 levels were significantly reduced, while P-selectin increased in patients in WHO stage 3 and decreased in patients in WHO stages 5-7. Serum E-selectin was not significantly different between asymptomatic and hospitalized patients. The lower MCP-2 levels after 1 week suggest that endothelial damage triggered by monocytes occurs early in COVID-19 disease progression. MCP-2 may also predict COVID-19 severity. The increase in P-selectin levels, which further increased in mild patients and reduced in severe patients after 1 week of hospitalization, suggests that the inactive form of the protein produced by the cleavage of the active protein from the platelet membrane is present. This may be used to identify a subset of patients that would benefit from targeted therapies. The unchanged levels of E-selectin in these patients suggest that endothelial damage is less relevant.


Subject(s)
COVID-19 , Chemokine CCL8/blood , E-Selectin/blood , Endothelium, Vascular , P-Selectin/blood , SARS-CoV-2/metabolism , Adult , Aged , COVID-19/blood , COVID-19/pathology , Endothelium, Vascular/injuries , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Female , Humans , Male , Middle Aged , Monocytes/metabolism , Monocytes/pathology
7.
Viruses ; 13(9)2021 08 29.
Article in English | MEDLINE | ID: covidwho-1374540

ABSTRACT

A relationship is emerging between SARS-CoV-2 infections and ANCA-associated vasculitis (AAV) because: (i) the pulmonary involvement of COVID-19 may mimic that observed in patients with AAV; (ii) the two diseases may occur together; (iii) COVID-19 may trigger AAV. However, few cases of AAV have been identified so far in COVID-19 patients. To define the frequency of ANCA autoimmunity in patients with SARS-CoV-2 infection, we analyzed the serum ANCAs and the serum PR3 and MPO antigens by immunoassays in 124 adult patients with a diagnosis of SARS-CoV-2 infection (16 were asymptomatic and 108 were hospitalized) and 48 control subjects. The serum ANCAs were significantly higher in the hospitalized patients compared with either the controls or the asymptomatic patients and increased with the progression of the COVID-19 severity. After one week of hospitalization, the values were significantly lower. In contrast, no differences emerged among the controls, asymptomatic and hospitalized patients for the PR3 and MPO serum levels. None of the patients had clinical signs of AAV with the exception of a severe pulmonary involvement. Further studies are necessary to define whether the increase in the serum ANCAs might mask subclinical vasculitis in a percentage of patients with SARS-CoV-2 infection or it is an epiphenomenon of SARS-CoV-2 infection with no clinical manifestations.


Subject(s)
Antibodies, Antineutrophil Cytoplasmic/blood , COVID-19/blood , COVID-19/virology , SARS-CoV-2 , Adult , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/blood , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/etiology , COVID-19/diagnosis , COVID-19/immunology , Disease Susceptibility , Female , Humans , Immunoassay , Male , Middle Aged , Pilot Projects , Symptom Assessment
8.
Front Pediatr ; 9: 697390, 2021.
Article in English | MEDLINE | ID: covidwho-1357534

ABSTRACT

Background: Clinical features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection seem to differ in children compared to that in adults. It has been hypothesized that the lower clinical severity in children could be influenced by differential expression of the main host functional receptor to SARS-CoV-2, the angiotensin-converting enzyme 2 (ACE2), but data are still conflicting. To explore the origin of age-dependent clinical features of coronavirus disease 2019 (COVID-19), we comparatively evaluated the expression in children and adult subjects of the most relevant mediators of the SARS-CoV-2 infection: ACE2, angiotensin-converting enzyme 1 (ACE1), transmembrane serine protease-2 (TMPRSS2), and neuropilin-1 (NRP1), at upper respiratory tract and small intestine level. Methods: The expression of ACE2, ACE1, TMPRSS2, and NRP1 in nasal epithelium and in small intestine epithelium was investigated by quantitative real-time PCR analysis. Results: We found no differences in ACE2, ACE1, and TMPRSS2 expression in the nasal epithelium comparing children and adult subjects. In contrast, nasal epithelium NRP1 expression was lower in children compared to that in adults. Intestinal ACE2 expression was higher in children compared to that in adults, whereas intestinal ACE1 expression was higher in adults. Intestinal TMPRSS2 and NRP1 expression was similar comparing children and adult subjects. Conclusions: The lower severity of SARS-CoV-2 infection observed in children may be due to a different expression of nasal NRP1, that promotes the virus interaction with ACE2. However, the common findings of intestinal symptoms in children could be due to a higher expression of ACE2 at this level. The insights from these data will be useful in determining the treatment policies and preventive measures for COVID-19.

9.
Sci Signal ; 14(690)2021 07 06.
Article in English | MEDLINE | ID: covidwho-1299215

ABSTRACT

Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO4 3-) units linked together by multiple high-energy phosphoanhydride bonds. In addition to being a source of energy, polyPs have cytoprotective and antiviral activities. Here, we investigated the antiviral activities of long-chain polyPs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In molecular docking analyses, polyPs interacted with several conserved amino acid residues in angiotensin-converting enzyme 2 (ACE2), the host receptor that facilitates virus entry, and in viral RNA-dependent RNA polymerase (RdRp). ELISA and limited proteolysis assays using nano- LC-MS/MS mapped polyP120 binding to ACE2, and site-directed mutagenesis confirmed interactions between ACE2 and SARS-CoV-2 RdRp and identified the specific amino acid residues involved. PolyP120 enhanced the proteasomal degradation of both ACE2 and RdRp, thus impairing replication of the British B.1.1.7 SARS-CoV-2 variant. We thus tested polyPs for functional interactions with the virus in SARS-CoV-2-infected Vero E6 and Caco2 cells and in primary human nasal epithelial cells. Delivery of a nebulized form of polyP120 reduced the amounts of viral positive-sense genomic and subgenomic RNAs, of RNA transcripts encoding proinflammatory cytokines, and of viral structural proteins, thereby presenting SARS-CoV-2 infection in cells in vitro.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Polyphosphates/pharmacology , SARS-CoV-2/drug effects , Administration, Inhalation , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , COVID-19/metabolism , COVID-19/virology , Caco-2 Cells , Chlorocebus aethiops , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/genetics , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Cytokines/metabolism , HEK293 Cells , Host Microbial Interactions/drug effects , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , In Vitro Techniques , Models, Biological , Molecular Docking Simulation , Nebulizers and Vaporizers , Polyphosphates/administration & dosage , Polyphosphates/chemistry , Proteasome Endopeptidase Complex/metabolism , Protein Interaction Domains and Motifs , Proteolysis/drug effects , RNA, Viral/genetics , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Sequence Homology, Amino Acid , Signal Transduction/drug effects , Vero Cells , Virus Replication/drug effects
10.
Diagnostics (Basel) ; 11(2)2021 Feb 12.
Article in English | MEDLINE | ID: covidwho-1085113

ABSTRACT

The COVID-19 pandemic has forced diagnostic laboratories to focus on the early diagnostics of SARS-CoV-2. The positivity of a molecular test cannot respond to the question regarding the viral capability to replicate, spread, and give different clinical effects. Despite the fact that some targets are covered by commercially-available assays, the identification of new biomarkers is desired in order to improve the quality of the information given by these assays. Therefore, since the subgenomic transcripts (sgN and sgE) are considered markers of viral activity, we evaluated these subgenomic transcripts in relation to the genomic amplification obtained using five different commercial CE-IVD tools. Methods: Five CE-IVD kits were compared in terms of their capability to detect both synthetic SARS-CoV-2 viral constructs (spiked in TMB or PBS medium) and targets (N, E, RdRp and Orf1ab genes) in twenty COVID-19-positive patients' swabs. The sgN and sgE were assayed by real-time RT-qPCR and digital PCR. Results: None of the diagnostic kits missed the viral target genes when they were applied to targets spiked in TMB or PBS (at dilutions ranging from 100 pg to 0.1 pg). Nevertheless, once they were applied to RNA extracted from the patients' swabs, the superimposability ranged from 50% to 100%, regardless of the extraction procedure. The sgN RNA transcript was detected only in samples with a higher viral load (Ct ≤ 22.5), while sgE was within all of the Ct ranges. Conclusions: The five kits show variable performances depending on the assay layout. It is worthy of note that the detection of the sgN transcript is associated with a higher viral load, thus representing a new marker of early and more severe infection.

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