Differential immune activation profile of SARS-CoV-2 and SARS-CoV infection in human lung and intestinal cells: Implications for treatment with IFN-β and IFN inducer

Shuai, Huiping; Chu, Hin; Hou, Yuxin; Yang, Dong; Wang, Yixin; Hu, Bingjie; Huang, Xiner; Zhang, Xi; Chai, Yue; Cai, Jian; Chan, Jasper Fuk Woo; Yuen, Kwok Yung

doi:10.1016/j.jinf.2020.07.016

Cited by 47 publications

(69 citation statements)

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“…An intriguing finding from this study is that while ILRUN regulates the type I IFN induction pathway, SARS-CoV-2 did not induce a noticeable type I IFN response in Caco-2 cells, indicating this is independent of the ILRUN-induced IFN expression. Another study has similarly observed a lack of type I IFN induction in Caco-2 cells infected with SARS-CoV-2, including at a high MOI (38). While one explanation for this result is that Caco-2 cells do not mount robust innate immune response to viral infection, previous studies have shown infection of Caco-2 cells with Sendai virus and Newcastle Disease virus induces a strong type I IFN response, while SARS-CoV-1 suppresses these cytokines (39).…”

Section: Discussionmentioning

confidence: 90%

“…SARS-CoV-2 appears to be particularly adept at immune evasion, encoding seven proteins that inhibit IFN-β promoter activation (43), among them the ORF6 protein that blocks both type I IFN induction and signalling pathways. Several groups have hypothesized that the lack of timely and robust antiviral response to SARS-CoV-2 infection contributes to COVID-19 pathogenesis (38, 43).…”

Section: Discussionmentioning

confidence: 99%

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ILRUN downregulates ACE2 expression and blocks infection of human cells by SARS-CoV-2

Tribolet

Alexander

Brice

et al. 2020

Preprint

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The human protein-coding gene ILRUN (inflammation and lipid regulator with UBA-like and NBR1-like domain, previously C6orf106) is a recently-characterised inhibitor of the transcription regulators p300 and CREB-binding protein (CBP). Here we have utilised RNA-seq to define cellular pathways regulated by ILRUN in the context of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) infection. We find that inhibition of ILRUN expression increases cellular expression of several members of the renin-angiotensin aldosterone system (RAAS), including the SARS-CoV-2 entry receptor angiotensin converting enzyme 2 (ACE2). Furthermore, inhibition of ILRUN results in increased SARS-CoV-2 replication. These data identify ILRUN as a novel inhibitor of SARS-CoV-2 replication and represents, to our knowledge, the first report of ILRUN as a regulator of the RAAS.SIGNIFICANCE STATEMENTThere is no doubt that the current rapid global spread of COVID-19 has had significant and far-reaching impacts on our health and economy and will continue to do so. Research in emerging infectious diseases, such as severe acute respiratory syndrome-associated coronavirus (SARS-CoV-2), is growing rapidly, with new breakthroughs in the understanding of host-virus interactions and the development of innovative and exciting therapeutic strategies and new knowledge and tools to better protect against the impacts of disease. The human protein-coding gene ILRUN is a recently-characterised inhibitor of the transcription regulators p300 and CREB-binding protein (CBP). Here we present the first evidence that ILRUN modulation has implications for SARS-CoV-2 infections. Virus infectivity assays confirmed that gene silencing of ILRUN had a proviral effect and increased SARS-CoV-2 replication, whilst over-expression of ILRUN inhibited SARS-CoV-2 production. Additionally, we observed that ILRUN also regulates the expression of key elements of the RAAS. These data have important implications for the development of antiviral strategies to deal with the current SARS-CoV-2 pandemic.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

ILRUN downregulates ACE2 expression and blocks infection of human cells by SARS-CoV-2

Tribolet

Alexander

Brice

et al. 2020

Preprint

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“…It is worth mentioning that SCFAs can also have systemic effects, which may be relevant for SARS-CoV-2 infection in different contexts. 31 …”

Section: Discussionmentioning

confidence: 99%

Microbiota-derived short-chain fatty acids do not interfere with SARS-CoV-2 infection of human colonic samples

et al. 2021

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Microbiota-derived molecules called short-chain fatty acids (SCFAs) play a key role in the maintenance of the intestinal barrier and regulation of immune response during infectious conditions. Recent reports indicate that SARS-CoV-2 infection changes microbiota and SCFAs production. However, the relevance of this effect is unknown. In this study, we used human intestinal biopsies and intestinal epithelial cells to investigate the impact of SCFAs in the infection by SARS-CoV-2. SCFAs did not change the entry or replication of SARS-CoV-2 in intestinal cells. These metabolites had no effect on intestinal cells’ permeability and presented only minor effects on the production of anti-viral and inflammatory mediators. Together our findings indicate that the changes in microbiota composition of patients with COVID-19 and, particularly, of SCFAs do not interfere with the SARS-CoV-2 infection in the intestine.

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“…This has been confirmed in Calu3 cells, primary human airway epithelial cells (pHAE), alveolar epithelial type 2 cells (AT2s), A549 lung alveolar cells and in a reconstituted human bronchial epithelium model (MucilAir ™ model), where SARS-CoV-2 infection failed to induce an appropriate type I and III IFN response (Blanco-Melo et al, 2020;Huang et al, 2020;Robinot et al, 2020;Shuai et al, 2020;Vanderheiden et al, 2020). According to recent reports, COVID-19 also causes an impaired type I IFN response in the periphery.…”

Section: Covid-19 Patients Show a Delayed Type I Interferon Responsementioning

confidence: 67%

Rationale for COVID-19 Treatment by Nebulized Interferon-β-1b–Literature Review and Personal Preliminary Experience

et al. 2020

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The inflammatory response to COVID-19 is specifically associated with an impaired type I interferon (IFN) response and complete blockade of IFN-β secretion. Clinically, nebulization of IFN-α-2b has been historically used in China to treat viral pneumonia associated with SARS-CoV. Very recent data show that the use of inhaled type I IFN is associated with decreased mortality in Chinese COVID-19 patients. However, IFN nebulization is currently not standard in Europe and the United States. Therefore, our group has set up a project aimed to evaluate the possibility to nebulize IFN-β-1b (a drug currently used in Europe to treat multiple sclerosis via subcutaneous injections) and to assess the safety of this new mode of administration in SARS-CoV-2 infected patients. We present here literature data that allowed us to build our hypothesis and to develop collaboration between clinical pharmacists, intensivists and nebulization engineers in order to gain first pre-clinical and clinical experience of IFN-β-1b nebulization. After validation of the nebulization method and verification of droplet size compatible with nebulization, the method has been applied to four intensive care patients treated at our university hospital, for whom none of the COVID-19 therapies initially used in France led to significant clinical improvement. All patients exhibited negative viral carriage and experienced clinical improvement 7–16 days after having initiated nebulized IFN-β-1b inhalation therapy. No side effects were observed. All patients were alive within a 90-days follow-up. Although it is not possible to draw firm conclusions on treatment efficacy based on this case report, our study shows that pulmonary IFN-β-1b administration is feasible, with a good safety profile. This procedure, which presents the advantage of directly targeting the lungs and reducing the risks of systemic side effects, may represent a promising therapeutic strategy for the care of patients with severe COVID-19. However, our preliminary observation requires confirmation by randomized controlled trials.

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Differential immune activation profile of SARS-CoV-2 and SARS-CoV infection in human lung and intestinal cells: Implications for treatment with IFN-β and IFN inducer

Cited by 47 publications

References 50 publications

ILRUN downregulates ACE2 expression and blocks infection of human cells by SARS-CoV-2

ILRUN downregulates ACE2 expression and blocks infection of human cells by SARS-CoV-2

Microbiota-derived short-chain fatty acids do not interfere with SARS-CoV-2 infection of human colonic samples

Rationale for COVID-19 Treatment by Nebulized Interferon-β-1b–Literature Review and Personal Preliminary Experience

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