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SARS-CoV-2 Systemic Effects: New Clues

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A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Virology".

Deadline for manuscript submissions: closed (25 November 2022) | Viewed by 50242

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Dr. Daria Bortolotti

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Guest Editor

Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy
Interests: viruses; host immunity to infections; innate immunity; infertility

Dr. Francesca Caccuri

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Guest Editor

Department of Molecular and Translational Medicine, Section of Microbiology, University of Brescia Medical School, Brescia, Italy
Interests: HIV; human respiratory viruses; vaccines; gene therapy; viral oncology; cell/host interaction; endothelial cell dysfunction; cancer microenvironment
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Special Issue Information

Dear Colleagues,

To date, much discussion has been had on SARS-CoV-2 lung infection associated with COVID-19 onset. Although the respiratory tract represents the main site of entry for the virus, even more evidence underlines the existence of an important systemic effect caused by the primary infection.

In particular, the involvement of different body compartments, such as the gastrointestinal tract, the cardiovascular system and the reproductive tract, appears even more clear.

The aim of this Special Issue of Microorganisms is to collect articles to provide a deeper knowledge on the systemic effect due to COVID-19.

Manuscripts covering all aspects of research relating to SARS-CoV-2 tissutal infection and its effect on the host are welcome, including work from an applied angle—such as novel diagnostics—through to more fundamental questions relating to the biology of the virus and its pathogenesis and epidemiology.

Dr. Daria Bortolotti
Dr. Francesca Caccuri
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review, Other

7 pages, 712 KiB

Open AccessEditorial

SARS-CoV-2 Systemic Effects: New Clues

by Silvia Beltrami, Sabrina Rizzo, Francesca Caccuri, Roberta Rizzo, Daria Bortolotti and Giovanna Schiuma

Microorganisms 2023, 11(5), 1209; https://doi.org/10.3390/microorganisms11051209 - 5 May 2023

Viewed by 2392

Abstract

To date, much discussion has been had on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lung infection associated with COVID-19 onset, of which the major manifestation is characterized by a “cytokine storm” [...] Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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Research

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16 pages, 1720 KiB

Open AccessArticle

TGF Beta as a Prognostic Biomarker of COVID-19 Severity in Patients with NAFLD—A Prospective Case–Control Study

by Frano Susak, Nina Vrsaljko, Adriana Vince and Neven Papic

Microorganisms 2023, 11(6), 1571; https://doi.org/10.3390/microorganisms11061571 - 13 Jun 2023

Cited by 6 | Viewed by 2062

Abstract

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease in Western countries, has been identified as a possible risk factor for COVID-19 severity. However, the immunological mechanisms by which NAFLD exacerbates COVID-19 remain unknown. Transforming growth factor-beta 1 (TGF-β1) has an important immunomodulatory and pro-fibrotic role, which has already been described in NAFLD. However, the role of TGF-β1 in COVID-19 remains unclear, and could also be the pathophysiology link between these two conditions. The aim of this case–control study was to analyze the expression of TGF-β1 in COVID-19 patients depending on the presence of NAFLD and COVID-19 severity. Serum TGF-β1 concentrations were measured in 60 hospitalized COVID-19 patients (30 with NAFLD). NAFLD was associated with higher serum TGF-β1 concentrations that increased with disease severity. Admission TGF-β1 concentrations showed good discriminative accuracy in predicting the development of critical disease and COVID-19 complications (need for advanced respiratory support, ICU admission, time to recovery, development of nosocomial infections and mortality). In conclusion, TGF-β1 could be an efficient biomarker for predicting COVID-19 severity and adverse outcomes in patients with NAFLD. Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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9 pages, 505 KiB

Open AccessArticle

Effect of Vitamin D₃ Supplementation vs. Dietary–Hygienic Measures on SARS-CoV-2 Infection Rates in Hospital Workers with 25-Hydroxyvitamin D3 [25(OH)D3] Levels ≥20 ng/mL

by Maria Elena Romero-Ibarguengoitia, Dalia Gutiérrez-González, Carlos Cantú-López, Miguel Ángel Sanz-Sánchez and Arnulfo González-Cantú

Microorganisms 2023, 11(2), 282; https://doi.org/10.3390/microorganisms11020282 - 21 Jan 2023

Cited by 4 | Viewed by 2231

Abstract

Background: There is scant information on the effect of supplementation with vitamin D3 in SARS-CoV-2 infection cases when patient 25-hydroxyvitamin D3 [25(OH)D3] levels are between 20–100 ng/mL. We aimed to evaluate the effect of supplementation with vitamin D3 vs. dietary–hygienic measures on the SARS-CoV-2 infection rate in participants with serum 25(OH)D3 levels ≥20 ng/mL. Methods: This study was quasi-experimental. We invited hospital workers with 25(OH)D3 levels between 20–100 ng/mL and no previous SARS-CoV-2 infection. They were randomized as follows: treatment options were a) vitamin D3 supplementation (52,000 IU monthly, G1) or b) dietary–hygienic measures (G2). We conducted a 3- to 6-month follow-up of SARS-CoV-2 infections. Participants with 25(OH)D3 levels <20 ng/mL were also analyzed. We divided these latter participants depending on whether they were supplemented (G3) or not (G4). Results: We analyzed 198 participants, with an average age of 44.4 (SD 9) years, and 130 (65.7%) were women. G1 had fewer cases of SARS-CoV-2 infection than G2 after a follow-up of 3- to 6-months (p < 0.05). There were no differences between G3 and G4 at the 3- and 6-month follow-up cutoff points (p > 0.05). Using a mixed effect Cox regression analysis in the 164 participants that completed six months of follow-up, vitamin D3 supplementation appeared to act as a protective factor against SARS-CoV-2 infection (HR 0.21, p = 0.008) in G1 and G2. None of the participants treated with the supplementation doses had serum 25(OH)D3 levels >100 ng/mL. Conclusions: Vitamin D3 supplementation in participants with 25(OH)D3 levels between 20–100 ng/mL have a lower rate of SARS-CoV-2 infection compared with the use of dietary–hygienic measures at six months follow-up. Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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11 pages, 1432 KiB

Open AccessArticle

Low Interferon-γ Levels in Cord and Peripheral Blood of Pregnant Women Infected with SARS-CoV-2

by Michele Cennamo, Evelina La Civita, Laura Sarno, Gianluigi Carbone, Sarah Di Somma, Serena Cabaro, Jacopo Troisi, Angelo Sirico, Francesco Paolo Improda, Maurizio Guida, Daniela Terracciano and Giuseppe Portella

Microorganisms 2023, 11(1), 223; https://doi.org/10.3390/microorganisms11010223 - 16 Jan 2023

Cited by 5 | Viewed by 2814

Abstract

COVID-19 is characterized by the immune system’s overreaction resulting in a ‘cytokine storm’, consisting in a massive release of cytokine into the bloodstream, leading to local and systemic inflammatory response. This clinical picture is further complicated in case of infection of patients with a peculiar immunological status, such as pregnancy. In this paper, we focused on Interferon-γ, which plays a pivotal immunomodulatory role in normal pregnancy and fetal development, as well as in defense against pathogens. In this study, we compared the levels of Interferon-γ and the Interferon autoantibodies of the peripheral and cord blood of pregnant women with confirmed mild COVID-19 and healthy pregnant women. The Interferon-γ was significantly lower both in the peripheral and cord blood of SARS-CoV-2-positive mothers, suggesting that infection can affect the fetal microenvironment even without severe maternal symptoms. In conclusion, further studies are needed to clarify whether lower levels of Interferon-γ due to SARS-CoV-2 infection affect the development or infection susceptibility of infants born to SARS-CoV-2-infected mothers. Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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9 pages, 235 KiB

Open AccessCommunication

Diabetes and SARS-CoV-2 Infection: The Potential Role of Antidiabetic Therapy in the Evolution of COVID-19

by Biagio Pinchera, Nicola Schiano Moriello, Antonio Riccardo Buonomo, Isabella Di Filippo, Anastasia Tanzillo, Giorgio Buzzo, Riccardo Villari, Ivan Gentile and Federico II COVID Team

Microorganisms 2023, 11(1), 145; https://doi.org/10.3390/microorganisms11010145 - 6 Jan 2023

Cited by 1 | Viewed by 2316

Abstract

Diabetes mellitus represents one of the most frequent comorbidities among patients with COVID-19, constituting a risk factor for a more severe prognosis than that of non-diabetic patients. However, the pathophysiological mechanism underlying this unfavorable outcome is still not completely clear. The goal of [...] Read more.

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

14 pages, 716 KiB

Open AccessArticle

Clinical and Functional Predictors of Response to a Comprehensive Pulmonary Rehabilitation in Severe Post-COVID-19 Patients

by Marc Spielmanns, Melissa Masha Buelow, Anna Maria Pekacka-Egli, Mikis Cecon, Sabine Spielmanns, Wolfram Windisch and Matthias Hermann

Microorganisms 2021, 9(12), 2452; https://doi.org/10.3390/microorganisms9122452 - 28 Nov 2021

Cited by 9 | Viewed by 2655

Abstract

Background: Pulmonary rehabilitation (PR) following severe and very severe COVID-19 infection is known to be effective, according to typical assessments. However, not all patients benefit from PR to the same extent. This analysis aimed to identify the impact of different factors on PR outcomes in post-COVID-19 patients. Methods: This prospective observational study included 184 post-COVID-19 patients. The achievement of the predicted reference walking distance (6 min walking distance (6-MWD)) served as a parameter with which to identify responders and non-responders to PR. Several parameters (e.g., Functional Independent Measurement (FIM); pulmonary function testing (Forced Vital Capacity, FVC); 6MWD) were assessed in order to estimate their impact on PR success. Logistic regression models and classification and regression trees were used for multivariate analysis. Results: A total of 94 patients (51%) reached their reference 6MWD by the end of PR. FVC (0.95 (0.93–0.97)), 6MWD at admission (0.99 (0.99–1.00)), and FIM motoric (0.96 (0.93–0.99)) correlated with the risk not reaching the reference distance. The most important variable was the 6MWD at admission. Classification and regression tree identified 6MWD ≥ 130 m at admission and FVC predicted of >83% as the strongest predictor for reaching predicted 6-MWD. Conclusion: Post-COVID-19 patients with lower 6MWD, lower motoric FIM scores and lower FVC at admission have a high risk of not reaching their target values of physical performance despite intensive rehabilitation. As well as identifying them, it is of utmost importance to develop optimal PR concepts for these patients. Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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14 pages, 3007 KiB

Open AccessArticle

TLR3 and TLR7 RNA Sensor Activation during SARS-CoV-2 Infection

by Daria Bortolotti, Valentina Gentili, Sabrina Rizzo, Giovanna Schiuma, Silvia Beltrami, Giovanni Strazzabosco, Mercedes Fernandez, Francesca Caccuri, Arnaldo Caruso and Roberta Rizzo

Microorganisms 2021, 9(9), 1820; https://doi.org/10.3390/microorganisms9091820 - 26 Aug 2021

Cited by 127 | Viewed by 7277

Abstract

(1) Background: Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent for the coronavirus disease (COVID-19) that has led to a pandemic that began in March 2020. The role of the SARS-CoV-2 components on innate and adaptive immunity is still unknown. We investigated the possible implication of pathogen-associated molecular patterns (PAMPs)–pattern recognition receptors (PRRs) interaction. (2) Methods: We infected Calu-3/MRC-5 multicellular spheroids (MTCSs) with a SARS-CoV-2 clinical strain and evaluated the activation of RNA sensors, transcription factors, and cytokines/interferons (IFN) secretion, by quantitative real-time PCR, immunofluorescence, and ELISA. (3) Results: Our results showed that the SARS-CoV-2 infection of Calu-3/MRC-5 multicellular spheroids induced the activation of the TLR3 and TLR7 RNA sensor pathways. In particular, TLR3 might act via IRF3, producing interleukin (IL)-1α, IL-1β, IL-4, IL-6, and IFN-α and IFN-β, during the first 24 h post-infection. Then, TLR3 activates the NFκB transduction pathway, leading to pro-inflammatory cytokine secretion. Conversely, TLR7 seems to mainly act via NFκB, inducing type 1 IFN, IFN-γ, and IFN-λ3, starting from the 48 h post-infection. (4) Conclusion: We showed that both TLR3 and TLR7 are involved in the control of innate immunity during lung SARS-CoV-2 infection. The activation of TLRs induced pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-4, and IL-6, as well as interferons. TLRs could be a potential target in controlling the infection in the early stages of the disease. Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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21 pages, 4469 KiB

Open AccessArticle

SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells

by Francesca Caccuri, Antonella Bugatti, Alberto Zani, Antonella De Palma, Dario Di Silvestre, Ekta Manocha, Federica Filippini, Serena Messali, Paola Chiodelli, Giovanni Campisi, Simona Fiorentini, Fabio Facchetti, Pierluigi Mauri and Arnaldo Caruso

Microorganisms 2021, 9(7), 1438; https://doi.org/10.3390/microorganisms9071438 - 3 Jul 2021

Cited by 27 | Viewed by 4556

Abstract

SARS-CoV-2-associated acute respiratory distress syndrome (ARDS) and acute lung injury are life-threatening manifestations of severe viral infection. The pathogenic mechanisms that lead to respiratory complications, such as endothelialitis, intussusceptive angiogenesis, and vascular leakage remain unclear. In this study, by using an immunofluorescence assay and in situ RNA-hybridization, we demonstrate the capability of SARS-CoV-2 to infect human primary lung microvascular endothelial cells (HL-mECs) in the absence of cytopathic effects and release of infectious particles. Preliminary data point to the role of integrins in SARS-CoV-2 entry into HL-mECs in the absence of detectable ACE2 expression. Following infection, HL-mECs were found to release a plethora of pro-inflammatory and pro-angiogenic molecules, as assessed by microarray analyses. This conditioned microenvironment stimulated HL-mECs to acquire an angiogenic phenotype. Proteome analysis confirmed a remodeling of SARS-CoV-2-infected HL-mECs to inflammatory and angiogenic responses and highlighted the expression of antiviral molecules as annexin A6 and MX1. These results support the hypothesis of a direct role of SARS-CoV-2-infected HL-mECs in sustaining vascular dysfunction during the early phases of infection. The construction of virus-host interactomes will be instrumental to identify potential therapeutic targets for COVID-19 aimed to inhibit HL-mEC-sustained inflammation and angiogenesis upon SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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12 pages, 1611 KiB

Open AccessEditor’s ChoiceCommunication

SARS-CoV-2 Infects Hamster Testes

by Rafael K. Campos, Vidyleison N. Camargos, Sasha R. Azar, Clint A. Haines, Eduardo J. Eyzaguirre and Shannan L. Rossi

Microorganisms 2021, 9(6), 1318; https://doi.org/10.3390/microorganisms9061318 - 17 Jun 2021

Cited by 21 | Viewed by 15349

Abstract

The COVID-19 pandemic continues to affect millions of people worldwide. Although SARS-CoV-2 is a respiratory virus, there is growing concern that the disease could cause damage and pathology outside the lungs, including in the genital tract. Studies suggest that SARS-CoV-2 infection can damage the testes and reduce testosterone levels, but the underlying mechanisms are unknown and evidence of virus replication in testicular cells is lacking. We infected golden Syrian hamsters intranasally, a model for mild human COVID-19, and detected viral RNA in testes samples without histopathological changes up to one month post-infection. Using an ex vivo infection model, we detected SARS-CoV-2 replication in hamster testicular cells. Taken together, our data raise the possibility that testes damage observed in severe cases of COVID-19 could be partly explained by direct SARS-CoV-2 infection of the testicular cells. Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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Review

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34 pages, 1384 KiB

Open AccessReview

Extra-Pulmonary Complications in SARS-CoV-2 Infection: A Comprehensive Multi Organ-System Review

by Taylor J. Louis, Ahmad Qasem, Latifa S. Abdelli and Saleh A. Naser

Microorganisms 2022, 10(1), 153; https://doi.org/10.3390/microorganisms10010153 - 12 Jan 2022

Cited by 33 | Viewed by 4922

Abstract

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is typically presented with acute symptoms affecting upper and lower respiratory systems. As the current pandemic progresses, COVID-19 patients are experiencing a series of nonspecific or atypical extra-pulmonary complications such as systemic inflammation, hypercoagulability state, and dysregulation of the renin–angiotensin–aldosterone system (RAAS). These manifestations often delay testing, diagnosis, and the urge to seek effective treatment. Although the pathophysiology of these complications is not clearly understood, the incidence of COVID-19 increases with age and the presence of pre-existing conditions. This review article outlines the pathophysiology and clinical impact of SARS-CoV-2 infection on extra-pulmonary systems. Understanding the broad spectrum of atypical extra-pulmonary manifestations of COVID-19 should increase disease surveillance, restrict transmission, and most importantly prevent multiple organ-system complications. Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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Other

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6 pages, 512 KiB

Open AccessBrief Report

Outliers Matter—Correlation between S1 IgG SARS-CoV-2 Antibodies and Neutralizing SARS-CoV-2 Antibodies

by Berthold Hocher, Anne Schönbrunn, Xin Chen, Bernhard K. Krämer and Volker von Baehr

Microorganisms 2022, 10(10), 2067; https://doi.org/10.3390/microorganisms10102067 - 19 Oct 2022

Cited by 3 | Viewed by 1818

Abstract

Vaccination against the SARS-CoV-2 virus or infection with SARS-CoV-2 will lead to the development of IgG antibodies against the S1 protein of the SARS-CoV-2 virus. However, even despite having high levels of IgG antibodies against the S1 protein of the SARS-CoV-2 virus, (re-)infection may occur. We thus examined 2994 consecutive blood samples of outpatients from the Berlin-Brandenburg area in Germany in which IgG antibodies against the S1 protein of the SARS-CoV-2 virus as well as neutralizing SARS-CoV-2 virus antibodies were determined from the same sample. When analyzing the entire study population (2994 outpatients), we saw that S1 IgG antibodies (women: 223.98 ± 3.81; men: 207.80 ± 4.59; p = 0.014) and neutralizing antibodies (women: 66.65 ± 0.82; men: 62.88 ± 1.01; p = 0.021) are slightly higher in women than in men. Curve fitting revealed a good non-linear relationship between S1 IgG and neutralizing SARS-CoV-2 antibodies. However, 51 out of the 2994 blood samples from individual subjects were positive with regard to the neutralizing antibodies and at the same time negative for S1 IgG antibodies, and 112 out of the 2994 blood samples from individual subjects were negative with regard to the neutralizing antibodies and at the same time positive for S1 IgG antibodies. In conclusion, our study shows that there is a relevant number of patients who, despite developing significant titers of S1 antibodies, do not have relevant amounts of neutralizing antibody titers and are probably at high risk of (re-)infection. Full article

(This article belongs to the Special Issue SARS-CoV-2 Systemic Effects: New Clues)

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