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Immunity, endothelial injury and complement-induced coagulopathy in COVID-19

Nature Reviews Nephrology volume 17, pages 46–64 (2021)Cite this article

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Abstract

In December 2019, a novel coronavirus was isolated from the respiratory epithelium of patients with unexplained pneumonia in Wuhan, China. This pathogen, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a pathogenic condition that has been termed coronavirus disease 2019 (COVID-19) and has reached pandemic proportions. As of 17 September 2020, more than 30 million confirmed SARS-CoV-2 infections have been reported in 204 different countries, claiming more than 1 million lives worldwide. Accumulating evidence suggests that SARS-CoV-2 infection can lead to a variety of clinical conditions, ranging from asymptomatic to life-threatening cases. In the early stages of the disease, most patients experience mild clinical symptoms, including a high fever and dry cough. However, 20% of patients rapidly progress to severe illness characterized by atypical interstitial bilateral pneumonia, acute respiratory distress syndrome and multiorgan dysfunction. Almost 10% of these critically ill patients subsequently die. Insights into the pathogenic mechanisms underlying SARS-CoV-2 infection and COVID-19 progression are emerging and highlight the critical role of the immunological hyper-response — characterized by widespread endothelial damage, complement-induced blood clotting and systemic microangiopathy — in disease exacerbation. These insights may aid the identification of new or existing therapeutic interventions to limit the progression of early disease and treat severe cases.

Key points

  • Although most patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience mild to moderate symptoms that resolve after 6–10 days, almost 20% of patients develop severe illness characterized by atypical interstitial bilateral pneumonia and acute respiratory distress syndrome, with a high fatality rate.

  • Accumulating evidence suggests that an unbalanced and unrestrained innate immune response, which comes at the expense of effective adaptive immunity, underpins the progression of coronavirus disease 2019 (COVID-19).

  • In severe cases of COVID-19, massive endothelial dysfunction, widespread coagulopathy and complement-induced thrombosis can lead to the development of systemic microangiopathy and thromboembolism; these complications can be life-threatening and ultimately lead to multi-organ failure.

  • The kidney is one of the main targets of COVID-19 complications, and abnormal kidney function is associated with a significantly increased risk of death in severely ill patients.

  • Most repurposed anti-viral drugs have failed to improve clinical outcomes in COVID-19; by contrast, therapeutic interventions that target the host response, including the hyper-immune response, complement activation and systemic thrombosis, seem to be more promising approaches to the treatment of severe COVID-19.

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Fig. 1: SARS-CoV-2 structure, genome composition and life cycle.
Fig. 2: Pathogenesis and outcomes of COVID-19.
Fig. 3: Effect of SARS-CoV-2 infection on endothelial cell function, systemic coagulation and thrombosis.
Fig. 4: The effects of COVID-19 on the kidney.

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Acknowledgements

The authors thank Kerstin Mierke, Istituto di Ricerche Mario Negri IRCCS, Italy, for help with English language editing of the manuscript before submission and Antonella Piccinelli, Istituto di Ricerche Mario Negri IRCCS, Italy, for preparing the figures before submission. L.P. is a recipient of the Career Development Program from Fondazione Aiuti per la Ricerca sulle Malattie Rare (ARMR), Bergamo, Italy. We are also grateful to Fondazione Aiuti per la Ricerca sulle Malattie Rare (ARMR) for research support for our studies on COVID-19 pathogenesis. L.F.P.N. and L.R. are supported by core funds at the Singapore Immunology Network (SIgN) through the Biomedical Medical Research Council (BMRC), A*STAR.

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Authors and Affiliations

  1. Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

    Luca Perico, Ariela Benigni, Federica Casiraghi & Giuseppe Remuzzi

  2. Infectious Diseases Horizontal Technology Centre (ID HTC), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Lisa F. P. Ng & Laurent Renia

  3. Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Lisa F. P. Ng & Laurent Renia

  4. Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

    Lisa F. P. Ng

  5. Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy

    Giuseppe Remuzzi

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  1. Luca Perico
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  2. Ariela Benigni
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  3. Federica Casiraghi
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  4. Lisa F. P. Ng
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  6. Giuseppe Remuzzi
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The authors contributed equally to all aspects of the article.

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Correspondence to Giuseppe Remuzzi.

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Nature Reviews Nephrology thanks C. Garlanda, C. Ince and A. Salama for their contribution to the peer review of this work.

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Glossary

Betacoronavirus

One of four genera (α, β, γ and δ) of enveloped, positive-strand RNA viruses that infects humans and mammals, causing respiratory diseases that can be mild or severe.

RNA-dependent RNA polymerase

(RdRp). An enzyme encoded by viral RNA that catalyses the synthesis of new RNA strands complementary to the initial RNA template included in the viral capsid.

Incubation period

The number of days between the initial exposure to a pathogen and the day in which the infected individual experiences the first symptoms of the disease.

Anosmia

Complete loss of the ability to detect one or more smells; anosmia can be temporary, as in the case of COVID-19, or permanent such as occurs in certain neurological conditions.

Ageusia

Complete loss of taste on the tongue, particularly the inability to perceive sweetness, sourness, bitterness and saltiness; ageusia can be temporary, as in the case of COVID-19, or permanent such as occurs in certain neurological conditions.

Pattern recognition receptors

(PRRs). Host sensors that detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) generated during infections or injury.

Cytokine storm

Also called hypercytokinaemia. An excessive and uncontrolled release of pro-inflammatory molecules by the cellular components of the innate immune system in response to a number of infectious and non-infectious aetiologies that can lead to multi-organ damage and failure.

VH gene

The heavy-chain-variable region (VH) gene gene is located along with diversity (D), joining (J) and constant (C) genes at three primary loci in the human genome and undergoes somatic rearrangements for the biosynthesis of the heavy (H) or light (L) chain of IgG.

Glucuronidases

A class of enzyme that includes beta-glucuronidases — a glycosidases that catalyse the breakdown of complex carbohydrates by hydrolysing β-d-glucuronic acid residues from the non-reducing end of glycosaminoglycans, such as heparan sulfate.

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Perico, L., Benigni, A., Casiraghi, F. et al. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol 17, 46–64 (2021). https://doi.org/10.1038/s41581-020-00357-4

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