Cells

2024

Jump to: 2023, 2022, 2021

16 pages, 2978 KiB

Open AccessArticle

A Gain-of-Function Cleavage of TonEBP by Coronavirus NSP5 to Suppress IFN-β Expression

by Hyun Park, Sang Min Lee, Su Ji Jeong, Yeong Cheon Kweon, Go Woon Shin, Whi Young Kim, Whaseon Lee-Kwon, Chan Young Park and Hyug Moo Kwon

Cells 2024, 13(19), 1614; https://doi.org/10.3390/cells13191614 - 26 Sep 2024

Viewed by 552

Abstract

Human coronaviruses (HCoVs) modify host proteins to evade the antiviral defense and sustain viral expansion. Here, we report tonicity-responsive enhancer (TonE) binding protein (TonEBP) as a cellular target of HCoVs. TonEBP was cleaved into N-terminal and C-terminal fragments (TonEBP NT and TonEBP CT, [...] Read more.

Human coronaviruses (HCoVs) modify host proteins to evade the antiviral defense and sustain viral expansion. Here, we report tonicity-responsive enhancer (TonE) binding protein (TonEBP) as a cellular target of HCoVs. TonEBP was cleaved into N-terminal and C-terminal fragments (TonEBP NT and TonEBP CT, respectively) by NSP5 from all the HCoVs tested. This cleavage resulted in the loss of TonEBP’s ability to stimulate the TonE-driven transcription. On the other hand, TonEBP NT promoted viral expansion in association with the suppression of IFN-β expression. TonEBP NT competed away NF-κB binding to the PRD II domain on the IFN-β promoter. A TonEBP mutant resistant to the cleavage by NSP5 did not promote the viral expansion nor suppress the IFN-β expression. These results demonstrate that HCoVs use a common strategy of targeting TonEBP to suppress the host immune defense. Full article

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Graphical abstract

18 pages, 4620 KiB

Open AccessArticle

Single-Cell RNA Sequencing Reveals HIF1A as a Severity-Sensitive Immunological Scar in Circulating Monocytes of Convalescent Comorbidity-Free COVID-19 Patients

by Lilly May, Chang-Feng Chu and Christina E. Zielinski

Cells 2024, 13(4), 300; https://doi.org/10.3390/cells13040300 - 6 Feb 2024

Cited by 2 | Viewed by 2026

Abstract

COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is characterized by a wide range of clinical symptoms and a poorly predictable disease course. Although in-depth transcriptomic investigations of peripheral blood samples from COVID-19 patients have been performed, the detailed molecular mechanisms underlying [...] Read more.

COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is characterized by a wide range of clinical symptoms and a poorly predictable disease course. Although in-depth transcriptomic investigations of peripheral blood samples from COVID-19 patients have been performed, the detailed molecular mechanisms underlying an asymptomatic, mild or severe disease course, particularly in patients without relevant comorbidities, remain poorly understood. While previous studies have mainly focused on the cellular and molecular dissection of ongoing COVID-19, we set out to characterize transcriptomic immune cell dysregulation at the single-cell level at different time points in patients without comorbidities after disease resolution to identify signatures of different disease severities in convalescence. With single-cell RNA sequencing, we reveal a role for hypoxia-inducible factor 1-alpha (HIF1A) as a severity-sensitive long-term immunological scar in circulating monocytes of convalescent COVID-19 patients. Additionally, we show that circulating complexes formed by monocytes with either T cells or NK cells represent a characteristic cellular marker in convalescent COVID-19 patients irrespective of their preceding symptom severity. Together, these results provide cellular and molecular correlates of recovery from COVID-19 and could help in immune monitoring and in the design of new treatment strategies. Full article

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2023

Jump to: 2024, 2022, 2021

31 pages, 4186 KiB

Open AccessReview

Understanding the Relationship of the Human Bacteriome with COVID-19 Severity and Recovery

by Hassan Zafar and Milton H. Saier, Jr.

Cells 2023, 12(9), 1213; https://doi.org/10.3390/cells12091213 - 22 Apr 2023

Viewed by 4259

Abstract

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) first emerged in 2019 in China and has resulted in millions of human morbidities and mortalities across the globe. Evidence has been provided that this novel virus originated in animals, mutated, and made the cross-species jump [...] Read more.

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) first emerged in 2019 in China and has resulted in millions of human morbidities and mortalities across the globe. Evidence has been provided that this novel virus originated in animals, mutated, and made the cross-species jump to humans. At the time of this communication, the Coronavirus disease (COVID-19) may be on its way to an endemic form; however, the threat of the virus is more for susceptible (older and immunocompromised) people. The human body has millions of bacterial cells that influence health and disease. As a consequence, the bacteriomes in the human body substantially influence human health and disease. The bacteriomes in the body and the immune system seem to be in constant association during bacterial and viral infections. In this review, we identify various bacterial spp. In major bacteriomes (oral, nasal, lung, and gut) of the body in healthy humans and compare them with dysbiotic bacteriomes of COVID-19 patients. We try to identify key bacterial spp. That have a positive effect on the functionality of the immune system and human health. These select bacterial spp. Could be used as potential probiotics to counter or prevent COVID-19 infections. In addition, we try to identify key metabolites produced by probiotic bacterial spp. That could have potential anti-viral effects against SARS-CoV-2. These metabolites could be subject to future therapeutic trials to determine their anti-viral efficacies. Full article

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2022

Jump to: 2024, 2023, 2021

17 pages, 6283 KiB

Open AccessArticle

Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins

by Marta Di Simone, Anna Maria Corsale, Elena Lo Presti, Nicola Scichilone, Carmela Picone, Lydia Giannitrapani, Francesco Dieli and Serena Meraviglia

Cells 2022, 11(21), 3449; https://doi.org/10.3390/cells11213449 - 31 Oct 2022

Cited by 1 | Viewed by 1950

Abstract

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the [...] Read more.

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients. Full article

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10 pages, 2376 KiB

Open AccessArticle

Screening, Expression, and Identification of Nanobody against SARS-CoV-2 Spike Protein

by Qianling Su, Wei Shi, Xianing Huang, Yakun Wan, Guanghui Li, Bengang Xing, Zhi Ping Xu, Hongbo Liu, Bruce D. Hammock, Xiaomei Yang, Shihua Yin and Xiaoling Lu

Cells 2022, 11(21), 3355; https://doi.org/10.3390/cells11213355 - 24 Oct 2022

Cited by 6 | Viewed by 3181

Abstract

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an infectious disease that has become a serious burden on global public health. This study screened and yielded specific nanobodies (Nbs) against SARS-CoV-2 spike protein receptor binding domain [...] Read more.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an infectious disease that has become a serious burden on global public health. This study screened and yielded specific nanobodies (Nbs) against SARS-CoV-2 spike protein receptor binding domain (RBD), following testing its basic characteristics. A nanobody phage library was established by immunizing a camel with RBD protein. After three rounds of panning, the positive colonies were screened by enzyme-linked immunosorbent assay (ELISA). By sequencing, four different sequences of nanobody gene fragments were selected. The four nanobody fusion proteins were expressed and purified, respectively. The specificity and affinity of the four nanobodies were identified by ELISA. Our results showed that an immune phage display library against SARS-CoV-2 has been successfully constructed with a library capacity of which was 4.7 × 10⁸ CFU. The four purified nanobodies showed specific high-affinity binding SARS-CoV-2 S-RBD. Among these, the antigen binding affinity of Nb61 was more comparable to that of commercial rabbit anti-SARS-CoV-2 S-RBD antibodies. In sum, our study has obtained four nanobody strains against SARS-CoV-2 S-RBD with significant affinity and specificity, therefore laying an essential foundation for further research as well as the applications of diagnostic and therapeutic tools of SARS-CoV-2. Full article

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20 pages, 8338 KiB

Open AccessArticle

Single-Cell Gene Expression Analysis Revealed Immune Cell Signatures of Delta COVID-19

by Abusaid M. Shaymardanov, Olga A. Antonova, Anastasia D. Sokol, Kseniia A. Deinichenko, Polina G. Kazakova, Mikhail M. Milovanov, Alexander V. Zakubansky, Alexandra I. Akinshina, Anastasia V. Tsypkina, Svetlana V. Romanova, Vladimir E. Muhin, Sergey I. Mitrofanov, Vladimir S. Yudin, Sergey M. Yudin, Antonida V. Makhotenko, Anton A. Keskinov, Sergey A. Kraevoy, Ekaterina A. Snigir, Dmitry V. Svetlichnyy and Veronika I. Skvortsova

Cells 2022, 11(19), 2950; https://doi.org/10.3390/cells11192950 - 21 Sep 2022

Cited by 1 | Viewed by 4495

Abstract

The coronavirus disease 2019 (COVID-19) is accompanied by a cytokine storm with the release of many proinflammatory factors and development of respiratory syndrome. Several SARS-CoV-2 lineages have been identified, and the Delta variant (B.1.617), linked with high mortality risk, has become dominant in [...] Read more.

The coronavirus disease 2019 (COVID-19) is accompanied by a cytokine storm with the release of many proinflammatory factors and development of respiratory syndrome. Several SARS-CoV-2 lineages have been identified, and the Delta variant (B.1.617), linked with high mortality risk, has become dominant in many countries. Understanding the immune responses associated with COVID-19 lineages may therefore aid the development of therapeutic and diagnostic strategies. Multiple single-cell gene expression studies revealed innate and adaptive immunological factors and pathways correlated with COVID-19 severity. Additional investigations covering host–pathogen response characteristics for infection caused by different lineages are required. Here, we performed single-cell transcriptome profiling of blood mononuclear cells from the individuals with different severity of the COVID-19 and virus lineages to uncover variant specific molecular factors associated with immunity. We identified significant changes in lymphoid and myeloid cells. Our study highlights that an abundant population of monocytes with specific gene expression signatures accompanies Delta lineage of SARS-CoV-2 and contributes to COVID-19 pathogenesis inferring immune components for targeted therapy. Full article

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22 pages, 4183 KiB

Open AccessArticle

Immune Determinants of Viral Clearance in Hospitalised COVID-19 Patients: Reduced Circulating Naïve CD4+ T Cell Counts Correspond with Delayed Viral Clearance

by Mihaela Zlei, Igor A. Sidorov, Simone A. Joosten, Mirjam H. M. Heemskerk, Sebenzile K. Myeni, Cilia R. Pothast, Caroline S. de Brouwer, A. Linda Boomaars-van der Zanden, Krista E. van Meijgaarden, Shessy T. Morales, Els Wessels, Jacqueline J. Janse, Jelle J. Goeman, Christa M. Cobbaert, Aloys C. M. Kroes, Suzanne C. Cannegieter, Meta Roestenberg, Leonardus G. Visser, Marjolein Kikkert, Mariet C. W. Feltkamp, Sesmu M. Arbous, Frank J. T. Staal, Tom H. M. Ottenhoff, Jacques J. M. van Dongen, Anna H. E. Roukens, Jutte J. C. de Vries, in collaboration with BEAT-COVID and in collaboration with LUMC COVID Show full author list Hide full author list

Cells 2022, 11(17), 2743; https://doi.org/10.3390/cells11172743 - 2 Sep 2022

Cited by 16 | Viewed by 3082

Abstract

Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to [...] Read more.

Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to 122 immune parameters in 102 hospitalised patients with moderate and severe COVID-19 in a longitudinal design. Delayed viral clearance was associated with more severe disease and was associated with higher levels of SARS-CoV-2-specific (neutralising) antibodies over time, increased numbers of neutrophils, monocytes, basophils, and a range of pro-inflammatory cyto-/chemokines illustrating ongoing, partially Th2 dominating, immune activation. In contrast, early viral clearance and less critical illness correlated with the peak of neutralising antibodies, higher levels of CD4 T cells, and in particular naïve CD4+ T cells, suggesting their role in early control of SARS-CoV-2 possibly by proving appropriate B cell help. Higher counts of naïve CD4+ T cells also correlated with lower levels of MIF, IL-9, and TNF-beta, suggesting an indirect role in averting prolonged virus-induced tissue damage. Collectively, our data show that naïve CD4+ T cell play a critical role in rapid viral T cell control, obviating aberrant antibody and cytokine profiles and disease deterioration. These data may help in guiding risk stratification for severe COVID-19. Full article

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17 pages, 1595 KiB

Open AccessCommunication

SARS-CoV-2 Spike Does Not Possess Intrinsic Superantigen-like Inflammatory Activity

by Carola Amormino, Valentina Tedeschi, Giorgia Paldino, Stefano Arcieri, Maria Teresa Fiorillo, Alessandro Paiardini, Loretta Tuosto and Martina Kunkl

Cells 2022, 11(16), 2526; https://doi.org/10.3390/cells11162526 - 15 Aug 2022

Cited by 12 | Viewed by 6642

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a rare hyperinflammatory disease occurring several weeks after SARS-CoV-2 infection. The clinical similarities between MIS-C and the toxic shock syndrome, together with the preferential expansion of T cells with a T-cell receptor variable β chain (TCRVβ) [...] Read more.

Multisystem inflammatory syndrome in children (MIS-C) is a rare hyperinflammatory disease occurring several weeks after SARS-CoV-2 infection. The clinical similarities between MIS-C and the toxic shock syndrome, together with the preferential expansion of T cells with a T-cell receptor variable β chain (TCRVβ) skewing, suggested a superantigen theory of MIS-C. For instance, recent in silico modelling evidenced the presence of a highly conserved motif within SARS-CoV-2 spike protein similar in structure to the superantigenic fragment of staphylococcal enterotoxin B (SEB). However, experimental data on the superantigenic activity of the SARS-CoV-2 spike have not yet been provided. Here, we assessed the superantigenic activity of the SARS-CoV-2 spike by analysing inflammatory cytokine production in both Jurkat cells and the peripheral blood CD4⁺ T cells stimulated with the SARS-CoV-2 spike or SEB as a control. We found that, unlike SEB, the SARS-CoV-2 spike does not exhibit an intrinsic superantigen-like activity. Full article

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15 pages, 2606 KiB

Open AccessArticle

T-Cell Defects Associated to Lack of Spike-Specific Antibodies after BNT162b2 Full Immunization Followed by a Booster Dose in Patients with Common Variable Immune Deficiencies

by Federica Pulvirenti, Stefano Di Cecca, Matilde Sinibaldi, Eva Piano Mortari, Sara Terreri, Christian Albano, Marika Guercio, Eleonora Sculco, Cinzia Milito, Simona Ferrari, Franco Locatelli, Concetta Quintarelli, Rita Carsetti and Isabella Quinti

Cells 2022, 11(12), 1918; https://doi.org/10.3390/cells11121918 - 14 Jun 2022

Cited by 13 | Viewed by 2541

Abstract

Following the third booster dose of the mRNA vaccine, Common Variable Immune Deficiencies (CVID) patients may not produce specific antibodies against the virus spike protein. The T-cell abnormalities associated with the absence of antibodies are still a matter of investigation. Spike-specific IgG and [...] Read more.

Following the third booster dose of the mRNA vaccine, Common Variable Immune Deficiencies (CVID) patients may not produce specific antibodies against the virus spike protein. The T-cell abnormalities associated with the absence of antibodies are still a matter of investigation. Spike-specific IgG and IgA, peripheral T cell subsets, CD40L and cytokine expression, and Spike-specific specific T-cells responses were evaluated in 47 CVID and 26 healthy donors after three doses of BNT162b2 vaccine. Testing was performed two weeks after the third vaccine dose. Thirty-six percent of the patients did not produce anti-SARS-CoV-2 IgG or IgA antibodies. Non responder patients had lower peripheral blood lymphocyte counts, circulating naïve and central memory T-cells, low CD40L expression on the CD4+CD45+RO+ and CD8+CD45+RO+ T-cells, high frequencies of TNFα and IFNγ expressing CD8+ T-cells, and defective release of IFNγ and TNFα following stimulation with Spike peptides. Non responders had a more complex disease phenotype, with higher frequencies of structural lung damage and autoimmunity, especially autoimmune cytopenia. Thirty-five percent of them developed a SARS-CoV-2 infection after immunization in comparison to twenty percent of CVID who responded to immunization with antibodies production. CVID-associated T cell abnormalities contributed to the absence of SARS-CoV-2 specific antibodies after full immunization. Full article

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21 pages, 3670 KiB

Open AccessArticle

Plasma Metabolomic Alterations Induced by COVID-19 Vaccination Reveal Putative Biomarkers Reflecting the Immune Response

by Ioanna Dagla, Aikaterini Iliou, Dimitra Benaki, Evagelos Gikas, Emmanuel Mikros, Tina Bagratuni, Efstathios Kastritis, Meletios A. Dimopoulos, Evangelos Terpos and Anthony Tsarbopoulos

Cells 2022, 11(7), 1241; https://doi.org/10.3390/cells11071241 - 6 Apr 2022

Cited by 17 | Viewed by 3980

Abstract

Vaccination is currently the most effective strategy for the mitigation of the COVID-19 pandemic. mRNA vaccines trigger the immune system to produce neutralizing antibodies (NAbs) against SARS-CoV-2 spike proteins. However, the underlying molecular processes affecting immune response after vaccination remain poorly understood, while [...] Read more.

Vaccination is currently the most effective strategy for the mitigation of the COVID-19 pandemic. mRNA vaccines trigger the immune system to produce neutralizing antibodies (NAbs) against SARS-CoV-2 spike proteins. However, the underlying molecular processes affecting immune response after vaccination remain poorly understood, while there is significant heterogeneity in the immune response among individuals. Metabolomics have often been used to provide a deeper understanding of immune cell responses, but in the context of COVID-19 vaccination such data are scarce. Mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR)-based metabolomics were used to provide insights based on the baseline metabolic profile and metabolic alterations induced after mRNA vaccination in paired blood plasma samples collected and analysed before the first and second vaccination and at 3 months post first dose. Based on the level of NAbs just before the second dose, two groups, “low” and “high” responders, were defined. Distinct plasma metabolic profiles were observed in relation to the level of immune response, highlighting the role of amino acid metabolism and the lipid profile as predictive markers of response to vaccination. Furthermore, levels of plasma ceramides along with certain amino acids could emerge as predictive biomarkers of response and severity of inflammation. Full article

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38 pages, 6050 KiB

Open AccessReview

Biotechnological Perspectives to Combat the COVID-19 Pandemic: Precise Diagnostics and Inevitable Vaccine Paradigms

by Mahender Aileni, Gulab Khan Rohela, Phanikanth Jogam, Shakuntala Soujanya and Baohong Zhang

Cells 2022, 11(7), 1182; https://doi.org/10.3390/cells11071182 - 31 Mar 2022

Cited by 14 | Viewed by 5044

Abstract

The outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause for the ongoing global public health emergency. It is more commonly known as coronavirus disease 2019 (COVID-19); the pandemic threat continues to spread aroundthe world with the fluctuating [...] Read more.

The outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause for the ongoing global public health emergency. It is more commonly known as coronavirus disease 2019 (COVID-19); the pandemic threat continues to spread aroundthe world with the fluctuating emergence of its new variants. The severity of COVID-19 ranges from asymptomatic to serious acute respiratory distress syndrome (ARDS), which has led to a high human mortality rate and disruption of socioeconomic well-being. For the restoration of pre-pandemic normalcy, the international scientific community has been conducting research on a war footing to limit extremely pathogenic COVID-19 through diagnosis, treatment, and immunization. Since the first report of COVID-19 viral infection, an array of laboratory-based and point-of-care (POC) approaches have emerged for diagnosing and understanding its status of outbreak. The RT-PCR-based viral nucleic acid test (NAT) is one of the rapidly developed and most used COVID-19 detection approaches. Notably, the current forbidding status of COVID-19 requires the development of safe, targeted vaccines/vaccine injections (shots) that can reduce its associated morbidity and mortality. Massive and accelerated vaccination campaigns would be the most effective and ultimate hope to end the COVID-19 pandemic. Since the SARS-CoV-2 virus outbreak, emerging biotechnologies and their multidisciplinary approaches have accelerated the understanding of molecular details as well as the development of a wide range of diagnostics and potential vaccine candidates, which are indispensable to combating the highly contagious COVID-19. Several vaccine candidates have completed phase III clinical studies and are reported to be effective in immunizing against COVID-19 after their rollout via emergency use authorization (EUA). However, optimizing the type of vaccine candidates and its route of delivery that works best to control viral spread is crucial to face the threatening variants expected to emerge over time. In conclusion, the insights of this review would facilitate the development of more likely diagnostics and ideal vaccines for the global control of COVID-19. Full article

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16 pages, 2749 KiB

Open AccessArticle

Multi-Design Differential Expression Profiling of COVID-19 Lung Autopsy Specimens Reveals Significantly Deregulated Inflammatory Pathways and SFTPC Impaired Transcription

by Matteo Fassan, Antonio Collesei, Valentina Angerilli, Marta Sbaraglia, Francesco Fortarezza, Federica Pezzuto, Monica De Gaspari, Gianluca Businello, Margherita Moni, Stefania Rizzo, Giulia Traverso, Veronica Colosso, Elisa Taschin, Francesca Lunardi, Aida Freire Valls, Francesca Schiavi, Cristina Basso, Fiorella Calabrese and Angelo Paolo Dei Tos

Cells 2022, 11(6), 1011; https://doi.org/10.3390/cells11061011 - 16 Mar 2022

Cited by 10 | Viewed by 3462

Abstract

The transcriptomic profiling of lung damage associated with SARS-CoV-2 infection may lead to the development of effective therapies to prevent COVID-19-related deaths. We selected a series of 21 autoptic lung samples, 14 of which had positive nasopharyngeal swabs for SARS-CoV-2 and a clinical [...] Read more.

The transcriptomic profiling of lung damage associated with SARS-CoV-2 infection may lead to the development of effective therapies to prevent COVID-19-related deaths. We selected a series of 21 autoptic lung samples, 14 of which had positive nasopharyngeal swabs for SARS-CoV-2 and a clinical diagnosis of COVID-19-related death; their pulmonary viral load was quantified with a specific probe for SARS-CoV-2. The remaining seven cases had no documented respiratory disease and were used as controls. RNA from formalin-fixed paraffin-embedded (FFPE) tissue samples was extracted to perform gene expression profiling by means of targeted (Nanostring) and comprehensive RNA-Seq. Two differential expression designs were carried out leading to relevant results in terms of deregulation. SARS-CoV-2 positive specimens presented a significant overexpression in genes of the type I interferon signaling pathway (IFIT1, OAS1, ISG15 and RSAD2), complement activation (C2 and CFB), macrophage polarization (PKM, SIGLEC1, CD163 and MS4A4A) and Cathepsin C (CTSC). CD163, Siglec-1 and Cathepsin C overexpression was validated by immunohistochemistry. SFTPC, the encoding gene for pulmonary-associated surfactant protein C, emerged as a key identifier of COVID-19 patients with high viral load. This study successfully recognized SARS-CoV-2 specific immune signatures in lung samples and highlighted new potential therapeutic targets. A better understanding of the immunopathogenic mechanisms of SARS-CoV-2 induced lung damage is required to develop effective individualized pharmacological strategies. Full article

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24 pages, 8213 KiB

Open AccessArticle

Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States

by Lena F. Schimke, Alexandre H. C. Marques, Gabriela Crispim Baiocchi, Caroline Aliane de Souza Prado, Dennyson Leandro M. Fonseca, Paula Paccielli Freire, Desirée Rodrigues Plaça, Igor Salerno Filgueiras, Ranieri Coelho Salgado, Gabriel Jansen-Marques, Antonio Edson Rocha Oliveira, Jean Pierre Schatzmann Peron, Gustavo Cabral-Miranda, José Alexandre Marzagão Barbuto, Niels Olsen Saraiva Camara, Vera Lúcia Garcia Calich, Hans D. Ochs, Antonio Condino-Neto, Katherine A. Overmyer, Joshua J. Coon, Joseph Balnis, Ariel Jaitovich, Jonas Schulte-Schrepping, Thomas Ulas, Joachim L. Schultze, Helder I. Nakaya, Igor Jurisica and Otávio Cabral-Marques Show full author list Hide full author list

Cells 2022, 11(5), 847; https://doi.org/10.3390/cells11050847 - 1 Mar 2022

Cited by 27 | Viewed by 7189

Abstract

Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison [...] Read more.

Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaki disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflammatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at the protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention. Full article

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18 pages, 1318 KiB

Open AccessReview

Comprehensive Analysis of the ILCs and Unconventional T Cells in Virus Infection: Profiling and Dynamics Associated with COVID-19 Disease for a Future Monitoring System and Therapeutic Opportunities

by Elena Lo Presti, Andrea De Gaetano, Giovanni Pioggia and Sebastiano Gangemi

Cells 2022, 11(3), 542; https://doi.org/10.3390/cells11030542 - 4 Feb 2022

Cited by 8 | Viewed by 2689

Abstract

This review is a comprehensive analysis of the effects of SARS-CoV-2 infection on Unconventional T cells and innate lymphoid cells (ILCs). COVID-19 affected patients show dysregulation of their adaptive immune systems, but many questions remain unsolved on the behavior of Unconventional cells and [...] Read more.

This review is a comprehensive analysis of the effects of SARS-CoV-2 infection on Unconventional T cells and innate lymphoid cells (ILCs). COVID-19 affected patients show dysregulation of their adaptive immune systems, but many questions remain unsolved on the behavior of Unconventional cells and ILCs during infection, considering their role in maintaining homeostasis in tissue. Therefore, we highlight the differences that exist among the studies in cohorts of patients who in general were categorized considering symptoms and hospitalization. Moreover, we make a critical analysis of the presence of particular clusters of cells that express activation and exhausted markers for each group in order to bring out potential diagnostic factors unconsidered before now. We also focus our attention on studies that take into consideration recovered patients. Indeed, it could be useful to determine Unconventional T cells’ and ILCs’ frequencies and functions in longitudinal studies because it could represent a way to monitor the immune status of SARS-CoV-2-infected subjects. Possible changes in cell frequencies or activation profiles could be potentially useful as prognostic biomarkers and for future therapy. Currently, there are no efficacious therapies for SARS-CoV-2 infection, but deep studies on involvement of Unconventional T cells and ILCs in the pathogenesis of COVID-19 could be promising for targeted therapies. Full article

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2021

Jump to: 2024, 2023, 2022

12 pages, 6222 KiB

Open AccessArticle

Analysis of TCR Repertoire by High-Throughput Sequencing Indicates the Feature of T Cell Immune Response after SARS-CoV-2 Infection

by Yifan Wang, Fugang Duan, Zhu Zhu, Meng Yu, Xiaodong Jia, Hui Dai, Pingzhang Wang, Xiaoyan Qiu, Yinying Lu and Jing Huang

Cells 2022, 11(1), 68; https://doi.org/10.3390/cells11010068 - 27 Dec 2021

Cited by 7 | Viewed by 4671

Abstract

Coronavirus disease 2019 (COVID-19) is a global infectious disease caused by the SARS-CoV-2 coronavirus. T cells play an essential role in the body’s fighting against the virus invasion, and the T cell receptor (TCR) is crucial in T cell-mediated virus recognition and clearance. [...] Read more.

Coronavirus disease 2019 (COVID-19) is a global infectious disease caused by the SARS-CoV-2 coronavirus. T cells play an essential role in the body’s fighting against the virus invasion, and the T cell receptor (TCR) is crucial in T cell-mediated virus recognition and clearance. However, little has been known about the features of T cell response in convalescent COVID-19 patients. In this study, using 5′RACE technology and PacBio sequencing, we analyzed the TCR repertoire of COVID-19 patients after recovery for 2 weeks and 6 months compared with the healthy donors. The TCR clustering and CDR3 annotation were exploited to discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. We first identified CD4⁺ and CD8⁺ T cell clones with certain clonal expansion after infection, and then observed the preferential recombination usage of V(D) J gene segments in CD4⁺ and CD8⁺ T cells of COVID-19 patients with different convalescent stages. More important, the TRBV6-5-TRBD2-TRBJ2-7 combination with high frequency was shared between CD4⁺ T and CD8⁺ T cells of different COVID-19 patients. Finally, we found the dominant characteristic motifs of the CDR3 sequence between recovered COVID-19 and healthy control. Our study provides novel insights on TCR in COVID-19 with different convalescent phases, contributing to our understanding of the immune response induced by SARS-CoV-2. Full article

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17 pages, 3936 KiB

Open AccessArticle

Cysteamine with In Vitro Antiviral Activity and Immunomodulatory Effects Has the Potential to Be a Repurposing Drug Candidate for COVID-19 Therapy

by Tonino Alonzi, Alessandra Aiello, Linda Petrone, Saeid Najafi Fard, Manuela D’Eletto, Laura Falasca, Roberta Nardacci, Federica Rossin, Giovanni Delogu, Concetta Castilletti, Maria Rosaria Capobianchi, Giuseppe Ippolito, Mauro Piacentini and Delia Goletti

Cells 2022, 11(1), 52; https://doi.org/10.3390/cells11010052 - 24 Dec 2021

Cited by 13 | Viewed by 3569

Abstract

The ongoing pandemic of coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), needs better treatment options both at antiviral and anti-inflammatory levels. It has been demonstrated that the aminothiol cysteamine, an already human applied drug, and its disulfide product [...] Read more.

The ongoing pandemic of coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), needs better treatment options both at antiviral and anti-inflammatory levels. It has been demonstrated that the aminothiol cysteamine, an already human applied drug, and its disulfide product of oxidation, cystamine, have anti-infective properties targeting viruses, bacteria, and parasites. To determine whether these compounds exert antiviral effects against SARS-CoV-2, we used different in vitro viral infected cell-based assays. Moreover, since cysteamine has also immune-modulatory activity, we investigated its ability to modulate SARS-CoV-2-specific immune response in vitro in blood samples from COVID-19 patients. We found that cysteamine and cystamine decreased SARS-CoV-2-induced cytopathic effects (CPE) in Vero E6 cells. Interestingly, the antiviral action was independent of the treatment time respect to SARS-CoV-2 infection. Moreover, cysteamine and cystamine significantly decreased viral production in Vero E6 and Calu-3 cells. Finally, cysteamine and cystamine have an anti-inflammatory effect, as they significantly decrease the SARS-CoV-2 specific IFN-γ production in vitro in blood samples from COVID-19 patients. Overall, our findings suggest that cysteamine and cystamine exert direct antiviral actions against SARS-CoV-2 and have in vitro immunomodulatory effects, thus providing a rational to test these compounds as a novel therapy for COVID-19. Full article

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4 pages, 189 KiB

Open AccessEditorial

Cellular Immunology and COVID-19

by Isabella Quinti

Cells 2021, 10(12), 3591; https://doi.org/10.3390/cells10123591 - 20 Dec 2021

Viewed by 2409

Abstract

In “Cellular Immunology and COVID-19” (a Special Issue of Cells), a panel of leading scientists provides an exhaustive overview of the different aspects of the immune mechanisms underlying COVID-19 [...] Full article

21 pages, 2758 KiB

Open AccessReview

COVID-19 and Rheumatoid Arthritis Crosstalk: Emerging Association, Therapeutic Options and Challenges

by Saikat Dewanjee, Ramesh Kandimalla, Rajkumar Singh Kalra, Chandrasekhar Valupadas, Jayalakshmi Vallamkondu, Viswakalyan Kolli, Sarbani Dey Ray, Arubala P. Reddy and P. Hemachandra Reddy

Cells 2021, 10(12), 3291; https://doi.org/10.3390/cells10123291 - 24 Nov 2021

Cited by 43 | Viewed by 6400

Abstract

Hyperactivation of immune responses resulting in excessive release of pro-inflammatory mediators in alveoli/lung structures is the principal pathological feature of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The cytokine hyperactivation in COVID-19 appears to be similar to [...] Read more.

Hyperactivation of immune responses resulting in excessive release of pro-inflammatory mediators in alveoli/lung structures is the principal pathological feature of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The cytokine hyperactivation in COVID-19 appears to be similar to those seen in rheumatoid arthritis (RA), an autoimmune disease. Emerging evidence conferred the severity and risk of COVID-19 to RA patients. Amid the evidence of musculoskeletal manifestations involving immune-inflammation-dependent mechanisms and cases of arthralgia and/or myalgia in COVID-19, crosstalk between COVID-19 and RA is often debated. The present article sheds light on the pathological crosstalk between COVID-19 and RA, the risk of RA patients in acquiring SARS-CoV-2 infection, and the aspects of SARS-CoV-2 infection in RA development. We also conferred whether RA can exacerbate COVID-19 outcomes based on available clinical readouts. The mechanistic overlapping in immune-inflammatory features in both COVID-19 and RA was discussed. We showed the emerging links of angiotensin-converting enzyme (ACE)-dependent and macrophage-mediated pathways in both diseases. Moreover, a detailed review of immediate challenges and key recommendations for anti-rheumatic drugs in the COVID-19 setting was presented for better clinical monitoring and management of RA patients. Taken together, the present article summarizes available knowledge on the emerging COVID-19 and RA crosstalk and their mechanistic overlaps, challenges, and therapeutic options. Full article

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13 pages, 1048 KiB

Open AccessArticle

Effect of BCG Revaccination on Occupationally Exposed Medical Personnel Vaccinated against SARS-CoV-2

by Espiridión Ramos-Martinez, Ramcés Falfán-Valencia, Gloria Pérez-Rubio, Warrison Athanasio Andrade, Jorge Rojas-Serrano, Enrique Ambrocio-Ortiz, Dennisse S. Galicia-Álvarez, Isaac Bárcenas-Montiel, Andrea Velasco-Medina and Guillermo Velázquez-Sámano

Cells 2021, 10(11), 3179; https://doi.org/10.3390/cells10113179 - 15 Nov 2021

Cited by 21 | Viewed by 3523

Abstract

The production of specific neutralizing antibodies by individuals is thought to be the best option for reducing the number of patients with severe COVID-19, which is the reason why multiple vaccines are currently being administered worldwide. We aimed to explore the effect of [...] Read more.

The production of specific neutralizing antibodies by individuals is thought to be the best option for reducing the number of patients with severe COVID-19, which is the reason why multiple vaccines are currently being administered worldwide. We aimed to explore the effect of revaccination with BCG, on the response to a subsequent anti-SARS-CoV-2 vaccine, in persons occupationally exposed to COVID-19 patients. Two groups of 30 randomized participants were selected: one group received a BCG revaccination, and the other group received a placebo. Subsequently, both groups were vaccinated against SARS-CoV-2. After each round of vaccination, the serum concentration of Th1/Th2 cytokines was determined. At the end of the protocol, neutralizing antibodies were determined and the HLA-DRB loci were genotyped. The participants from the BCG group and anti-SARS-CoV-2 vaccine group had increased serum cytokine concentrations (i.e., IL-1β, IL-4, IL-6, IL-12p70, IL-13, IL-18, GM-CSF, INF-γ, and TNF-α) and higher neutralizing antibody titers, compared to the group with Placebo–anti-SARS-CoV-2. Twelve HLA-DRB1 alleles were identified in the Placebo–anti-SARS-CoV-2 group, and only nine in the group revaccinated with BCG. The DRB1*04 allele exhibited increased frequency in the Placebo–anti-SARS-CoV-2 group; however, no confounding effects were found with this allele. We conclude that revaccination with BCG synergizes with subsequent vaccination against SARS-CoV-2 in occupationally exposed personnel. Full article

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28 pages, 1695 KiB

Open AccessReview

Insights into COVID-19 Vaccine Development Based on Immunogenic Structural Proteins of SARS-CoV-2, Host Immune Responses, and Herd Immunity

by Jitendra Kumar Chaudhary, Rohitash Yadav, Pankaj Kumar Chaudhary, Anurag Maurya, Nimita Kant, Osamah Al Rugaie, Hoineiting Rebecca Haokip, Deepika Yadav, Rakesh Roshan, Ramasare Prasad, Apurva Chatrath, Dharmendra Singh, Neeraj Jain and Puneet Dhamija

Cells 2021, 10(11), 2949; https://doi.org/10.3390/cells10112949 - 29 Oct 2021

Cited by 27 | Viewed by 6557

Abstract

The first quarter of the 21st century has remarkably been characterized by a multitude of challenges confronting human society as a whole in terms of several outbreaks of infectious viral diseases, such as the 2003 severe acute respiratory syndrome (SARS), China; the 2009 [...] Read more.

The first quarter of the 21st century has remarkably been characterized by a multitude of challenges confronting human society as a whole in terms of several outbreaks of infectious viral diseases, such as the 2003 severe acute respiratory syndrome (SARS), China; the 2009 influenza H1N1, Mexico; the 2012 Middle East respiratory syndrome (MERS), Saudi Arabia; and the ongoing coronavirus disease 19 (COVID-19), China. COVID-19, caused by SARS-CoV-2, reportedly broke out in December 2019, Wuhan, the capital of China’s Hubei province, and continues unabated, leading to considerable devastation and death worldwide. The most common target organ of SARS-CoV-2 is the lungs, especially the bronchial and alveolar epithelial cells, culminating in acute respiratory distress syndrome (ARDS) in severe patients. Nevertheless, other tissues and organs are also known to be critically affected following infection, thereby complicating the overall aetiology and prognosis. Excluding H1N1, the SARS-CoV (also referred as SARS-CoV-1), MERS, and SARS-CoV-2 are collectively referred to as coronaviruses, and taxonomically placed under the realm Riboviria, order Nidovirales, suborder Cornidovirineae, family Coronaviridae, subfamily Orthocoronavirinae, genus Betacoronavirus, and subgenus Sarbecovirus. As of 23 September 2021, the ongoing SARS-CoV-2 pandemic has globally resulted in around 229 million and 4.7 million reported infections and deaths, respectively, apart from causing huge psychosomatic debilitation, academic loss, and deep economic recession. Such an unprecedented pandemic has compelled researchers, especially epidemiologists and immunologists, to search for SARS-CoV-2-associated potential immunogenic molecules to develop a vaccine as an immediate prophylactic measure. Amongst multiple structural and non-structural proteins, the homotrimeric spike (S) glycoprotein has been empirically found as the most suitable candidate for vaccine development owing to its immense immunogenic potential, which makes it capable of eliciting both humoral and cell-mediated immune responses. As a consequence, it has become possible to design appropriate, safe, and effective vaccines, apart from related therapeutic agents, to reduce both morbidity and mortality. As of 23 September 2021, four vaccines, namely, Comirnaty, COVID-19 vaccine Janssen, Spikevax, and Vaxzevria, have received the European Medicines Agency’s (EMA) approval, and around thirty are under the phase three clinical trial with emergency authorization by the vaccine-developing country-specific National Regulatory Authority (NRA). In addition, 100–150 vaccines are under various phases of pre-clinical and clinical trials. The mainstay of global vaccination is to introduce herd immunity, which would protect the majority of the population, including immunocompromised individuals, from infection and disease. Here, we primarily discuss category-wise vaccine development, their respective advantages and disadvantages, associated efficiency and potential safety aspects, antigenicity of SARS-CoV-2 structural proteins and immune responses to them along with the emergence of SARS-CoV-2 VOC, and the urgent need of achieving herd immunity to contain the pandemic. Full article

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15 pages, 1726 KiB

Open AccessFeature PaperArticle

B Cell Response Induced by SARS-CoV-2 Infection Is Boosted by the BNT162b2 Vaccine in Primary Antibody Deficiencies

by Federica Pulvirenti, Ane Fernandez Salinas, Cinzia Milito, Sara Terreri, Eva Piano Mortari, Concetta Quintarelli, Stefano Di Cecca, Gianluca Lagnese, Alessandra Punziano, Marika Guercio, Livia Bonanni, Stefania Auria, Francesca Villani, Christian Albano, Franco Locatelli, Giuseppe Spadaro, Rita Carsetti and Isabella Quinti

Cells 2021, 10(11), 2915; https://doi.org/10.3390/cells10112915 - 27 Oct 2021

Cited by 39 | Viewed by 3347

Abstract

Background: Patients with primary antibody deficiencies are at risk in the current COVID-19 pandemic due to their impaired response to infection and vaccination. Specifically, patients with common variable immunodeficiency (CVID) generated poor spike-specific antibody and T cell responses after immunization. Methods: Thirty-four CVID [...] Read more.

Background: Patients with primary antibody deficiencies are at risk in the current COVID-19 pandemic due to their impaired response to infection and vaccination. Specifically, patients with common variable immunodeficiency (CVID) generated poor spike-specific antibody and T cell responses after immunization. Methods: Thirty-four CVID convalescent patients after SARS-CoV-2 infection, 38 CVID patients immunized with two doses of the BNT162b2 vaccine, and 20 SARS-CoV-2 CVID convalescents later and immunized with BNT162b2 were analyzed for the anti-spike IgG production and the generation of spike-specific memory B cells and T cells. Results: Spike-specific IgG was induced more frequently after infection than after vaccination (82% vs. 34%). The antibody response was boosted in convalescents by vaccination. Although immunized patients generated atypical memory B cells possibly by extra-follicular or incomplete germinal center reactions, convalescents responded to infection by generating spike-specific memory B cells that were improved by the subsequent immunization. Poor spike-specific T cell responses were measured independently from the immunological challenge. Conclusions: SARS-CoV-2 infection primed a more efficient classical memory B cell response, whereas the BNT162b2 vaccine induced non-canonical B cell responses in CVID. Natural infection responses were boosted by subsequent immunization, suggesting the possibility to further stimulate the immune response by additional vaccine doses in CVID. Full article

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15 pages, 2321 KiB

Open AccessArticle

Molecular Basis of a Dominant SARS-CoV-2 Spike-Derived Epitope Presented by HLA-A*02:01 Recognised by a Public TCR

by Christopher Szeto, Andrea T. Nguyen, Christian A. Lobos, Demetra S. M. Chatzileontiadou, Dhilshan Jayasinghe, Emma J. Grant, Alan Riboldi-Tunnicliffe, Corey Smith and Stephanie Gras

Cells 2021, 10(10), 2646; https://doi.org/10.3390/cells10102646 - 3 Oct 2021

Cited by 18 | Viewed by 4045

Abstract

The data currently available on how the immune system recognises the SARS-CoV-2 virus is growing rapidly. While there are structures of some SARS-CoV-2 proteins in complex with antibodies, which helps us understand how the immune system is able to recognise this new virus; [...] Read more.

The data currently available on how the immune system recognises the SARS-CoV-2 virus is growing rapidly. While there are structures of some SARS-CoV-2 proteins in complex with antibodies, which helps us understand how the immune system is able to recognise this new virus; however, we lack data on how T cells are able to recognise this virus. T cells, especially the cytotoxic CD8+ T cells, are critical for viral recognition and clearance. Here we report the X-ray crystallography structure of a T cell receptor, shared among unrelated individuals (public TCR) in complex with a dominant spike-derived CD8+ T cell epitope (YLQ peptide). We show that YLQ activates a polyfunctional CD8+ T cell response in COVID-19 recovered patients. We detail the molecular basis for the shared TCR gene usage observed in HLA-A*02:01+ individuals, providing an understanding of TCR recognition towards a SARS-CoV-2 epitope. Interestingly, the YLQ peptide conformation did not change upon TCR binding, facilitating the high-affinity interaction observed. Full article

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13 pages, 1400 KiB

Open AccessArticle

Adipose-Tissue-Derived Mesenchymal Stem Cells Mediate PD-L1 Overexpression in the White Adipose Tissue of Obese Individuals, Resulting in T Cell Dysfunction

by Assia Eljaafari, Julien Pestel, Brigitte Le Magueresse-Battistoni, Stephanie Chanon, Julia Watson, Maud Robert, Emmanuel Disse and Hubert Vidal

Cells 2021, 10(10), 2645; https://doi.org/10.3390/cells10102645 - 3 Oct 2021

Cited by 19 | Viewed by 2778

Abstract

The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 [...] Read more.

The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals. Full article

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19 pages, 6991 KiB

Open AccessArticle

Neutrophil Extracellular Traps Contribute to COVID-19 Hyperinflammation and Humoral Autoimmunity

by Jiram Torres-Ruiz, Abdiel Absalón-Aguilar, Miroslava Nuñez-Aguirre, Alfredo Pérez-Fragoso, Daniel Alberto Carrillo-Vázquez, José Luis Maravillas-Montero, Nancy R. Mejía-Domínguez, Luis Llorente, Beatriz Alcalá-Carmona, Jaquelin Lira-Luna, Carlos Núñez-Álvarez, Guillermo Juárez-Vega, David Meza-Sánchez, Thierry Hernández-Gilsoul, Miguel Tapia-Rodríguez and Diana Gómez-Martín

Cells 2021, 10(10), 2545; https://doi.org/10.3390/cells10102545 - 26 Sep 2021

Cited by 40 | Viewed by 6370

Abstract

The coronavirus disease 2019 (COVID-19) is related to enhanced production of NETs, and autoimmune/autoinflammatory phenomena. We evaluated the proportion of low-density granulocytes (LDG) by flow cytometry, and their capacity to produce NETs was compared with that of conventional neutrophils. NETs and their protein [...] Read more.

The coronavirus disease 2019 (COVID-19) is related to enhanced production of NETs, and autoimmune/autoinflammatory phenomena. We evaluated the proportion of low-density granulocytes (LDG) by flow cytometry, and their capacity to produce NETs was compared with that of conventional neutrophils. NETs and their protein cargo were quantified by confocal microscopy and ELISA. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and the degradation capacity of NETs were addressed in serum. MILLIPLEX assay was used to assess the cytokine levels in macrophages’ supernatant and serum. We found a higher proportion of LDG in severe and critical COVID-19 which correlated with severity and inflammatory markers. Severe/critical COVID-19 patients had higher plasmatic NE, LL-37 and HMGB1-DNA complexes, whilst ISG-15-DNA complexes were lower in severe patients. Sera from severe/critical COVID-19 patients had lower degradation capacity of NETs, which was reverted after adding hrDNase. Anti-NET antibodies were found in COVID-19, which correlated with ANA and ANCA positivity. NET stimuli enhanced the secretion of cytokines in macrophages. This study unveils the role of COVID-19 NETs as inducers of pro-inflammatory and autoimmune responses. The deficient degradation capacity of NETs may contribute to the accumulation of these structures and anti-NET antibodies are related to the presence of autoantibodies. Full article

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18 pages, 2150 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Highly Specific Memory B Cells Generation after the 2nd Dose of BNT162b2 Vaccine Compensate for the Decline of Serum Antibodies and Absence of Mucosal IgA

by Eva Piano Mortari, Cristina Russo, Maria Rosaria Vinci, Sara Terreri, Ane Fernandez Salinas, Livia Piccioni, Claudia Alteri, Luna Colagrossi, Luana Coltella, Stefania Ranno, Giulia Linardos, Marilena Agosta, Christian Albano, Chiara Agrati, Concetta Castilletti, Silvia Meschi, Paolo Romania, Giuseppe Roscilli, Emiliano Pavoni, Vincenzo Camisa, Annapaola Santoro, Rita Brugaletta, Nicola Magnavita, Alessandra Ruggiero, Nicola Cotugno, Donato Amodio, Marta Luisa Ciofi Degli Atti, Daniela Giorgio, Nicoletta Russo, Guglielmo Salvatori, Tiziana Corsetti, Franco Locatelli, Carlo Federico Perno, Salvatore Zaffina and Rita Carsetti Show full author list Hide full author list

Cells 2021, 10(10), 2541; https://doi.org/10.3390/cells10102541 - 26 Sep 2021

Cited by 58 | Viewed by 12861

Abstract

Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after [...] Read more.

Specific memory B cells and antibodies are a reliable read-out of vaccine efficacy. We analysed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase, thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that the first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies, thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterilizing immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA. Full article

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18 pages, 1936 KiB

Open AccessArticle

Neutrophil Maturation, Reactivity and Granularity Research Parameters to Characterize and Differentiate Convalescent Patients from Active SARS-CoV-2 Infection

by Iwona Kwiecień, Elżbieta Rutkowska, Katarzyna Kulik, Krzysztof Kłos, Katarzyna Plewka, Agata Raniszewska, Piotr Rzepecki and Andrzej Chciałowski

Cells 2021, 10(9), 2332; https://doi.org/10.3390/cells10092332 - 6 Sep 2021

Cited by 20 | Viewed by 3111

Abstract

Studying the dynamics changes of neutrophils during innate immune response in coronavirus 2019 (COVID-19) can help understand the pathogenesis of this disease. The aim of the study was to assess the usefulness of new neutrophil activation parameters: Immature Granulocyte (IG), Neutrophil Reactivity Intensity [...] Read more.

Studying the dynamics changes of neutrophils during innate immune response in coronavirus 2019 (COVID-19) can help understand the pathogenesis of this disease. The aim of the study was to assess the usefulness of new neutrophil activation parameters: Immature Granulocyte (IG), Neutrophil Reactivity Intensity (NEUT-RI), Neutrophil Granularity Intensity (NEUT-GI), and data relating to granularity, activity, and neutrophil volume (NE-WX, NE-WY, NE-WZ) available in hematology analyzers to distinguish convalescent patients from patients with active SARS-CoV-2 infection and healthy controls (HC). The study group consisted of 79 patients with a confirmed positive RT-PCR test for SARS-CoV2 infection, 71 convalescent patients, and 20 HC. We observed leukopenia with neutrophilia in patients with active infection compared to convalescents and HC. The IG median absolute count was higher in convalescent patients than in COVID-19 and HC (respectively, 0.08 vs. 0.03 vs. 0.02, p < 0.0001). The value of the NEUT-RI parameter was the highest in HC and the lowest in convalescents (48.3 vs. 43.7, p < 0.0001). We observed the highest proportion of NE-WX, NE-WY, and NE-WZ parameters in HC, without differences between the COVID-19 and convalescent groups. New neutrophil parameters can be useful tools to assess neutrophils’ activity and functionalities in the immune response during infection and recovery from COVID-19 disease. Full article

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21 pages, 3993 KiB

Open AccessArticle

Two-Step In Vitro Model to Evaluate the Cellular Immune Response to SARS-CoV-2

by Juliana G. Melgaço, Tamiris Azamor, Andréa M. V. Silva, José Henrique R. Linhares, Tiago P. dos Santos, Ygara S. Mendes, Sheila M. B. de Lima, Camilla Bayma Fernandes, Jane da Silva, Alessandro F. de Souza, Luciana N. Tubarão, Danielle Brito e Cunha, Tamires B. S. Pereira, Catarina E. L. Menezes, Milene D. Miranda, Aline R. Matos, Braulia C. Caetano, Jéssica S. C. C. Martins, Thyago L. Calvo, Natalia F. Rodrigues, Carolina Q. Sacramento, Marilda M. Siqueira, Milton O. Moraes, Sotiris Missailidis, Patrícia C. C. Neves and Ana Paula D. Ano Bom Show full author list Hide full author list

Cells 2021, 10(9), 2206; https://doi.org/10.3390/cells10092206 - 26 Aug 2021

Cited by 5 | Viewed by 5606

Abstract

The cellular immune response plays an important role in COVID-19, caused by SARS-CoV-2. This feature makes use of in vitro models’ useful tools to evaluate vaccines and biopharmaceutical effects. Here, we developed a two-step model to evaluate the cellular immune response after SARS-CoV-2 [...] Read more.

The cellular immune response plays an important role in COVID-19, caused by SARS-CoV-2. This feature makes use of in vitro models’ useful tools to evaluate vaccines and biopharmaceutical effects. Here, we developed a two-step model to evaluate the cellular immune response after SARS-CoV-2 infection-induced or spike protein stimulation in peripheral blood mononuclear cells (PBMC) from both unexposed and COVID-19 (primo-infected) individuals (Step1). Moreover, the supernatants of these cultures were used to evaluate its effects on lung cell lines (A549) (Step2). When PBMC from the unexposed were infected by SARS-CoV-2, cytotoxic natural killer and nonclassical monocytes expressing inflammatory cytokines genes were raised. The supernatant of these cells can induce apoptosis of A549 cells (mock vs. Step2 [mean]: 6.4% × 17.7%). Meanwhile, PBMCs from primo-infected presented their memory CD4⁺ T cells activated with a high production of IFNG and antiviral genes. Supernatant from past COVID-19 subjects contributed to reduce apoptosis (mock vs. Step2 [ratio]: 7.2 × 1.4) and to elevate the antiviral activity (iNOS) of A549 cells (mock vs. Step2 [mean]: 31.5% × 55.7%). Our findings showed features of immune primary cells and lung cell lines response after SARS-CoV-2 or spike protein stimulation that can be used as an in vitro model to study the immunity effects after SARS-CoV-2 antigen exposure. Full article

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7 pages, 752 KiB

Open AccessBrief Report

Expansion of Myeloid Derived Suppressor Cells Contributes to Platelet Activation by L-Arginine Deprivation during SARS-CoV-2 Infection

by Alessandra Sacchi, Germana Grassi, Stefania Notari, Simona Gili, Veronica Bordoni, Eleonora Tartaglia, Rita Casetti, Eleonora Cimini, Davide Mariotti, Gabriele Garotto, Alessia Beccacece, Luisa Marchioni, Michele Bibas, Emanuele Nicastri, Giuseppe Ippolito and Chiara Agrati

Cells 2021, 10(8), 2111; https://doi.org/10.3390/cells10082111 - 17 Aug 2021

Cited by 37 | Viewed by 3252

Abstract

Massive platelet activation and thrombotic events characterize severe COVID-19, highlighting their critical role in SARS-CoV-2-induced immunopathology. Since there is a well-described expansion of myeloid-derived suppressor cells (MDSC) in severe COVID-19, we evaluated their possible role in platelet activation during SARS-CoV-2 infection. During COVID-19, [...] Read more.

Massive platelet activation and thrombotic events characterize severe COVID-19, highlighting their critical role in SARS-CoV-2-induced immunopathology. Since there is a well-described expansion of myeloid-derived suppressor cells (MDSC) in severe COVID-19, we evaluated their possible role in platelet activation during SARS-CoV-2 infection. During COVID-19, a lower plasmatic L-arginine level was observed compared to healthy donors, which correlated with MDSC frequency. Additionally, activated GPIIb/IIIa complex (PAC-1) expression was higher on platelets from severe COVID-19 patients compared to healthy controls and inversely correlated with L-arginine plasmatic concentration. Notably, MDSC were able to induce PAC-1 expression in vitro by reducing L-arginine concentration, indicating a direct role of PMN-MDSC in platelet activation. Accordingly, we found a positive correlation between ex vivo platelet PAC-1 expression and PMN-MDSC frequency. Overall, our data demonstrate the involvement of PMN-MDSC in triggering platelet activation during COVID-19, highlighting a novel role of MDSC in driving COVID-19 pathogenesis. Full article

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16 pages, 2491 KiB

Open AccessArticle

Differences in the Concentration of Anti-SARS-CoV-2 IgG Antibodies Post-COVID-19 Recovery or Post-Vaccination

by Andrzej Tretyn, Joanna Szczepanek, Monika Skorupa, Joanna Jarkiewicz-Tretyn, Dorota Sandomierz, Joanna Dejewska, Karolina Ciechanowska, Aleksander Jarkiewicz-Tretyn, Wojciech Koper and Krzysztof Pałgan

Cells 2021, 10(8), 1952; https://doi.org/10.3390/cells10081952 - 31 Jul 2021

Cited by 67 | Viewed by 10817

Abstract

At the end of 2020, population-based vaccination programs with new generation mRNA-based vaccines began almost all over the world. The aim of the study was to evaluate the titer of anti-SARS-CoV-2 IgG antibodies against the S1 subunit of the virus’s spike protein as [...] Read more.

At the end of 2020, population-based vaccination programs with new generation mRNA-based vaccines began almost all over the world. The aim of the study was to evaluate the titer of anti-SARS-CoV-2 IgG antibodies against the S1 subunit of the virus’s spike protein as a marker of the humoral response in 477 patients and the concentration of interferon-gamma as an indicator of cellular response in 28 individuals. In our studies, we used serological enzyme-linked immunosorbent assays. IgG was measured in weeks 2 and 3 after the first dose and 1–5 weeks after the second dose of an mRNA vaccine in seropositive and seronegative individuals as well as in symptomatic and asymptomatic convalescents. High levels of antibodies were observed in 98% of our vaccinated cohort, and the presence of protective T cells was confirmed in the blood samples of all participants. The humoral immune response is diversified and is visible as early as 2–3 weeks after the first dose of the mRNA vaccine. The level of protection increased significantly after the second dose, with the increase being much greater in pre-vaccine healthy subjects and less in convalescents. In the second and third weeks after the second dose, the concentration of IgG antibodies was the highest, and in the following weeks, it decreased gradually. Regular serological measurements on eight subjects show that antibody titers are lower four months after vaccination than before the second dose. Full article

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17 pages, 2913 KiB

Open AccessEditor’s ChoiceArticle

Kinetics of Anti-SARS-CoV-2 Antibody Responses 3 Months Post Complete Vaccination with BNT162b2; A Prospective Study in 283 Health Workers

by Evangelos Terpos, Ioannis P. Trougakos, Vangelis Karalis, Ioannis Ntanasis-Stathopoulos, Sentiljana Gumeni, Filia Apostolakou, Aimilia D. Sklirou, Maria Gavriatopoulou, Stamatia Skourti, Efstathios Kastritis, Eleni Korompoki, Ioannis Papassotiriou and Meletios A. Dimopoulos

Cells 2021, 10(8), 1942; https://doi.org/10.3390/cells10081942 - 30 Jul 2021

Cited by 33 | Viewed by 3626

Abstract

The aim of this study was to investigate the kinetics of neutralizing antibodies (NAbs) and anti-SARS-CoV-2 anti-S-RBD IgGs up to three months after the second vaccination dose with the BNT162b2 mRNA vaccine. NAbs and anti-S-RBD levels were measured on days 1 (before the [...] Read more.

The aim of this study was to investigate the kinetics of neutralizing antibodies (NAbs) and anti-SARS-CoV-2 anti-S-RBD IgGs up to three months after the second vaccination dose with the BNT162b2 mRNA vaccine. NAbs and anti-S-RBD levels were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and three months after the second vaccination (D111) (NCT04743388). 283 health workers were included in this study. NAbs showed a rapid increase from D8 to D36 at a constant rate of about 3% per day and reached a median (SD) of 97.2% (4.7) at D36. From D36 to D50, a slight decrease in NAbs values was detected and it became more prominent between D50 and D111 when the rate of decline was determined at −0.11 per day. The median (SD) NAbs value at D111 was 92.7% (11.8). A similar pattern was also observed for anti-S-RBD antibodies. Anti-S-RBDs showed a steeper increase during D22–D36 and a lower decline rate during D36–D111. Prior COVID-19 infection and younger age were associated with superior antibody responses over time. In conclusion, we found a persistent but declining anti-SARS-CoV-2 humoral immunity at 3 months following full vaccination with BNT162b2 in healthy individuals. Full article

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19 pages, 919 KiB

Open AccessReview

Interplay between Neutrophils, NETs and T-Cells in SARS-CoV-2 Infection—A Missing Piece of the Puzzle in the COVID-19 Pathogenesis?

by Paulina Niedźwiedzka-Rystwej, Ewelina Grywalska, Rafał Hrynkiewicz, Dominika Bębnowska, Mikołaj Wołącewicz, Adam Majchrzak and Miłosz Parczewski

Cells 2021, 10(7), 1817; https://doi.org/10.3390/cells10071817 - 19 Jul 2021

Cited by 8 | Viewed by 3944

Abstract

Since the end of 2019, a new, dangerous virus has caused the deaths of more than 3 million people. Efforts to fight the disease remain multifaceted and include prophylactic strategies (vaccines), the development of antiviral drugs targeting replication, and the mitigation of the [...] Read more.

Since the end of 2019, a new, dangerous virus has caused the deaths of more than 3 million people. Efforts to fight the disease remain multifaceted and include prophylactic strategies (vaccines), the development of antiviral drugs targeting replication, and the mitigation of the damage associated with exacerbated immune responses (e.g., interleukin-6-receptor inhibitors). However, numerous uncertainties remain, making it difficult to lower the mortality rate, especially among critically ill patients. While looking for a new means of understanding the pathomechanisms of the disease, we asked a question—is our immunity key to resolving these uncertainties? In this review, we attempt to answer this question, and summarize, interpret, and discuss the available knowledge concerning the interplay between neutrophils, neutrophil extracellular traps (NETs), and T-cells in COVID-19. These are considered to be the first line of defense against pathogens and, thus, we chose to emphasize their role in SARS-CoV-2 infection. Although immunologic alterations are the subject of constant research, they are poorly understood and often underestimated. This review provides background information for the expansion of research on the novel, immunity-oriented approach to diagnostic and treatment possibilities. Full article

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13 pages, 1367 KiB

Open AccessArticle

MiRNA Profiling in Plasma and Placenta of SARS-CoV-2-Infected Pregnant Women

by Irma Saulle, Micaela Garziano, Claudio Fenizia, Gioia Cappelletti, Francesca Parisi, Mario Clerici, Irene Cetin, Valeria Savasi and Mara Biasin

Cells 2021, 10(7), 1788; https://doi.org/10.3390/cells10071788 - 15 Jul 2021

Cited by 28 | Viewed by 3548

Abstract

MicroRNAs are gene expression regulators associated with several human pathologies, including those generated by viral infections. Their role in SARS-CoV-2 infection and COVID-19 has been investigated and reviewed in many informative studies; however, a thorough miRNA outline in SARS-CoV-2-infected pregnant women (SIPW), at [...] Read more.

MicroRNAs are gene expression regulators associated with several human pathologies, including those generated by viral infections. Their role in SARS-CoV-2 infection and COVID-19 has been investigated and reviewed in many informative studies; however, a thorough miRNA outline in SARS-CoV-2-infected pregnant women (SIPW), at both systemic and placental levels, is missing. To fill this gap, blood and placenta biopsies collected at delivery from 15 asymptomatic SIPW were immediately analysed for: miRNA expression (n = 84) (QPCR array), antiviral/immune mRNA target expression (n = 74) (QGene) and cytokine/chemokines production (n = 27) (Multiplex ELISA). By comparing these results with those obtained from six uninfected pregnant women (UPW), we observed that, following SARS-CoV-2 infection, the transcriptomic profile of pregnant women is significantly altered in different anatomical districts, even in the absence of clinical symptoms and vertical transmission. This characteristic combination of miRNA and antiviral/immune factors seems to control both the infection and the dysfunctional immune reaction, thus representing a positive correlate of protection and a potential therapeutic target against SARS-CoV-2. Full article

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18 pages, 373 KiB

Open AccessReview

Cytokine Storm Syndrome in SARS-CoV-2 Infections: A Functional Role of Mast Cells

by Bahareh Hafezi, Lily Chan, Jason P. Knapp, Negar Karimi, Kimia Alizadeh, Yeganeh Mehrani, Byram W. Bridle and Khalil Karimi

Cells 2021, 10(7), 1761; https://doi.org/10.3390/cells10071761 - 12 Jul 2021

Cited by 37 | Viewed by 6808

Abstract

Cytokine storm syndrome is a cascade of escalated immune responses disposing the immune system to exhaustion, which might ultimately result in organ failure and fatal respiratory distress. Infection with severe acute respiratory syndrome-coronavirus-2 can result in uncontrolled production of cytokines and eventually the [...] Read more.

Cytokine storm syndrome is a cascade of escalated immune responses disposing the immune system to exhaustion, which might ultimately result in organ failure and fatal respiratory distress. Infection with severe acute respiratory syndrome-coronavirus-2 can result in uncontrolled production of cytokines and eventually the development of cytokine storm syndrome. Mast cells may react to viruses in collaboration with other cells and lung autopsy findings from patients that died from the coronavirus disease that emerged in 2019 (COVID-19) showed accumulation of mast cells in the lungs that was thought to be the cause of pulmonary edema, inflammation, and thrombosis. In this review, we present evidence that a cytokine response by mast cells may initiate inappropriate antiviral immune responses and cause the development of cytokine storm syndrome. We also explore the potential of mast cell activators as adjuvants for COVID-19 vaccines and discuss the medications that target the functions of mast cells and could be of value in the treatment of COVID-19. Recognition of the cytokine storm is crucial for proper treatment of patients and preventing the release of mast cell mediators, as impeding the impacts imposed by these mediators could reduce the severity of COVID-19. Full article

10 pages, 485 KiB

Open AccessReview

The Role of Th17 Response in COVID-19

by Diana Martonik, Anna Parfieniuk-Kowerda, Magdalena Rogalska and Robert Flisiak

Cells 2021, 10(6), 1550; https://doi.org/10.3390/cells10061550 - 19 Jun 2021

Cited by 97 | Viewed by 7746

Abstract

COVID-19 is an acute infectious disease of the respiratory system caused by infection with the SARS-CoV-2 virus (Severe Acute Respiratory Syndrome Coronavirus 2). Transmission of SARS-CoV-2 infections occurs through droplets and contaminated objects. A rapid and well-coordinated immune system response is the first [...] Read more.

COVID-19 is an acute infectious disease of the respiratory system caused by infection with the SARS-CoV-2 virus (Severe Acute Respiratory Syndrome Coronavirus 2). Transmission of SARS-CoV-2 infections occurs through droplets and contaminated objects. A rapid and well-coordinated immune system response is the first line of defense in a viral infection. However, a disturbed and over-activated immune response may be counterproductive, causing damage to the body. Severely ill patients hospitalised with COVID-19 exhibit increased levels of many cytokines, including Interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor (TNF). Increasing evidence suggests that Th17 cells play an important role in the pathogenesis of COVID-19, not only by activating cytokine cascade but also by inducing Th2 responses, inhibiting Th1 differentiation and suppressing Treg cells. This review focuses on a Th17 pathway in the course of the immune response in COVID-19, and explores plausible targets for therapeutic intervention. Full article

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