The dynamic changes in cytokine responses in COVID-19: a snapshot of the current state of knowledge

Buszko, Maja; Park, Jung Hyun; Verthelyi, Daniela; Sen, Ranjan; Young, Howard A.; Rosenberg, Amy S.

doi:10.1038/s41590-020-0779-1

Cited by 84 publications

(72 citation statements)

References 18 publications

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“…Elevated sCD25 in blood can result from the upregulation of CD25 expression on activated immune cells and/or enhanced proteolytic cleavage of membrane CD25 under inflammation. Contrasting with high concentrations of sCD25 in COVID‐19, sFasL and sCD62L were reported being decreased, 18 indicating there was no ubiquitous enhancement of proteolytic cleavage activity. Therefore, the elevation of sCD25 in COVID‐19 is probably primarily driven by the upregulation of surface CD25 expression on activated immune cells.…”

Section: Resultsmentioning

confidence: 88%

High levels of soluble CD25 in COVID‐19 severity suggest a divergence between anti‐viral and pro‐inflammatory T‐cell responses

et al. 2021

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Objectives We aimed to gain an understanding of the paradox of the immunity in COVID‐19 patients with T cells showing both functional defects and hyperactivation and enhanced proliferation. Methods A total of 280 hospitalised patients with COVID‐19 were evaluated for cytokine profiles and clinical features including viral shedding. A mouse model of acute infection by lymphocytic choriomeningitis virus (LCMV) was applied to dissect the relationship between immunological, virological and pathological features. The results from the mouse model were validated by published data set of single‐cell RNA sequencing (scRNA‐seq) of immune cells in bronchoalveolar lavage fluid (BALF) of COVID‐19 patients. Results The levels of soluble CD25 (sCD25), IL‐6, IL‐8, IL‐10 and TNF‐α were higher in severe COVID‐19 patients than non‐severe cases, but only sCD25 was identified as an independent risk factor for disease severity by multivariable binary logistic regression analysis and showed a positive association with the duration of viral shedding. In agreement with the clinical observation, LCMV‐infected mice with high levels of sCD25 demonstrated insufficient anti‐viral response and delayed viral clearance. The elevation of sCD25 in mice was mainly contributed by the expansion of CD25+CD8+ T cells that also expressed the highest level of PD‐1 with pro‐inflammatory potential. The counterpart human CD25+PD‐1+ T cells were expanded in BALF of COVID‐19 patients with severe disease compared to those with modest disease. Conclusion These results suggest that high levels of sCD25 in COVID‐19 patients probably result from insufficient anti‐viral immunity and indicate an expansion of pro‐inflammatory T cells that contribute to disease severity.

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Section: Resultsmentioning

confidence: 88%

High levels of soluble CD25 in COVID‐19 severity suggest a divergence between anti‐viral and pro‐inflammatory T‐cell responses

et al. 2021

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“…Using mouse models, it has been observed that the pharmacological blockade of BTK results in impaired immunity due to inhibition of macrophages (41). Importantly, BTK-driven macrophage inhibition is mediated by blocking the activation of both the inflammasome and NF-κB (41). Of note, both inflammasome and NF-κB pathways are known to play an essential role in cytokine storm in severe COVID-19 (42,43).…”

Section: Btk Inhibition Blunts the Hyperinflammatory Response In Lungmentioning

confidence: 99%

Relevance of the Bruton Tyrosine Kinase as a Target for COVID-19 Therapy

Rada¹,

Qusairy

Massip-Salcedo

et al. 2020

Molecular Cancer Research

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The outbreak of the novel coronavirus disease 2019 has emerged as one of the biggest global health threats worldwide. As of October 2020, over 44 million confirmed cases and more than 1,160,000 deaths have been reported globally, and the toll is likely to be much higher before the pandemic is over. There are currently little therapeutic options available and new potential targets are intensively investigated. Recently, Bruton Tyrosine Kinase (BTK) has emerged as an interesting candidate. Elevated levels of BTK activity have been reported in blood monocytes from patients with severe COVID-19, compared to those from healthy volunteers. Importantly, various studies confirmed empirically that administration of BTK inhibitors (Acalabrutinib and Ibrutinib) decreased the duration of mechanical ventilation and mortality rate for hospitalized patients with severe COVID-19. Herein, we review the current information regarding the role of BTK in SARS-CoV-2 infections and the suitability of its inhibitors as drugs to treat COVID-19. Implications:The use of BTK inhibitors in the management of COVID-19 shows promise in reducing the severity of the immune response to the infection and thus mortality. However, BTK inhibition may be contributing in other ways to inhibit the effects of the virus and this will need to be carefully studied.

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“…This connection between caspase-1 and COVID-19 has significant therapeutic implications since preventing the pyroptotic lymphocyte death rather than inhibition of the inflammatory response may be a more ideal option. The failure of cytokine targeted therapies could therefore suggest that adaptive immune dysfunction weighs more than an inflammatory response in disease progression (48).…”

Section: Discussionmentioning

confidence: 99%

Caspases in COVID-19 Disease and Sequela and the Therapeutic Potential of Caspase Inhibitors

Plassmeyer¹,

Alpan²,

Corley

et al. 2020

Preprint

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At present, there are is no effective vaccine and only one FDA approved early-stage therapy against infection with the SARS-CoV-2 virus to prevent disease progression. The excessive inflammation and tissue damage associated with COVID-19 can lead to immediate (i.e. respiratory failure, sepsis, and ultimately, death) or long-term health problems (i.e. fatigue, dyspnea, cough, joint pain, anosmia) and the risk for these complications are higher in the elderly population, certain ethnic groups, as well as those with various co-morbid conditions. Cellular caspases play a role in the pathophysiology of a number of disorders that overlap with the list of co-morbid conditions seen in severe COVID-19. In this study, we assessed transcriptional states of caspases in immune cells from COVID-19 patients and profiled intra-cellular caspases in immune cells and red blood cells derived from a spectrum of COVID-19 patients hospitalized with acute disease or convalescent. Gene expression levels of select caspases were increased in in vitro SARS-CoV-2 infection models and single cell RNA-Seq data of peripheral blood from COVID-19 patients showed a distinct pattern of caspase expression in T cell, neutrophils, and dendritic cells. Flow cytometric evaluation of CD4 T cells showed up-regulation of caspase-1 in hospitalized COVID-19 patients compared to unexposed controls, with the exception of a subset of patients with asthma and chronic rhinosinusitis (CRS). Convalescent COVID-19 patients with lingering symptoms (long haulers) showed persistent up-regulation of caspase-1 in CD4 T cells that was attenuated ex vivo following co-culture with a select pan-caspase inhibitor. Further, we observed elevated caspase 3 levels in red blood cells from COVID-19 patients compared to controls that were responsive to caspase inhibition. Taken together, our results expose an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate, reduce, or prevent severe COVID-19 outcomes.

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The dynamic changes in cytokine responses in COVID-19: a snapshot of the current state of knowledge

Cited by 84 publications

References 18 publications

High levels of soluble CD25 in COVID‐19 severity suggest a divergence between anti‐viral and pro‐inflammatory T‐cell responses

High levels of soluble CD25 in COVID‐19 severity suggest a divergence between anti‐viral and pro‐inflammatory T‐cell responses

Relevance of the Bruton Tyrosine Kinase as a Target for COVID-19 Therapy

Caspases in COVID-19 Disease and Sequela and the Therapeutic Potential of Caspase Inhibitors

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