tetano
Editor, Senior Moderator
Clin Microbiol Rev
. 2021 May 12;34(3):e00299-20.
doi: 10.1128/CMR.00299-20. Print 2021 Jun 16.
Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis
Santhamani Ramasamy[SUP] 1 [/SUP], Selvakumar Subbian[SUP] 2 [/SUP]
Affiliations
Abstract
SUMMARYSevere 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 1? (IL-1?), IL-6, tumor necrosis factor ? (TNF-?), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1?), 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.
. 2021 May 12;34(3):e00299-20.
doi: 10.1128/CMR.00299-20. Print 2021 Jun 16.
Critical Determinants of Cytokine Storm and Type I Interferon Response in COVID-19 Pathogenesis
Santhamani Ramasamy[SUP] 1 [/SUP], Selvakumar Subbian[SUP] 2 [/SUP]
Affiliations
- PMID: 33980688
- DOI: 10.1128/CMR.00299-20
Abstract
SUMMARYSevere 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 1? (IL-1?), IL-6, tumor necrosis factor ? (TNF-?), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1?), 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.