Low type I interferon response in COVID‑19 patients: Interferon response may be a potential treatment for COVID‑19

Salman, Ahmed Abdulwahid; Waheed, Mohammed Hussein; Ali-Abdulsahib, Akeel Abd; Atwan, Zeenah Weheed

doi:10.3892/br.2021.1419

Cited by 21 publications

(16 citation statements)

References 53 publications

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“…Taken together our data clearly demonstrate that BE from children are less susceptible to SARS-CoV-2 infection. Our data suggest that an accelerated interferon response might contribute to this resistance supporting timed interferon application as therapeutically beneficial concept in the treatment of SARS-CoV-2 infections (56)(57)(58).…”

Section: Discussionmentioning

confidence: 60%

SARS-CoV-2 transmission via apical syncytia release from primary bronchial epithelia and infectivity restriction in children epithelia

Beucher¹,

Blondot²,

Celle

et al. 2021

Preprint

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The beta-coronavirus SARS-CoV-2 is at the origin of a persistent worldwide pandemic. SARS-CoV-2 infections initiate in the bronchi of the upper respiratory tract and are able to disseminate to the lower respiratory tract eventually causing acute severe respiratory syndrome with a high degree of mortality in the elderly. Here we use reconstituted primary bronchial epithelia from adult and children donors to follow the infection dynamic following infection with SARS-CoV-2. We show that in bronchial epithelia derived from adult donors, infections initiate in multi-ciliated cells. Then, infection rapidly spread within 24-48h throughout the whole epithelia. Within 3-4 days, large apical syncytia form between multi-ciliated cells and basal cells, which dissipate into the apical lumen. We show that these syncytia are a significant source of the released infectious dose. In stark contrast to these findings, bronchial epithelia reconstituted from children donors are intrinsically more resistant to virus infection and show active restriction of virus spread. This restriction is paired with accelerated release of IFN compared to adult donors. Taken together our findings reveal apical syncytia formation as an underappreciated source of infectious virus for either local dissemination or release into the environment. Furthermore, we provide direct evidence that children bronchial epithelia are more resistant to infection with SARS-CoV-2 providing experimental support for epidemiological observations that SARS-CoV-2 cases fatality is linked to age.

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Section: Discussionmentioning

confidence: 60%

SARS-CoV-2 transmission via apical syncytia release from primary bronchial epithelia and infectivity restriction in children epithelia

Beucher¹,

Blondot²,

Celle

et al. 2021

Preprint

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“…Further, induction of the innate immune response is dependent on interferon (IFN) stimulation. Coronaviruses, including SARS-CoV-2, evade IFN based responses, by expressing open reading frames, such as ORF7a, thus abolishing IFN pathways ( Salman et al, 2021 ). As such, a more stable ORF7, due to a A105V mutation, may reduce immune response and, consequently, more severe COVID symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…As such, patients infected with A105V had higher values of CRP, compared with non-A105V infected patients. The increase in inflammation is associated with acute respiratory distress, distributive shock, myocardial injury, and hemodynamic changes (Reyes et al, 2020 (Salman et al, 2021). As such, a more stable ORF7, due to a A105V mutation, may reduce immune response and, consequently, more severe COVID symptoms.…”

Section: Viral Protein Modificationsmentioning

confidence: 99%

Introduction and Characteristics of SARS-CoV-2 in North-East of Romania During the First COVID-19 Outbreak

et al. 2021

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Romania officially declared its first Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) case on February 26, 2020. The first and largest coronavirus disease 2019 (COVID-19) outbreak in Romania was recorded in Suceava, North-East region of the country, and originated at the Suceava regional county hospital. Following sheltering-in-place measures, infection rates decreased, only to rise again after relaxation of measures. This study describes the spread of SARS-CoV-2 in Suceava and other parts of Romania and analyses the mutations and their association with clinical manifestation of the disease during the period of COVID-19 outbreak. Sixty-two samples were sequenced via high-throughput platform and screened for variants. For selected mutations, putative biological significance was assessed, and their effects on disease severity. Phylogenetic analysis was conducted on Romanian genomes (n = 112) and on sequences originating from Europe, United Kingdom, Africa, Asia, South, and North America (n = 876). The results indicated multiple introduction events for SARS-CoV-2 in Suceava, mainly from Italy, Spain, United Kingdom, and Russia although some sequences were also related to those from the Czechia, Belgium, and France. Most Suceava genomes contained mutations common to European lineages, such as A20268G, however, approximately 10% of samples were missing such mutations, indicating a possible different arrival route. While overall genome regions ORF1ab, S, and ORF7 were subject to most mutations, several recurring mutations such as A105V were identified, and these were mainly present in severe forms of the disease. Non-synonymous mutations, such as T987N (Thr987Asn in NSP3a domain), associated with changes in a protein responsible for decreasing viral tethering in human host were also present. Patients with diabetes and hypertension exhibited higher risk ratios (RR) of acquiring severe forms of the disease and these were mainly related to A105V mutation. This study identified the arrival routes of SARS-CoV-2 in Romania and revealed potential associations between the SARS-CoV-2 genomic organization circulating in the country and the clinical manifestation of COVID-19 disease.

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“…Notably, IFNAR2 has been implicated in severe COVID-19 infection (Pairo-Castineira et al, 2021). Since type 1 interferons have shown some initial efficacy in treating COVID-19 infection (Sallard et al, 2020), it is possible that the SARS-CoV-2 virus interaction with both receptor and soluble ACE2 interferes with type 1 interferon response, as low levels of type 1 interferons have been found in COVID-19 patients (Salman et al, 2021). Another connection of ACE2 with immunity may be mediated by the toll-like receptor TLR8 (a strong ACE2 ERC), among TLRs believed to regulate platelet circulation in response to inflammation (Beaulieu & Freedman, 2010) providing possible avenues for interaction with soluble ACE2 in blood.…”

Section: Discussionmentioning

confidence: 99%

Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations

Aa¹,

Cheng²,

Werren³

2021

PeerJ

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Angiotensin-converting enzyme 2 (ACE2) is the cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken an approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that “coevolve” with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact with ACE2, while additional predicted novel ACE2 interactors are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as Coagulation Factor V and fibrinogen components FGA, FGB, and FGG, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). ACE2 also connects to proteins involved in cytokine signaling and immune response (e.g. XCR1, IFNAR2 and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has elucidated possible functions for relatively uncharacterized proteins and possible new functions for well-characterized ones. Suggestions are made for the validation of ERC-predicted ACE2 protein interactions. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.

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Low type I interferon response in COVID‑19 patients: Interferon response may be a potential treatment for COVID‑19

Cited by 21 publications

References 53 publications

SARS-CoV-2 transmission via apical syncytia release from primary bronchial epithelia and infectivity restriction in children epithelia

SARS-CoV-2 transmission via apical syncytia release from primary bronchial epithelia and infectivity restriction in children epithelia

Introduction and Characteristics of SARS-CoV-2 in North-East of Romania During the First COVID-19 Outbreak

Novel ACE2 protein interactions relevant to COVID-19 predicted by evolutionary rate correlations

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