T-cell hyperactivation and paralysis in severe COVID-19 infection revealed by single-cell analysis

Kalfaoglu, Bahire; Almeida‐Santos, José; Tye, Chanidapa Adele; Satou, Yorifumi; Ono, M.

doi:10.1101/2020.05.26.115923

Cited by 15 publications

(9 citation statements)

References 56 publications

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“…In summary, Gal-3 is a lectin that exhibits a pleiotropic role in mediating the acute and chronic consequences of infection and inflammation. Multiple studies have shown Gal-3 to be highly upregulated in patients suffering from severe COVID-19 ( De Biasi et al, 2020 ; Kalfaoglu et al, 2020 ; Liu et al, 2020 ). On a cellular level, Gal-3 is most highly expressed in monocytes, macrophages, and dendritic cells during severe COVID-19 infection ( Liu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, significantly elevated levels of Gal-3 have been shown in the serum of patients suffering from severe COVID-19 as compared to those with mild disease ( De Biasi et al, 2020 ). On a cellular level, Gal-3 was shown to be most elevated in immune cells during severe COVID-19 ( Kalfaoglu et al, 2020 ) The highest levels of Gal-3 were seen in infected macrophages, monocytes, and dendritic cells, the very cells responsible for initiating CSS ( Liu et al, 2020 ). A pathway through which Gal-3 may contribute to the development of CSS is detailed in Figure 2 .…”

Section: Gal-3 In Severe Infection: Promoting Immunologic Sequelae Ofmentioning

confidence: 99%

“…Patients suffering from severe coronavirus disease 2019 (COVID-19) show highly elevated levels of Gal-3, TNFα, IL-1β, and IL-6, as compared to those with moderate disease ( De Biasi et al, 2020 ; Wang et al, 2020a ). Inhibition of Gal-3 significantly reduces the levels of these cytokines, and so may show promise in reducing inflammatory sequelae associated with COVID-19 ( De Biasi et al, 2020 ; Kalfaoglu et al, 2020 ; Liu et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Immunopathology of galectin-3: an increasingly promising target in COVID-19

et al. 2020

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The pandemic brought on by the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has become a global health crisis, with over 22 million confirmed cases and 777,000 fatalities due to coronavirus disease 2019 (COVID-19) reported worldwide. The major cause of fatality in infected patients, now referred to as the “Cytokine Storm Syndrome” (CSS), is a direct result of aberrant immune activation following SARS-CoV2 infection and results in excess release of inflammatory cytokines, such as interleukin (IL)-1, tumor necrosis factor α (TNF-α), and IL-6, by macrophages, monocytes, and dendritic cells. Single cell analysis has also shown significantly elevated levels of galectin 3 (Gal-3) in macrophages, monocytes, and dendritic cells in patients with severe COVID-19 as compared to mild disease. Inhibition of Gal-3 reduces the release of IL-1, IL-6, and TNF-α from macrophages in vitro, and as such may hold promise in reducing the incidence of CSS. In addition, Gal-3 inhibition shows promise in reducing transforming growth factor ß (TGF-ß) mediated pulmonary fibrosis, likely to be a major consequence in survivors of severe COVID-19. Finally, a key domain in the spike protein of SARS-CoV2 has been shown to bind N-acetylneuraminic acid (Neu5Ac), a process that may be essential to cell entry by the virus. This Neu5Ac-binding domain shares striking morphological, sequence, and functional similarities with human Gal-3. Here we provide an updated review of the literature linking Gal-3 to COVID-19 pathogenesis. Dually targeting galectins and the Neu5Ac-binding domain of SARS-CoV2 shows tentative promise in several stages of the disease: preventing viral entry, modulating the host immune response, and reducing the post-infectious incidence of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Gal-3 In Severe Infection: Promoting Immunologic Sequelae Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immunopathology of galectin-3: an increasingly promising target in COVID-19

et al. 2020

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“…Detailed investigation of Tregs in the lung tissues of severe COVID-19 patients and their molecular signatures would provide insight on these questions. However, in silico analyses performed on the transcriptomic data of CD4 + T-cells from the COVID-19 patient's bronchoalveolar lavage suggest that IL2 transcripts were reduced in severe cases compared with mild cases [10]. Therefore, reduced IL2 would lead to enhanced apoptosis of Tregs and is also confirmed by reduced levels of FoxP3.…”

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confidence: 98%

Potential of regulatory T-cell-based therapies in the management of severe COVID-19

et al. 2020

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, inflammation-mediated severe lung damage and defective haemostasis are the main underlying reasons for morbidity and mortality in coronavirus disease 2019 (COVID-19) patients [1]. Several immunotherapies that target various inflammatory processes have been successfully used in COVID-19 patients and many other strategies are under evaluation [2, 3]. However, in view of dysregulated immune responses in severe COVID-19 patients, we suggest that CD4 + CD25 + FoxP3 + regulatory T-cell (Treg)-based strategies could be considered for patient management. Vigorous antimicrobial responses triggered against the pathogen can be detrimental to the host due to collateral tissue damage. Therefore, regulatory mechanisms, and in particular Tregs, are in place to ensure that inflammation is kept in check. Tregs are either thymus-derived or induced in the periphery and are classically known for stimulating immune tolerance, and preventing autoimmune and inflammatory diseases [4]. Tregs inhibit the activation of both innate and adaptive immune cells via inhibitory surface molecules (like cytotoxic T-lymphocyte antigen-4 (CTLA-4) and lymphocyte-activation gene-3) and secretion of immunosuppressive cytokines (interleukin (IL)-10, transforming growth factor-β and IL-35). Both Treg subsets are equally important to prevent inflammation-induced tissue damage during acute infections and to promote tissue repair, which is particularly shown in the influenza infection model [4, 5].

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“…The most common reported comorbidities associated with poor outcomes in include hypertension, diabetes, cardiovascular disease, and chronic respiratory infections [4,5]. However, the underlying molecular mechanisms in severe COVID-19 and their interplay with such comorbidities or clinical factors are poorly understood [6].…”

Section: Introductionmentioning

confidence: 99%

Identification of biological correlates associated with respiratory failure in COVID-19

Tannenbaum

Deasy

2020

Preprint

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Background: Coronavirus disease 2019 (COVID-19) is a global public health concern. Recently, a genome-wide association study (GWAS) was performed with participants recruited from Italy and Spain by an international consortium group. Methods: Summary GWAS statistics for 1610 patients with COVID-19 respiratory failure and 2205 controls were downloaded. In the current study, we analyzed the summary statistics with the information of loci and p-values for 8,582,968 single-nucleotide polymorphisms (SNPs), using gene ontology analysis to determine the top biological processes implicated in respiratory failure in COVID-19 patients. Results: We considered the top 708 SNPs, using a p-value cutoff of 5x10-5, which were mapped to the nearest genes, leading to 144 unique genes. The list of genes was input into a curated database to conduct gene ontology and protein-protein interaction (PPI) analyses. The top-ranked biological processes were wound healing, epithelial structure maintenance, muscle system processes, and cardiac-relevant biological processes with a false discovery rate < 0.05. In the PPI analysis, the largest connected network consisted of 8 genes. Through literature search, 7 out of the 8 genes were found to be implicated in both pulmonary and cardiac diseases. Conclusion: Gene ontology and protein-protein interaction analyses identified cardio-pulmonary processes that may partially explain the risk of respiratory failure in COVID-19 patients.

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T-cell hyperactivation and paralysis in severe COVID-19 infection revealed by single-cell analysis

Cited by 15 publications

References 56 publications

Immunopathology of galectin-3: an increasingly promising target in COVID-19

Immunopathology of galectin-3: an increasingly promising target in COVID-19

Potential of regulatory T-cell-based therapies in the management of severe COVID-19

Identification of biological correlates associated with respiratory failure in COVID-19

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