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

Abstract

SUMMARY 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.

Machine learning identifies molecular regulators and therapeutics for targeting SARS‐CoV2‐induced cytokine release

“…To identify signaling pathways activated in myeloid cells in response to the NTD of S1 spike protein, we employed a combination of phenotypic screening with machine learning‐based modeling. We identified previously known kinases including JAK1 (Luo et al , 2020 ), MAPK12 (Bachstetter & Van Eldik, 2010 ), and IRAK1 (Ramasamy & Subbian, 2021 ) and several new host cell‐specific kinases including EPHA7, MAP3K8, and MAP3K2 that are important for the release of cytokines and chemokines in myeloid cells (Fig 2C ). The molecular mechanisms of how the NTD of the spike protein activates multiple kinases and how these newly identified kinases promote cytokine release in myeloid cells warrant further investigations.…”

The Immunology of SARS-CoV-2 Infection and Vaccines in Solid Organ Transplant Recipients

“…IFNγ was initially discovered as a potent antiviral agent [ 122 ]. The intranasal administration of IFNγ exerted a prophylactic effect in high-risk volunteers (i.e., medical workers and personnel in SARS-CoV-2 “red zones” in Russia) [ 123 ].…”

SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns

“…Acute respiratory distress syndrome (ARDS), pulmonary edema, acute kidney injury, severe sepsis with shock, and even multiple organ failure are associated with the highest rates of mortality ( 2 ). Since March 2020 many efforts have been done to ascertain and elucidate COVID-19 pathogenesis, however the complete clinical picture following SARS-CoV-2 infection is not yet fully understood although it is known that the underlying cause of severe disease is a cytokine dysregulation and hyperinflammation status triggered by an impaired in interferon responses ( 3 ).…”