Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and a mortality rate of about 2.2%, as of 10 December 2020. About 20% of COVID-19 patients exhibit moderate to severe symptoms. Severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Most of the severe and critically ill COVID-19 patients have had preexisting comorbidities, including hypertension, diabetes, cardiovascular diseases, and respiratory diseases. These conditions are known to perturb the levels of cytokines, chemokines, and angiotensin-converting enzyme 2 (ACE2), an essential receptor involved in SARS-CoV-2 entry into the host cells. ACE2 downregulation during SARS-CoV-2 infection activates the angiotensin II/angiotensin receptor (AT1R)-mediated hypercytokinemia and hyperinflammatory syndrome. However, several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the nucleocapsid (N) protein, can inhibit IFN type I and II (IFN-I and -II) production. Thus, hyperinflammation, in combination with the lack of IFN responses against SARS-CoV-2 early on during infection, makes the patients succumb rapidly to COVID-19. Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling and IFN therapy would favor the disease prognosis in COVID-19. This review describes critical host and viral factors underpinning the inflammatory "cytokine storm" induction and IFN antagonism during COVID-19 pathogenesis. Therapeutic approaches to reduce hyperinflammation and their limitations are also discussed.

Keywords: ACE2; SARS-CoV-2; antibodies; cell surface receptors; comorbidities; inflammation; innate immunity; interferon; intracellular signaling; proinflammatory cytokines.

FIG 1

Interaction of cellular pathways and networks for cytokine induction and IFN antagonism during COVID-19. The SARS-CoV-2 proteins that potentially inhibit IFN induction, IFN signaling, and ISGs are indicated in bold italics. NSP, nonstructural proteins; M, matrix protein; N, nucleoprotein; S, spike protein; ORF, open reading frame; inhibitor, blocks the putative pathways and acts as an IFN antagonist.

FIG 2

Potential mechanisms that downregulate ACE2 expression and enhance cytokine storm in COVID-cases with comorbidities. Induction of ACE2, CD209, and other host factors enhances SARS-CoV-2 replication and infection, which further activates macrophages to produce inflammatory cytokines. In comorbid conditions, such as hypertension and diabetes, downregulation of ACE2 can activate macrophages and the renin-angiotensin system, leading to cytokine storm and inflammation.

FIG 3

Cytokine storm-mediated hyperinflammation and therapeutic strategies during COVID-19. (A) The proinflammatory cytokines, such as IL-1, IL-6, and TNF-α, mediate the signaling to induce several inflammatory substances and cytokines, including IL-1, IL-6, TNF-α, IL-8, IL-10, and IL-12, which are essential for the functions of the immune system in healthy humans. (B) Overt induction of these cytokines in COVID-19 and their association with hyperinflammation suggest that the use of cytokine signaling blockers, such as IL-6R antibodies (tocilizumab, sarilumab), anti-IL-6 antibody (siltuximab), IL-1R antagonist (anakinra), or JAK1/2 inhibitors (ruxolitinib, baricitinib), might reduce cytokine induction and the severity of COVID-19. On the other hand, inhibition of cytokines would cause immunosuppression and make the patient susceptible to opportunistic infections and reactivation of latent life-threatening infections. Further studies are required to recommend/block these agents as COVID-19 therapeutics.