Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19

Park, Annsea; Iwasaki, Akiko

doi:10.1016/j.chom.2020.05.008

Cited by 793 publications

(990 citation statements)

References 77 publications

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“…To better understand the role of type I interferon signaling we infected both IFNAR -/and IRF3/7 -/and showed that despite similar kinetics of viral clearance, there was significant blunting of ISG response, suggesting that viral replication is resistant to interferon signaling as was previously show with SARS-CoV-1 14 and has been suggested in SARS-CoV-2 given its vast array of interferon antagonists 19 . While endogenous type I interferon signaling seems to have little effect on SARS-CoV-2 replication, it clearly orchestrates a proinflammatory immune response and may cause immunopathology in patients.…”

Section: Discussionmentioning

confidence: 81%

Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Israelow

Song

Mao

et al. 2020

Preprint

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Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-Cov-2) has caused over 5,000,000 cases of Coronavirus disease (COVID-19) with significant fatality rate. 1-3 Due to the urgency of this global pandemic, numerous therapeutic and vaccine trials have begun without customary safety and efficacy studies. 4 Laboratory mice have been the stalwart of these types of studies; however, they do not support infection by SARS-CoV-2 due to the inability of its spike (S) protein to engage the mouse ortholog of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, 5 these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and antibody production and exhibit pathologic findings found in COVID-19 patients as well as non-human primate models. Moreover, we show that type I interferons are unable to control SARS-CoV2 replication and drive pathologic responses. Thus, the hACE2-AAV mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patientderived virus in mice of diverse genetic backgrounds. This represents a much-needed platform for rapidly testing prophylactic and therapeutic strategies to combat COVID-19. Development of SARS-CoV-2 mouse model

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Section: Discussionmentioning

confidence: 81%

Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Israelow

Song

Mao

et al. 2020

Preprint

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“…The mechanisms of this innate immune system were suggested in the study by Paki and Iwasaki; 44 Interferon (IFN) response is an adaptive form of the immune system and its timing can vary with viral load and/or genetic differences. An early IFN response can lead to rapid viral clearance before its replication, resulting in milder diseases.…”

Section: Resultsmentioning

confidence: 99%

Extrapulmonary manifestations of COVID-19 in children: a comprehensive review and pathophysiological considerations

Pousa¹,

Mendonça²,

Oliveira³

et al. 2021

Jornal de Pediatria

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Objective The aim of this review was to summarize the most common extrapulmonary manifestations in pediatric patients with COVID-19, as well as to discuss clinical, epidemiological, and pathophysiological aspects of these clinical presentations in children. Source of data An extensive search of literature was performed in order to identify pediatric cases with extrapulmonary manifestations between January 1, 2020 and June 21, 2020. Generic keywords, such as “Novel coronavirus” or “Novel coronavirus 2019” or “2019 nCoV” or “COVID-19” or “SARS-CoV-2” were searched on PubMed database, associated either with age filters or generic pediatric terms. Summary of findings A total of 28 articles, including 199 patients, were considered suitable to review and data extraction. The main findings were summarized in tables. The main non-pulmonary manifestations in pediatric patients, in decreasing order of frequency, were gastrointestinal, renal, cardiovascular, neurological, hematological and lymphatic, cutaneous, hepatic, ocular, olfactory, and gustatory. Multisystem impairment and Kawasaki-like disease were also described. Conclusions Differences in immune response of children and variations of tissue expression of angiotensin converting enzyme 2, the virus receptor, are likely to influence clinical, epidemiological, and pathophysiological patterns of the disease.

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“…Suppression of IFN signaling by SARS-CoV-2 has been reported by several studies 26,27 , possibly explaining only a moderate effect of SARS-CoV-2 infection on dACE2 induction in our experiments. While type I and type III IFNs are barely detectable in COVID-19 patients 28,29 , high levels of IFN-γ have been reported 29,30 . Specifically, a 3'-scRNA-seq analysis showed ACE2 induction by SARS-CoV-2 infection in ciliated epithelia, where high levels of IFN-γ producing immune cells were also detected 5 .…”

Section: Discussionmentioning

confidence: 95%

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Onabajo

Banday

Yan

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, primate-specific isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In vitro, dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results reconcile current knowledge on ACE2 expression and suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, inflammatory tumor microenvironment, or viral co-infections is unlikely to affect the cellular entry of SARS-CoV-2 and promote infection.

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Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19

Cited by 793 publications

References 77 publications

Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Extrapulmonary manifestations of COVID-19 in children: a comprehensive review and pathophysiological considerations

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

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