Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig

Lei, Changhai; Qian, Kunxi; Tian, Li; Zhang, Sheng; Fu, Wenyan; Ding, Min; Hu, Shi

doi:10.1038/s41467-020-16048-4

Cited by 375 publications

(445 citation statements)

References 30 publications

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“…Intriguingly, however, type I interferon production is suppressed in SARS-COV-2 infection; in addition, multiple studies suggest that interferon gamma production correlates with disease severity (34)(35)(36)(37). In one such predicted mechanism, interferon induces ACE2 receptor expression, (38) which is also the receptor for the SARS-COV-2 spike protein S that mediates infection of host target cells (10)(11)(12). Thus, interferon and its downstream signaling partners can have complex and potentially opposing effects in the context of SARS-COV-2 pathology and the ensuing balance of inflammation.…”

Section: Discussionmentioning

confidence: 99%

COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status

Thomas

Stefanoni

et al. 2020

Preprint

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Previous studies suggest a role for systemic reprogramming of host metabolism during viral pathogenesis to fuel rapidly expanding viral proliferation, for example by providing free amino acids and fatty acids as building blocks. In addition, general alterations in metabolism can provide key understanding of pathogenesis. However, little is known about the specific metabolic effects of SARS-COV-2 infection. The present study evaluated the serum metabolism of COVID-19 patients (n=33), identified by a positive nucleic acid test of a nasopharyngeal swab, as compared to COVID-19-negative control patients (n=16). Targeted and untargeted metabolomics analyses specifically identified alterations in the metabolism of tryptophan into the kynurenine pathway, which is wellknown to be involved in regulating inflammation and immunity. Indeed, the observed changes in tryptophan metabolism correlated with serum interleukin-6 (IL-6) levels. Metabolomics analysis also confirmed widespread dysregulation of nitrogen metabolism in infected patients, with decreased circulating levels of most amino acids, except for tryptophan metabolites in the kynurenine pathway, and increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and kidney dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis in COVID-19 patients.Metabolite levels in these pathways correlated with clinical laboratory markers of inflammation and disease severity (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). In conclusion, this initial observational study of the metabolic consequences of COVID-19 infection in a clinical cohort identified amino acid metabolism (especially kynurenine and cysteine/taurine) and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status

Thomas

Stefanoni

et al. 2020

Preprint

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“…3a). We then detected the inhibitory ability of ACE2-Ig, a fusion protein consisting of the extracellular domain (Met 1-Ser 740) of human ACE2 linked to the Fc region of human IgG1 at the Cterminus 13 . Both S-D614 and S-G614 pseudoviruses were potently inhibited by ACE2-Ig, and the IC50 (the concentration causing 50% inhibition of pseudoviral infection) values were 0.13 and 0.15 μg/mL, respectively (Fig.…”

Section: Evaluating Viral Entry Efficacies Between S-d614 and S-g614mentioning

confidence: 99%

D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity

Gao

et al. 2020

Preprint

143

140

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22Coronavirus disease 2019 is caused by severe acute respiratory 23 syndrome coronavirus 2 (SARS-CoV-2). The spike protein that mediates 24 SARS-CoV-2 entry into host cells, is one of the major targets for vaccines and 25 therapeutics. Thus, insights into the sequence variations of S protein are key to 26 understanding the infection and antigenicity of SARS-CoV-2. Here, we observed a 27 dominant mutational variant at the 614 position of S protein (aspartate to glycine, 28 D614G mutation). Using pseudovirus-based assay, we found that S-D614 and 29 S-G614 protein pseudotyped viruses share a common receptor, human 30 angiotensin-converting enzyme 2 (ACE2), which could be blocked by recombinant 31 ACE2 with the fused Fc region of human IgG1. However, S-D614 and S-G614 32 protein demonstrated functional differences. First, S-G614 protein could be cleaved 33 by serine protease elastase-2 more efficiently. Second, S-G614 pseudovirus 34 infected 293T-ACE2 cells significantly more efficiently than the S-D614 pseudovirus, 35 Moreover, 93% (38/41) sera from convalescent COVID-19 patients could neutralize 36 both S-D614 and S-G614 pseudotyped viruses with comparable efficiencies, but 37 about 7% (3/41) convalescent sera showed decreased neutralizing activity against 38 S-G614 pseudovirus. These findings have important implications for SARS-CoV-2 39 transmission and immune interventions.40 42 43 44 SARS-CoV-2 is a novel coronavirus reported in 2019 that caused the recent 45 outbreak of coronavirus disease-2019 (COVID-19) 1 . By June 17, 2020, the World 46 Health Organization (WHO) reported that 8.06 million people worldwide had been 47 infected with SARS-CoV-2, and 440,290 individuals died of COVID-19. This 48 pandemic had a significant adverse impact on international social and economic 49 activities. The RNA genome of SARS-CoV-2 was rapidly sequenced to facilitate 50 diagnostic testing, molecular epidemiologic source tracking, and development of 51 vaccines and therapeutic strategies 2 . Coronaviruses are enveloped, 52 positive-stranded RNA viruses that contain the largest known RNA genomes to 53 date. The mutation rate for RNA viruses is extremely high, which may contribute to 54 its transmission and virulence. The only significant variation in the SARS-CoV-2 55 spike (S) protein is a non-synonymous D614G (Aspartate (D) to Glycine (G)) 56 mutation 3 . Primary data showed that S-G614 is a more pathogenic strain of 57 SARS-CoV-2 with high transmission efficiency 3 , however whether D614G 58 conversion in S protein affect the viral entry and infectivity in cell model is still 59 unclear. 60 61The S protein of coronavirus, the major determinant of host and tissue tropism, is a 62 major target for vaccines, neutralizing antibodies, and viral entry inhibitors 4,5 . 63Similar to SARS-CoV, the cellular receptor of SARS-CoV-2 is 64 angiotensin-converting enzyme 2 (ACE2); however, the SARS-CoV-2 S protein has 65 a 10-to 20-fold higher affinity for ACE2 than the corresponding S protein of 66 SARS-CoV 6,7 . Coronaviruses use two d...

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“…On the one hand, these drugs could increase ACE2 expression and potentiate SARS-CoV-2 cell entry [24]. On the other hand, increased ACE2 production would result in a higher circulating level of soluble ACE2, which neutralizes SARS-CoV-2 [25]. Yet, the precise role of the available RAAStargeting drugs in COVID-19 disease waits to be unraveled.…”

Section: Infection With Sars-cov-2mentioning

confidence: 99%