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15 pages, 1691 KB

Open AccessArticle

tRNA Modifications: A Tale of Two Viruses—SARS-CoV-2 and ZIKV

by Patrick Eldin and Laurence Briant

Int. J. Mol. Sci. 2025, 26(15), 7479; https://doi.org/10.3390/ijms26157479 - 2 Aug 2025

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tRNA modifications are crucial for efficient protein synthesis, impacting codon recognition, tRNA stability, and translation rates. RNA viruses hijack the host’s translational machinery, including the pool of modified tRNA, to translate their own genomes. However, the mismatch between viral and host codon usage [...] Read more.

tRNA modifications are crucial for efficient protein synthesis, impacting codon recognition, tRNA stability, and translation rates. RNA viruses hijack the host’s translational machinery, including the pool of modified tRNA, to translate their own genomes. However, the mismatch between viral and host codon usage can lead to a limited availability of specific tRNA leading to ribosome stalling, posing a significant challenge for efficient protein translation. While some viruses address this challenge through codon optimization, we show here that SARS-CoV-2 (Coronavirus) and the Zika virus (ZIKV; Flavivirus) adopt a different approach, manipulating the host tRNA epitranscriptome. Analysis of codon bias indices confirmed a substantial divergence between viral and host codon usage, revealing a strong preference in viral genes for codons decoded by tRNAs requiring U34 wobble modification. Monitoring tRNA modification dynamics in infected cells showed that both SARS-CoV2 and ZIKV enhance U34 tRNA modifications during infection. Strikingly, impairing U34 tRNAs profoundly impacted viral replication, underscoring the strict reliance of SARS-CoV-2 and ZIKV on manipulating the host tRNA epitranscriptome to support the efficient translation of their genome. 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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19 pages, 3154 KB

Open AccessArticle

The Relationship Between Kidney Biomarkers, Inflammation, Severity, and Mortality Due to COVID-19—A Two-Timepoint Study

by Sara Soares Tozoni, Ana Carolina Gadotti, Erika Sousa Dias, Julia Bacarin Monte Alegre, Beatriz Akemi Von Spitzenbergen, Marina de Castro Deus, Thyago Proença de Moraes and Andrea Novais Moreno-Amaral

Int. J. Mol. Sci. 2025, 26(13), 6086; https://doi.org/10.3390/ijms26136086 - 25 Jun 2025

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Abstract

About a quarter of COVID-19 patients develop acute kidney injury (AKI), worsening prognosis and increasing mortality. Severe COVID-19 often triggers a hyperactive immune response, influencing disease outcomes. This study examined the correlation between kidney injury biomarkers, inflammatory mediators, and mortality in COVID-19 patients. [...] Read more.

About a quarter of COVID-19 patients develop acute kidney injury (AKI), worsening prognosis and increasing mortality. Severe COVID-19 often triggers a hyperactive immune response, influencing disease outcomes. This study examined the correlation between kidney injury biomarkers, inflammatory mediators, and mortality in COVID-19 patients. Blood samples from 390 COVID-19 patients were collected at admission and before the outcome. Serum Cystatin C (CysC), albumin, and plasma NGAL were measured via nephelometry, while inflammatory mediators (IL-4, IL-6, IL-10, IL-15, IFN-γ, TNF-α, and IL-1β) were assessed by ELISA. Most patients were male, with hypertension and diabetes as common comorbidities, and a high ICU admission rate. Lower albumin and elevated CysC and NGAL were linked to mortality. Increased inflammatory mediators correlated with lower albumin and higher CysC and NGAL, reinforcing the connection between systemic inflammation and kidney dysfunction. Elevated cytokines and kidney injury biomarkers, including NGAL, CysC, and low albumin, are strongly associated with higher mortality in COVID-19 patients. These findings highlight the role of inflammation and kidney function markers in identifying high-risk individuals, improving patient management, and mitigating complications. Monitoring these biomarkers remains crucial for managing long-term health impacts and future outbreaks 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, 1044 KB

Open AccessArticle

Cytokines from Macrophages Activated by Spike S1 of SARS-CoV-2 Cause eNOS/Arginase Imbalance in Endothelial Cells

by Giulia Recchia Luciani, Rossana Visigalli, Valeria Dall’Asta, Bianca Maria Rotoli and Amelia Barilli

Int. J. Mol. Sci. 2025, 26(12), 5916; https://doi.org/10.3390/ijms26125916 - 19 Jun 2025

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Abstract

Multiple lines of evidence suggest that endothelial dysfunction is a key player in the pathogenesis of COVID-19, with cytokine storm as one of the main primary causes. Among the mechanisms underlying endothelial damage, clinical findings identify alterations in arginine metabolism, as patients with [...] Read more.

Multiple lines of evidence suggest that endothelial dysfunction is a key player in the pathogenesis of COVID-19, with cytokine storm as one of the main primary causes. Among the mechanisms underlying endothelial damage, clinical findings identify alterations in arginine metabolism, as patients with severe COVID-19 exhibit lower levels of nitric oxide synthase (eNOS) and upregulated arginase. In this study, we investigated, in human endothelial cells (HUVECs), the effect of conditioned medium from macrophages activated with SARS-CoV-2 Spike protein (CM_S1) on arginine metabolism. The results indicate that CM_S1 causes a marked decrease in eNOS and an increase in arginase, along with a greater intracellular arginine content and the induction of the CAT2 transporter. These effects are ascribable to the inflammatory mediators released by macrophages in CM_S1, mainly TNFα and IL-1β. Since infliximab, an antibody targeting TNFα, and baricitinib, an inhibitor of the JAK/STAT pathway, correct the observed imbalance between eNOS and arginase, our findings suggest the potential efficacy of a combined therapy to counteract endothelial dysfunction in COVID-19. 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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11 pages, 442 KB

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

Cited by 2 | Viewed by 1253

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 [...] Read more.

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 KB

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

Cited by 1 | Viewed by 1446

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 [...] Read more.

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 KB

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

Cited by 2 | Viewed by 1335

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, [...] Read more.

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 KB

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

Cited by 3 | Viewed by 1815

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 [...] Read more.

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 KB

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

Cited by 1 | Viewed by 1785

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), [...] Read more.

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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