The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity

Osuchowski, Marcin F.; Winkler, Martin Sebastian; Skirecki, Tomasz; Cajander, Sara; Shankar-Hari, Manu; Lachmann, Gunnar; Monneret, Guillaume; Venet, Fabienne; Bauer, Michael; Brunkhorst, Frank M.; Weis, Sebastian; García-Salido, Alberto; Kox, Matthijs; Cavaillon, Jean Marc; Uhle, Florian; Weigand, Markus; Flohé, Stefanie B.; Wiersinga, W. Joost; Almansa, Raquel; Fuente, Amanda de la; Martín‐Loeches, Ignacio; Meisel, Christian; Spinetti, Thibaud; Schefold, Joerg C.; Cillóniz, Catia; Torres, Antoni; Giamarellos‐Bourboulis, Evangelos J.; Ferrer, Ricard; Girardis, Massimo; Cossarizza, Andrea; Netea, Mihai G.; Poll, Tom van der; Bermejo-Martín, Jesús F.; Rubio, Ignacio

doi:10.1016/s2213-2600(21)00218-6

Cited by 432 publications

(433 citation statements)

References 285 publications

(354 reference statements)

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“…Furthermore, loss of taste or smell and gastrointestinal symptoms are reported in patients [ 13 , 14 , 15 ]. Disease severity seems associated with various factors such as age, sex, but mostly overall health condition; people with co-morbidities such as diabetes, cardiovascular problems, or hypertension are more likely to experience more severe effects of SARS-Cov-2 infection [ 16 , 17 ].…”

Section: Sars-cov-2: Structural Characteristics and Diffusionmentioning

confidence: 99%

Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

Paolini

Borella

Biasi

et al. 2021

Cells

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Cell death mechanisms are crucial to maintain an appropriate environment for the functionality of healthy cells. However, during viral infections, dysregulation of these processes can be present and can participate in the pathogenetic mechanisms of the disease. In this review, we describe some features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some immunopathogenic mechanisms characterizing the present coronavirus disease (COVID-19). Lymphopenia and monocytopenia are important contributors to COVID-19 immunopathogenesis. The fine mechanisms underlying these phenomena are still unknown, and several hypotheses have been raised, some of which assign a role to cell death as far as the reduction of specific types of immune cells is concerned. Thus, we discuss three major pathways such as apoptosis, necroptosis, and pyroptosis, and suggest that all of them likely occur simultaneously in COVID-19 patients. We describe that SARS-CoV-2 can have both a direct and an indirect role in inducing cell death. Indeed, on the one hand, cell death can be caused by the virus entry into cells, on the other, the excessive concentration of cytokines and chemokines, a process that is known as a COVID-19-related cytokine storm, exerts deleterious effects on circulating immune cells. However, the overall knowledge of these mechanisms is still scarce and further studies are needed to delineate new therapeutic strategies.

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Section: Sars-cov-2: Structural Characteristics and Diffusionmentioning

confidence: 99%

Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

Paolini

Borella

Biasi

et al. 2021

Cells

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“…Age, various comorbidities, including diabetes, obesity, lung and cardiovascular diseases, as well as genetic polymorphisms correlate with a higher risk of respiratory failure (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Monocytes and Macrophages in COVID-19

2021

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COVID-19 is a contagious viral disease caused by SARS-CoV-2 that led to an ongoing pandemic with massive global health and socioeconomic consequences. The disease is characterized primarily, but not exclusively, by respiratory clinical manifestations ranging from mild common cold symptoms, including cough and fever, to severe respiratory distress and multi-organ failure. Macrophages, a heterogeneous group of yolk-sac derived, tissue-resident mononuclear phagocytes of complex ontogeny present in all mammalian organs, play critical roles in developmental, homeostatic and host defense processes with tissue-dependent plasticity. In case of infection, they are responsible for early pathogen recognition, initiation and resolution of inflammation, as well as repair of tissue damage. Monocytes, bone-marrow derived blood-resident phagocytes, are recruited under pathological conditions such as viral infections to the affected tissue to defend the organism against invading pathogens and to aid in efficient resolution of inflammation. Given their pivotal function in host defense and the potential danger posed by their dysregulated hyperinflammation, understanding monocyte and macrophage phenotypes in COVID-19 is key for tackling the disease’s pathological mechanisms. Here, we outline current knowledge on monocytes and macrophages in homeostasis and viral infections and summarize concepts and key findings on their role in COVID-19. While monocytes in the blood of patients with moderate COVID-19 present with an inflammatory, interferon-stimulated gene (ISG)-driven phenotype, cellular dysfunction epitomized by loss of HLA-DR expression and induction of S100 alarmin expression is their dominant feature in severe disease. Pulmonary macrophages in COVID-19 derived from infiltrating inflammatory monocytes are in a hyperactivated state resulting in a detrimental loop of pro-inflammatory cytokine release and recruitment of cytotoxic effector cells thereby exacerbating tissue damage at the site of infection.

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“…Traits that have been previously associated with critically ill COVID-19 status and infectious diseases such as alanine aminotransferase, BMI, C-reactive protein, and neutrophil cell count were further investigated. 15,16…”

Section: Screening For Critically Ill Covid-19 Status Associated Traitsmentioning

confidence: 99%

Critically ill COVID-19 status associated trait genetics reveals CDK6 inhibitors as potential treatment

Klinger¹,

Ravarani²,

Bannard

et al. 2021

Preprint

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Despite the recent development of vaccines and monoclonal antibodies preventing SARS-CoV-2 infection, treating critically ill COVID-19 patients still remains a top goal. In principle, drug repurposing – the use of an already existing drug for a new indication – could provide a shortcut to a treatment. However, drug repurposing is often very speculative due to lack of clinical evidence. We report here on a methodology to find and test drug target candidates for drug repurposing. Using UK Biobank data, we matched critically ill COVID-19 cases with healthy controls and screened for significant differences in 33 blood cell types, 30 blood biochemistries, and body mass index. Significant differences in traits that have been associated with critically ill COVID-19 status in prior literature, such as alanine aminotransferase, body mass index, C-reactive protein, and neutrophil cell count, were further investigated. In-depth statistical analysis of COVID-19 associated traits and their genetics using regression modeling and propensity score stratification identified cyclin-dependent kinase 6 (CDK6) as a more promising drug target for the selective treatment of critically ill COVID-19 patients than the previously reported interleukin 6. Four existing CDK6 inhibitors -- abemaciclib, ribociclib, trilaciclib, and palbociclib -- have been approved for the treatment of breast cancer. Clinical evidence for CDK6 inhibitors in treating critically ill COVID-19 patients has been reported. Further clinical investigations are ongoing.

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The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity

Cited by 432 publications

References 285 publications

Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

Cell Death in Coronavirus Infections: Uncovering Its Role during COVID-19

Monocytes and Macrophages in COVID-19

Critically ill COVID-19 status associated trait genetics reveals CDK6 inhibitors as potential treatment

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