Pathophysiology and Therapeutic Interventions in COVID-19

The clinical syndrome of COVID-19 arises when SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) on host cells, permitting viral entry and replication. Subsequent downregulation of ACE2 disrupts the renin–angiotensin system (RAS), favouring vasoconstriction, inflammation and thrombosis. Concurrent activation of the kallikrein–kinin axis may precipitate a bradykinin-driven increase in vascular permeability, contributing to pulmonary oedema and multi-organ injury. Immune dysregulation, characterised by a hyperinflammatory ‘cytokine storm’, further amplifies tissue damage. Therapeutic strategies target each stage of this pathogenic cascade: antiviral agents to inhibit viral replication; monoclonal antibodies to neutralise viral particles; immunomodulators, such as corticosteroids and cytokine antagonists, to temper excessive inflammation; and anticoagulants to prevent thromboembolic complications. Novel approaches seek to restore ACE2/RAS balance, block bradykinin signalling or modulate host receptors to reduce susceptibility to infection. Integrating these interventions into a coherent treatment algorithm remains a global priority.

Research from Nature Portfolio

A large-scale cohort analysis has associated chronic use of ursodeoxycholic acid (UDCA) with a modest reduction in COVID-19 hospitalisation and mortality among patients with underlying cholestatic liver disease, supporting further clinical trials of UDCA as a prophylactic agent. Investigations into receptor regulation have revealed that farnesoid X receptor (FXR) directly controls ACE2 transcription in pulmonary and gastrointestinal tissues; pharmacological inhibition of FXR downregulates ACE2 expression in organoid and animal models, reducing SARS-CoV-2 infectivity in ex vivo human lungs and correlating with improved clinical outcomes in retrospective cohorts. Foundational single-cell transcriptomic mapping of healthy human lungs has demonstrated co-expression of ACE2 with key elements of the bradykinin, RAS and coagulation systems in alveolar cells, illuminating mechanistic links between viral entry and the triad of severe respiratory failure, cardiovascular instability and coagulopathy.

Pathophysiology and Therapeutic Interventions in COVID-19 publication trend

The graph below shows the total number of articles in pathophysiology and therapeutic interventions in covid-19 across all publications each year (not limited to Nature Index journals).

Technical terms

ACE2: a membrane enzyme that serves as the entry receptor for SARS-CoV-2 and regulates the balance of vasoconstrictive and vasodilatory peptides.

Renin–angiotensin system (RAS): a hormonal network controlling blood pressure, fluid balance and inflammatory responses, disrupted in COVID-19.

Bradykinin: a vasoactive peptide that increases vascular permeability and may drive pulmonary oedema in infection.

Farnesoid X receptor (FXR): a nuclear receptor that regulates bile acid metabolism and transcription of ACE2 in multiple tissues.

Ursodeoxycholic acid (UDCA): a bile acid used in cholestatic liver disease, repurposed to modulate ACE2 expression and attenuate severe COVID-19 outcomes.

References

1. Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial. The Lancet Respiratory Medicine (2023).
2. Ursodeoxycholic acid and severe COVID-19 outcomes in a cohort study using the OpenSAFELY platform. Communications Medicine (2024).
3. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Critical Care (2020).
4. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife (2020).
5. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. eLife (2020).
6. FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature (2022).
7. Understanding the Pathophysiology of COVID-19: Could the Contact System Be the Key?. Frontiers in Immunology (2020).
8. SARS-CoV-2 receptor is co-expressed with elements of the kinin–kallikrein, renin–angiotensin and coagulation systems in alveolar cells. Scientific Reports (2020).
9. Outcomes Associated With Use of a Kinin B2 Receptor Antagonist Among Patients With COVID-19. JAMA Network Open (2020).
10. Safety and Outcomes Associated with the Pharmacological Inhibition of the Kinin–Kallikrein System in Severe COVID-19. Viruses (2021).