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Recent Advances in Pathophysiology and Immunology Related to SARS-CoV-2 Infection

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 May 2025 | Viewed by 4031

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Dr. Vito D’Agnano

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Guest Editor

Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, 80131 Naples, Italy
Interests: COVID-19; lung cancer; NSCLC; immune checkpoint inhibitors; ICIs; interstitial lung diseases; IPF; immunopathology

Special Issue Information

Dear Colleagues,

It has been three years since the worldwide spread of COVID-19, an extremely severe pandemic caused by a newly identified virus, termed SARS-CoV-2, a highly contagious betacoronavirus. The clinical spectrum of COVID-19 is extremely heterogeneous, ranging from an asymptomatic course to a very severe clinical scenario, with respiratory failure and death.

From a pathophysiological perspective, the chain of events from the first viral contact to the clinical manifestation, although known, may be unpredictable from one subject to another. In addition, the resolution phase of COVID-19 is not homogenous amongst patients. Whilst innate as well as adaptive immunity are crucial to combat infection, an excessive and dysregulated immune response is recognized to be counter-productive.

To enhance our comprehension of the pathophysiology and immunology of COVID-19, this Special Issue aims to collect the most recent evidence and advances in this specific field. Original research articles and comprehensive reviews covering the pathophysiological and immunological biomolecular aspects of SARS-CoV-2 infection and its clinical manifestations are welcomed in this Special Issue.

Dr. Vito D’Agnano
Guest Editor

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Keywords

SARS-CoV-2
COVID-19
immunology
pathophysiology
immunopathology

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Published Papers (5 papers)

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Research

11 pages, 442 KiB

Open AccessArticle

Coronavirus Disease 2019-Associated Thrombotic Microangiopathy: A Single-Center Experience

by Marija Malgaj Vrečko, Andreja Aleš-Rigler, Špela Borštnar and Željka Večerić-Haler

Int. J. Mol. Sci. 2024, 25(22), 12475; https://doi.org/10.3390/ijms252212475 - 20 Nov 2024

Viewed by 220

Abstract

Coronavirus disease 2019 (COVID-19) can lead to various multisystem disorders, including thrombotic microangiopathy (TMA). We present here eight patients with COVID-19-associated TMA who were treated at our center. Our aim was to summarize the demographic and clinical characteristics of the patients and discuss the possible role of COVID-19. One patient presented with thrombotic thrombocytopenic purpura (TTP) and seven with atypical hemolytic–uremic syndrome (aHUS.) Most patients had no obvious symptoms of COVID-19, and TMA occurred after viremia. Two patients had concomitant non-COVID-19-related triggers for TMA: exposure to tacrolimus and everolimus; first presentation of antiphospholipid syndrome. The patient with TTP was treated with therapeutic plasma exchange (TPE), steroids and caplacizumab, resulting in complete hematologic recovery. Six patients with aHUS were treated with TPE with or without steroids, four of whom received a C5 complement inhibitor and one an intravenous immunoglobulin. One patient with aHUS was treated with a C5 complement inhibitor and a steroid. We observed one partial and one complete recovery of renal function, while five patients experienced renal failure. There were no deaths. We believe that COVID-19 may act as a trigger for TMA in patients who have either pre-existing endothelial injury or an underlying predisposition to complement activation, and may also trigger autoimmune diseases. As a consequence of the different underlying pathophysiologies, the treatment of COVID-19-associated TMA requires a specific approach based on the subtype of the syndrome and possible concomitant triggers. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology and Immunology Related to SARS-CoV-2 Infection)

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18 pages, 2642 KiB

Open AccessArticle

Dynamic Changes in Lymphocyte Populations and Their Relationship with Disease Severity and Outcome in COVID-19

by Ákos Vince Andrejkovits, Adina Huțanu, Doina Ramona Manu, Minodora Dobreanu and Anca Meda Văsieșiu

Int. J. Mol. Sci. 2024, 25(22), 11921; https://doi.org/10.3390/ijms252211921 - 6 Nov 2024

Viewed by 486

Abstract

Studies suggest that the dynamic changes in cellular response might correlate with disease severity and outcomes in SARS-CoV-2 patients. The study aimed to investigate the dynamic changes of lymphocyte subsets in patients with COVID-19. In this regard, 53 patients with COVID-19 were prospectively included, classified as mild, moderate, and severe. The peripheral lymphocyte profiles (LyT, LyB, and NK cells), as well as CD4+/CD8+, CD3+/CD19+, CD3+/NK and CD19+/NK ratios, and their dynamic changes during hospitalization and correlation with disease severity and outcome were assessed. We found significant differences in CD3+ lymphocytes between severity groups (p < 0.0001), with significantly decreased CD3+CD4+ and CD3+CD8+ in patients with severe disease (p < 0.0001 and p = 0.048, respectively). Lower CD3+/CD19+ and CD3+/NK ratios among patients with severe disease (p = 0.019 and p = 0.010, respectively) were found. The dynamic changes of lymphocyte subsets showed a significant reduction in NK cells (%) and a significant increase in CD3+CD4+ and CD3+CD8+ cells in patients with moderate and severe disease. The ROC analysis on the relationship between CD3+ cells and fatal outcome yielded an AUC of 0.723 (95% CI 0.583–0.837; p = 0.007), while after addition of age and SpO₂, ferritin and NLR, the AUC significantly improved to 0.927 (95%CI 0.811–0.983), p < 0.001 with a sensitivity of 90.9% (95% CI 58.7–99.8%) and specificity of 85.7% (95% CI 69.7–95.2%). The absolute number of CD3+ lymphocytes might independently predict fatal outcomes in COVID-19 patients and T-lymphocyte subset evaluation in high-risk patients might be useful in estimating disease progression. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology and Immunology Related to SARS-CoV-2 Infection)

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16 pages, 1431 KiB

Open AccessArticle

Transpulmonary Plasma Endothelin-1 Arterial:Venous Ratio Differentiates Survivors from Non-Survivors in Critically Ill Patients with COVID-19-Induced Acute Respiratory Distress Syndrome

by Alice G. Vassiliou, Anastasia Roumpaki, Chrysi Keskinidou, Nikolaos Athanasiou, Stamatios Tsipilis, Edison Jahaj, Charikleia S. Vrettou, Vassiliki Giannopoulou, Asimenia Halioti, Georgios Ferentinos, Ioanna Dimopoulou, Anastasia Kotanidou, David Langleben and Stylianos E. Orfanos

Int. J. Mol. Sci. 2024, 25(19), 10640; https://doi.org/10.3390/ijms251910640 - 2 Oct 2024

Viewed by 687

Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49–1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93–1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52–1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78–1.34)] compared to the survivors [0.57 (0.48–0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology and Immunology Related to SARS-CoV-2 Infection)

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14 pages, 973 KiB

Open AccessArticle

Prospective Variation of Cytokine Trends during COVID-19: A Progressive Approach from Disease Onset until Outcome

by Marina de Castro Deus, Ana Carolina Gadotti, Erika Sousa Dias, Júlia Bacarin Monte Alegre, Beatriz Akemi Kondo Van Spitzenbergen, Gabriela Bohnen Andrade, Sara Soares Tozoni, Rebecca Benicio Stocco, Marcia Olandoski, Felipe Francisco Bondan Tuon, Ricardo Aurino Pinho, Lucia de Noronha, Cristina Pellegrino Baena and Andrea Novais Moreno-Amaral

Int. J. Mol. Sci. 2024, 25(19), 10578; https://doi.org/10.3390/ijms251910578 - 1 Oct 2024

Viewed by 997

Abstract

COVID-19 is characterized by pronounced hypercytokinemia. The cytokine switch, marked by an imbalance between pro-inflammatory and anti-inflammatory cytokines, emerged as a focal point of investigation throughout the COVID-19 pandemic. However, the kinetics and temporal dynamics of cytokine release remain contradictory, making the development of new therapeutics difficult, especially in severe cases. This study collected serum samples from SARS-CoV-2 infected patients at 72 h intervals and monitored them for various cytokines at each timepoint until hospital discharge or death. Cytokine levels were analyzed based on time since symptom onset and patient outcomes. All cytokines studied prospectively were strong predictors of mortality, particularly IL-4 (AUC = 0.98) and IL-1β (AUC = 0.96). First-timepoint evaluations showed elevated cytokine levels in the mortality group (p < 0.001). Interestingly, IFN-γ levels decreased over time in the death group but increased in the survival group. Patients who died exhibited sustained levels of IL-1β and IL-4 and increased IL-6 levels over time. These findings suggest cytokine elevation is crucial in predicting COVID-19 mortality. The dynamic interplay between IFN-γ and IL-4 highlights the balance between Th1/Th2 immune responses and underscores IFN-γ as a powerful indicator of immune dysregulation throughout the infection. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology and Immunology Related to SARS-CoV-2 Infection)

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14 pages, 1951 KiB

Open AccessArticle

Antibody Responses in SARS-CoV-2-Exposed and/or Vaccinated Individuals Target Conserved Epitopes from Multiple CoV-2 Antigens

by David Yao, Raj S. Patel, Adrien Lam, Quarshie Glover, Cindy Srinivasan, Alex Herchen, Bruce Ritchie and Babita Agrawal

Int. J. Mol. Sci. 2024, 25(18), 9814; https://doi.org/10.3390/ijms25189814 - 11 Sep 2024

Viewed by 975

Abstract

There is a need to investigate novel strategies in order to create an effective, broadly protective vaccine for current and future severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks. The currently available vaccines demonstrate compromised efficacy against emerging SARS-CoV-2 variants of concern (VOCs), short-lived immunity, and susceptibility to immune imprinting due to frequent boosting practices. In this study, we examined the specificity of cross-reactive IgG antibody responses in mRNA-vaccinated, AstraZeneca-vaccinated, and unvaccinated donors to identify potentially conserved, cross-reactive epitopes to target in order to create a broadly protective SARS-CoV-2 vaccine. Our study provides evidence for cross-reactive IgG antibodies specific to eight different spike (S) variants. Furthermore, the specificities of these cross-variant IgG antibody titers were associated to some extent with spike S₁- and S₂-subunit-derived epitopes P₁ and P₂, respectively. In addition, nucleocapsid (N)- and membrane (M)-specific IgG antibody titers correlated with N- and M-derived epitopes conserved across beta-CoVs, P_3–7. This study reveals conserved epitopes of viral antigens, targeted by natural and/or vaccine-induced human immunity, for future designs of next-generation COVID-19 vaccines. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology and Immunology Related to SARS-CoV-2 Infection)

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