Sphingosine prevents binding of SARS–CoV-2 spike to its cellular receptor ACE2

Edwards, Michael J.; Becker, Katrin Anne; Gripp, Barbara; Hoffmann, Markus; Keitsch, Simone; Wilker, Barbara; Soddemann, Matthias; Gulbins, Anne; Carpinteiro, Elisa; Patel, Sameer H.; Wilson, Gregory C.; Pöhlmann, Stefan; Walter, Silke; Faßbender, Klaus; Ahmad, Syed A.; Carpinteiro, Alexander; Gulbins, Erich

doi:10.1074/jbc.ra120.015249

Cited by 42 publications

(51 citation statements)

References 30 publications

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“…We have previously shown that sphingosine also inhibits infection of human cells with SARS-CoV-2 ( 23 ). We therefore tested whether ambroxol alters cellular sphingosine concentrations.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells

Carpinteiro

Gripp

Hoffmann

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…We have previously shown that sphingosine also inhibits infection of human cells with SARS-CoV-2 ( 23 ). We therefore tested whether ambroxol alters cellular sphingosine concentrations.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells

Carpinteiro

Gripp

Hoffmann

et al. 2021

Journal of Biological Chemistry

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“…The S proteins of SARS-CoV and SARS-CoV-2 show organizational homology and preserved ectodomains, so that previous approaches are applied to stop binding of SARS-CoV to its host cell receptor, angiotensin-converting enzyme 2 (ACE2) through a non-pH dependent endocytosis, since SARS-CoV-2 also employs ACE2 for cell entry[ 5 , 6 ]. In molecular modelling analysis, it has shown similarities between the RBDs of SARS-CoV and SARS-CoV-2 (also called S proteins), which are the most immunogenic part of the virus and probably bind the same ACE2 receptors in order to gain cell entry[ 7 , 8 ], thus suggesting that a similar pathogenic mechanism is involved in both viral infections. Interestingly, ACE2 receptors are not only expressed on alveolar epithelial type II cells, which represent 83% of all ACE2-expressing cells, but also on heart, kidney, endothelium, and gut cells[ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Exploration of sex-specific and age-dependent COVID-19 fatality rate in Bangladesh population

Al-Bari¹,

Hossain²,

Zahan³

2021

WJR

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Coronavirus disease-2019 (COVID-19), a respiratory tract infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health emergency and a threat the entire world. The COVID-19 shows a wide spectrum of clinical presentations, severity, and fatality rates. Although the fatal outcomes of the COVID-19 pandemic are evident in all age groups, the most devastating impact on the health consequences and death from COVID-19 are associated with older adults, especially older men. COVID-19 pandemic is affecting different countries in the world especially in the 65+ years age male group. In fact, several genes involved into the regulation of the immune system are strategically placed on the X-chromosome and trigger a gendered mediated antiviral fight. The aim of this study is to explore and exploit whether a relationship exists between male sex and COVID-19 mortality and the relationship is age dependent. Herein we discuss the possible role of physiological and immunological sex differences into the higher morbidity and mortality of SARS-CoV-2 between females and males. Deciphering gender differences in COVID-19 offers a window into the principles of immunity against SARS-CoV-2 infection and this information on ageing dependent gender disparity might contribute to our current understanding of COVID-19 infection and disease treatment.

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“…Indeed, two phase II studies with pulmonal amitriptyline already reported with favorable results [42]. Nevertheless, clinical development of sphingosine inhalation itself is also underway at least [7] and could potentially garner a lot more attention soon, as sphingosine was very recently shown to prevent viral entry of SARS-CoV-2 [43].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Inhaled Sphingosine for Treating Lung Infection in a Mouse Model of Critical Illness

2020

Cell Physiol Biochem

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BACKGROUND/AIMS: Sphingosine, a sphingoid long chain base, is a natural lipid with antimicrobial properties. Recent animal studies have shown that preventive sphingosine inhalation can rescue susceptible mice, such as cystic fibrosis-, burn injured- or aged mice from bacterial pulmonary infection. While preventing lung infections in susceptible patients has obvious clinical merit, treatment strategies for an established infection are also direly needed, particularly in the times of rising antibiotic resistance. Here, we tested the potential of sphingosine in treating an established pulmonary infection. METHODS: We used a cecal ligation and puncture (CLP) model in male CF-1 mice and a Pseudomonas aeruginosa strain that was isolated from a septic patient (P. aeruginosa 762). We determined susceptibility to intranasal infection and ascertained when the pulmonary infection was established by continuous core body temperature monitoring. We quantified sphingosine levels in the tracheal epithelium by immunohistochemistry and studied the effects on sphingosine on bacterial membrane permeabilization and intracellular acidification using fluorescent probes. RESULTS: We first determined that septic mice are highly susceptible to P. aeruginosa infection 2 days after indu-cing sepsis. Additionally, at this time, sphingosine levels in the tracheal epithelium are significantly reduced as compared to levels in healthy mice. Secondly, upon intranasal Pseudomonas inoculation, we ascertained that pulmonary infection was established as early as 2.5 h after inoculation as evidenced by a significant drop in core body temperature. Using these times of infection susceptibility and detection (2 days post CLP, 2.5h after inoculation) we treated with inhaled sphingosine and observed pulmonary bacterial loads reduced to levels found in infected healthy mice after inoculation and decreased infection-associated mortality. Further, our data demonstrate that sphingosine induces outer membrane permeabilization, disrupting the membrane potential and leading to intracellular acidification of the bacteria. CONCLUSION: Sphingosine shows efficacy in treating P. aeruginosa lung infections not only prophylactically, but also therapeutically.

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Sphingosine prevents binding of SARS–CoV-2 spike to its cellular receptor ACE2

Cited by 42 publications

References 30 publications

Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells

Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells

Exploration of sex-specific and age-dependent COVID-19 fatality rate in Bangladesh population

Therapeutic Inhaled Sphingosine for Treating Lung Infection in a Mouse Model of Critical Illness

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