The trinity of COVID-19: immunity, inflammation and intervention

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract - severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1. Chronology of events during SARS-CoV-2 infection.

When severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells expressing the surface receptors angiotensin-converting enzyme 2 (ACE2) and TMPRSS2, the active replication and release of the virus cause the host cell to undergo pyroptosis and release damage-associated molecular patterns, including ATP, nucleic acids and ASC oligomers. These are recognized by neighbouring epithelial cells, endothelial cells and alveolar macrophages, triggering the generation of pro-inflammatory cytokines and chemokines (including IL-6, IP-10, macrophage inflammatory protein 1α (MIP1α), MIP1β and MCP1). These proteins attract monocytes, macrophages and T cells to the site of infection, promoting further inflammation (with the addition of IFNγ produced by T cells) and establishing a pro-inflammatory feedback loop. In a defective immune response (left side) this may lead to further accumulation of immune cells in the lungs, causing overproduction of pro-inflammatory cytokines, which eventually damages the lung infrastructure. The resulting cytokine storm circulates to other organs, leading to multi-organ damage. In addition, non-neutralizing antibodies produced by B cells may enhance SARS-CoV-2 infection through antibody-dependent enhancement (ADE), further exacerbating organ damage. Alternatively, in a healthy immune response (right side), the initial inflammation attracts virus-specific T cells to the site of infection, where they can eliminate the infected cells before the virus spreads. Neutralizing antibodies in these individuals can block viral infection, and alveolar macrophages recognize neutralized viruses and apoptotic cells and clear them by phagocytosis. Altogether, these processes lead to clearance of the virus and minimal lung damage, resulting in recovery. G-CSF, granulocyte colony-stimulating factor; TNF, tumour necrosis factor.

Fig. 2. The structure of the trimeric spike protein of SARS-CoV-2.

The receptor-binding domain (RBD) is shown interacting with its receptor, human angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Adapted from Protein Data Bank IDs 6VSB and 6VW1 (ref.150).

Fig. 3. Potential therapeutic approaches against SARS-CoV-2.

(1) Antibodies against the spike protein (raised through vaccination or by adoptive transfer) could block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from interacting with the angiotensin-converting enzyme 2 (ACE2) receptor on host cells. (2) Protease inhibitors against the serine protease TMPRSS2 can prevent spike protein cleavage, which is necessary for viral fusion into the host cell. Blocking either ACE2 interaction or viral fusion could prevent the virus from infecting the host cell. (3) Virus-specific memory CD8+ T cells from a previous vaccination or infection can differentiate into effector cells during rechallenge. When they identify infected cells presenting virus-specific epitopes, they degranulate and kill infected cells before they can produce mature virions. (4) In a novel treatment method that targets the cytokine storm symptoms, the blood of patients with coronavirus disease 2019 (COVID-19) can be passed through customized columns that are specially designed to trap pro-inflammatory cytokines, before the purified blood is passed back into patients.

Fig. 4. Sequence alignment and structural comparison of SARS-CoV and SARS-CoV-2 spike proteins.

a | Sequence alignment of severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, with conserved amino acid residues shown in black and non-conserved residues shown in colours. b | The 3D structure of SARS-CoV-2 (Protein Data Bank ID 6VSB, peach ribbon) is superimposed on the SARS-CoV receptor-binding motif (RBM) complex with the neutralizing antibody (nAb; red ribbon) interfacing with the RBM (Protein Data Bank 2DD8 (ref.), purple ribbon). Peach and purple spheres denote the RBMs of SARS-CoV-2 and SARS-CoV, respectively. Magenta spheres denote non-synonymous alterations in the SARS-CoV-2 spike protein that have been reported.