Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19

Wong, Lok-Yin Roy; Zheng, Jian; Wilhelmsen, Kevin; Li, Kun; Ortiz, Miguel; Schnicker, Nicholas; Thurman, Andrew L.; Pezzulo, Alejandro A.; Szachowicz, Peter J; Li, Pengfei; Pan, R. Martin Du; Klumpp, Klaus; Aswad, Fred; Rebo, Justin; Narumiya, Shuh; Murakami, Makoto; Zúñiga, Sonia; Sola, Isabel; Enjuanes, Luis; Meyerholz, David K.; Fortney, Kristen; McCray, Paul B.; Perlman, Stanley

doi:10.1038/s41586-022-04630-3

Cited by 128 publications

(165 citation statements)

References 49 publications

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“… 33 – 35 The Q498R and Q493R mutations were detected in mouse-adapted SARS-CoV-2 by passage 10 and passage 20, respectively, and have not since been detected in any SARS-CoV-2 variants from other animals. 36 Based on our data reported here, combined with previous studies, we propose that mouse is a possible host for evolution of Omicron variants.…”

Section: Discussionsupporting

confidence: 71%

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.2 variant compared to BA.1 and their possible mouse origins

Cao³

et al. 2022

Cell Res

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The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies show that the Omicron BA.2 spike trimer exhibits 11-fold and 2-fold higher potency in binding to human ACE2 than the spike trimer from the wildtype (WT) and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains (RBDs) in the spike trimer are in open conformation, ready for ACE2 binding, thus providing a basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to efficiently inhibit Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency. In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants via a human-cat-mouse-human circle, which could have important implications in establishing an effective strategy for combating SARS-CoV-2 viral infections.

show abstract

Section: Discussionsupporting

confidence: 71%

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.2 variant compared to BA.1 and their possible mouse origins

Cao³

et al. 2022

Cell Res

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show abstract

“…[32][33][34] Surprisingly, the Q498R and Q493R mutations were detected in mouse-adapted SARS-CoV-2 by passage 10 and passage 20, respectively, and have not since been detected in any SARS-CoV-2 variants from other animals. 35 Based on our data reported here, combined with previous studies, we propose mouse is likely a host for evolution of Omicron variants.…”

Section: Discussionsupporting

confidence: 71%

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.1 and BA.2 variants and their mouse origins

Cao³

et al. 2022

Preprint

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The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies reveal that the BA.2 spike trimer have 11-fold and 2-fold higher potency to human ACE2 than the spike trimer from the wildtype and Omicron BA.1 strains. The structure of the BA.2 spike timer reveals that all three receptor-binding domains (RBD) in the spike trimer are in open conformation, ready for high affinity binding to human ACE2, providing the basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to have efficient inhibition of Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to the mouse ACE2 with high potency. In contrast, the wildtype spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants from human-cat-mouse-human circle, which could have important implications in establishing an effective strategy in combating viral infection.

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“…Studies show that oxidative stress may induce the expression of PLA2G2D in mouse and human monocyte-derived macrophages through lipid peroxidation. The high expression of PLA2G2D increases viral infection, and mice lacking PLAG2D are protected from COVID-19 invasion ( 46 , 47 ). Besides, it has been reported that upregulation of PLA2G2D could be a potential biomarker for cancer immunotherapy ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

The Metabolic Signature of AML Cells Treated With Homoharringtonine

Chang

Wang

et al. 2022

Front. Oncol.

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Acute myeloid leukemia (AML) is a hematologic malignancy. The overall prognosis is poor and therapeutic strategies still need to be improved. Studies have found that abnormalities in metabolisms promote the survival of AML cells. In recent years, an increasing number of studies have reported the effectiveness of a protein synthesis inhibitor, homoharringtonine (HHT), for the treatment of AML. In this study, we demonstrated that HHT effectively inhibited AML cells, especially MV4-11, a cell line representing human AML carrying the poor prognostic marker FLT3-ITD. We analyzed the transcriptome of MV4-11 cells treated with HHT, and identified the affected metabolic pathways including the choline metabolism process. In addition, we generated a line of MV4-11 cells that were resistant to HHT. The transcriptome analysis showed that the resistant mechanism was closely related to the ether lipid metabolism pathway. The key genes involved in these processes were AL162417.1, PLA2G2D, and LPCAT2 by multiple intergroup comparison and Venn analysis. In conclusion, we found that the treatment of HHT significantly changed metabolic signatures of AML cells, which may contribute to the precise clinical use of HHT and the development of novel strategies to treat HHT-resistant AML.

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Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19

Cited by 128 publications

References 49 publications

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.2 variant compared to BA.1 and their possible mouse origins

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.2 variant compared to BA.1 and their possible mouse origins

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.1 and BA.2 variants and their mouse origins

The Metabolic Signature of AML Cells Treated With Homoharringtonine

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