METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection

doi:10.1016/j.celrep.2021.109091

. 2021 May 11;35(6):109091.

doi: 10.1016/j.celrep.2021.109091. Epub 2021 May 3.

METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection

Na Li ¹, Hui Hui ², Bill Bray ¹, Gwendolyn Michelle Gonzalez ³, Mark Zeller ⁴, Kristian G Anderson ⁴, Rob Knight ⁵, Davey Smith ⁶, Yinsheng Wang ³, Aaron F Carlin ⁶, Tariq M Rana ⁷

Affiliations

¹ Division of Genetics, Program in Immunology, Institute for Genomic Medicine, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA.
² Division of Genetics, Program in Immunology, Institute for Genomic Medicine, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Bioinformatics Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
³ Environmental Toxicology Graduate Program and Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA.
⁴ Department of Immunology and Microbiology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁵ Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Center for Microbiome Innovations, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
⁶ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
⁷ Division of Genetics, Program in Immunology, Institute for Genomic Medicine, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA. Electronic address: trana@ucsd.edu.

PMID: 33961823
PMCID: PMC8090989
DOI: 10.1016/j.celrep.2021.109091

METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection

Na Li et al. Cell Rep. 2021.

. 2021 May 11;35(6):109091.

doi: 10.1016/j.celrep.2021.109091. Epub 2021 May 3.

Authors

Na Li ¹, Hui Hui ², Bill Bray ¹, Gwendolyn Michelle Gonzalez ³, Mark Zeller ⁴, Kristian G Anderson ⁴, Rob Knight ⁵, Davey Smith ⁶, Yinsheng Wang ³, Aaron F Carlin ⁶, Tariq M Rana ⁷

Affiliations

¹ Division of Genetics, Program in Immunology, Institute for Genomic Medicine, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA.
² Division of Genetics, Program in Immunology, Institute for Genomic Medicine, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Bioinformatics Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
³ Environmental Toxicology Graduate Program and Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA.
⁴ Department of Immunology and Microbiology, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁵ Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Center for Microbiome Innovations, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
⁶ Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
⁷ Division of Genetics, Program in Immunology, Institute for Genomic Medicine, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA. Electronic address: trana@ucsd.edu.

PMID: 33961823
PMCID: PMC8090989
DOI: 10.1016/j.celrep.2021.109091

Abstract

It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlining molecular mechanism. N⁶-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of the SARS-CoV-2 gene in regulating the host cell innate immune response. Our data show that the SARS-CoV-2 virus has m6A modifications that are enriched in the 3' end of the viral genome. We find that depletion of the host cell m6A methyltransferase METTL3 decreases m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increases RIG-I binding and subsequently enhances the downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in patients with severe coronavirus disease 2019 (COVID-19). These findings will aid in the understanding of COVID-19 pathogenesis and the design of future studies regulating innate immunity for COVID-19 treatment.

Keywords: METTL3; RIG-I; SARS-CoV-2; host innate immunity; inflammation; m(6)A RNA modification.

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Conflict of interest statement

Declaration of interests T.M.R. is a founder of ViRx Pharmaceuticals and has an equity interest in the company. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies.

Figures

None

Graphical abstract

Figure 1

Figure 1

SARS-CoV-2 viral RNA contains m6A modifications, and METTL3 depletion reduced m6A levels in SARS-CoV-2 viral RNA (A) Genome browser tracks for input and MeRIP of SARS-CoV-2 viral RNA isolated from Vero cells. Reads were aligned with Bowtie2, and peaks were called by MACS2 without removing duplicates (upper panel) or with removing duplicates (lower panel). Input is indicated in blue and MeRIP in red. Bed files of the called peaks are shown under the MeRIP track of each condition. The scale of the peak density is set to be the same for all groups and is shown in the corner. Enlarged view shows the enrichment of m6A signals in the nucleocapsid (N) region of the SARS-CoV-2 virus. (B) MeRIP-qPCR of SARS-CoV-2 viral RNA. IgG control and m6A antibody were added in IP lysates containing equal amounts of viral RNA. Primers amplifying different regions of the N (N-1 to N-4) and E genes were used to quantify viral RNA. N = 2. (C) METTL3 is present in both the nuclear and cytosolic fractions of Caco-2 cells. Levels of METTL3, the nuclear fraction marker lamin A/C, and the cytosolic fraction marker protein beta-actin were examined by western blotting. (D) METTL3 knockdown (KD) efficiency was examined by qRT-PCR in Caco-2 cells. Two different shRNAs were used to target METTL3. N = 3. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05. (E) Cell proliferation of control and METTL3 KD Caco-2 cells was evaluated by colorimetric MTS assay. N = 3. (F) Genome browser tracks for input and MeRIP of SARS-CoV-2 viral RNA from control and METTL3 KD Caco-2 cells infected with SARS-CoV-2. Reads were aligned with STAR, and peaks were called by MACS2 without removing duplicates. Input is indicated in blue, MeRIP of control in red, and MeRIP of METTL3 KD in green. Bed files of the called peaks are shown under the MeRIP track of each condition. The scale of the peak density is set to be the same for all groups and is shown in the corner. Enlarged view shows the m6A signals in the N region of the SARS-CoV-2 virus. (G) MeRIP-qPCR of viral RNAs from SARS-CoV-2-infected control and METTL3 KD Caco-2 cells. IgG control and m6A antibody were added in IP lysates containing equal amounts of viral RNA. Primers amplifying different regions of the N (N-1 to N-4) and E genes were used to quantify viral RNA. GAPDH served as a negative control. N = 3. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001. See also Figures S1 and S2 and Tables S1, S2, and S4.

Figure 2

Figure 2

METTL3 depletion reduced viral load and proviral gene expression during SARS-CoV-2 infection (A and B) METTL3 (A) and METTL14 (B) KD efficiency was examined by qRT-PCR in Caco-2, Caco-2-shControl, Caco-2-shMETTL3 (A), or Caco-2-shMETTL14 (B) cells after SARS-CoV-2 infection. N = 3. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05 and ^∗∗∗p < 0.001. (C) SARS-CoV-2 gene expression of mock-infected Caco-2 cells, and SARS-CoV-2-infected Caco-2, Caco-2-shControl, Caco-2-shMETTL3, and Caco-2-shMETTL14 cells. Cells were collected for RNA extraction and RT-qPCR analysis. Fold change of SARS-CoV-2 N and E genes over GAPDH were calculated and are presented. N = 3. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗∗p < 0.01, ^∗∗∗p < 0.001. (D) SARS-CoV-2 viral genome copy number of infected Caco-2, Caco-2-shControl, Caco-2-shMETTL3, and Caco-2-shMETTL14 cells. Supernatants were collected for RNA extraction and qRT-PCR detection. N = 3. (E) Read coverage of SARS-CoV-2 genome of viral infected shControl and shMETTL3 Caco-2 cells analyzed by RNA-seq. The scale of all the samples was set to be the same. N = 3. (F) Downregulated proviral host genes in METTL3-depleted Caco-2 cells compared with control cells during SARS-CoV-2 infection. The red star marks genes with altered m6A levels determined by MeRIP-seq for cellular RNAs in control and METTL3 KD cells during SARS-CoV-2 infection. (G) Genome browser tracks for examples of the downregulated proviral genes with reduced m6A levels (listed in F and marked with a red star) in METTL3 KD cells compared with control Caco-2 cells during SARS-CoV-2 infection. Input is indicated in blue, MeRIP of control in red, and MeRIP of METTL3 KD in green. Bed files of the called peaks are shown under the MeRIP track of each condition. The scale of the peak density is set to be the same in the control and METTL3 KD groups. See also Figure S2 and Tables S2, S3, and S4.

Figure 3

Figure 3

METTL3/METTL14 depletion enhances innate immune response effector gene expression during SARS-CoV-2 infection (A) Gene Ontology (GO) analysis of upregulated genes comparing shMETTL3 with shControl Caco-2 cells after SARS-CoV-2 infection. All of the biological process categories shown have a false discovery rate (FDR) < 0.001. (B) Log2 fold change of shMETTL3 compared with shControl Caco-2 cells is shown for upregulated immune response genes after SARS-CoV-2 infection. (C) Gene expression of innate immune pathway downstream effectors was examined in shControl, shMETTL3, or shMETTL14 Caco-2 cells after SARS-CoV-2 infection. Gene expression changes were compared between shControl and KD cells. N = 3. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001. (D) Gene expression of innate immune pathway downstream effectors was examined in Calu-3, shControl, shMETTL3, or shMETTL14 Calu-3 cells after SARS-CoV-2 infection. Gene expression changes were compared between shControl and KD cells. N = 3. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001. (E) 1.2 ×ばつ 10¹³ copies of IVT-SARS-CoV-2-N (IVT-CoV-2) RNA with or without calf alkaline phosphatase (CIP) were transfected to Caco-2 cells seeded in 24-well plates, and downstream inflammatory and ISG gene expression was examined by qRT-PCR. N = 3. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001. See also Figures S2 and S3 and Tables S3 and S4.

Figure 4

Figure 4

Reduction of m6A levels in SARS-CoV-2 viral RNA by METTL3 depletion leads to an increased recognition by RIG-I (A) Graphic illustration of RIG-I RNA immunoprecipitation (RIP) experiments. (B) 6 ×ばつ 10¹³ copies of IVT-CoV-2 RNA with or without CIP treatment were used in RIG-I RIP experiments. RIG-I were equally immunoprecipitated by RIG-I antibody for CIP-treated or nontreated groups. IgG serves as a negative control (left panel). RIG-I-bound RNA was extracted by phenol-chloroform-isoamyl alcohol and purified by RNA Clean & Concentrator Kits. The purified RNA was reverse transcribed and quantified by qPCR. N = 4. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗∗p < 0.01 and ^∗∗∗p < 0.001. (right panel). (C) Graphic illustration of biotinylated RNA pull-down experiments. (D) Biotinylated IVT-CoV-2 RNA (1 ×ばつ 10¹⁴ copies) was treated with or without CIP and used in RNA pull-down assays. RNA-bound RIG-I proteins were detected by western blot. (E) RIG-I RIP assay for SARS-CoV-2 virus from infected Caco-2 cells. 5 ×ばつ 10⁹ copies of SARS-CoV-2 viral RNA were incubated with Caco-2 cell lysates and immunoprecipitated with IgG control and anti-RIG-I antibody (left panel). IgG or RIG-I-bound RNA was extracted by phenol-chloroform-isoamyl alcohol and purified by RNA Clean & Concentrator Kits. The purified RNA was reverse transcribed and quantified by qPCR. N = 4. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗∗∗p < 0.001 (right panel). (F) METTL3 expression in control and METTL3 KD Caco-2 cells was examined by western blotting. (G) Equal amounts of IVT-CoV-2 RNA were transfected into control and METTL3-depleted Caco-2 cells, cell lysates were incubated with RIG-I antibody, and IP efficiency was examined by western blotting (left panel). RIG-I-bound RNA was purified and quantified as described before. N = 4. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗∗p < 0.01 (right panel). (H) RIG-I RIP assay for SARS-CoV-2 virus from control and METTL3 KD Caco-2 cells after SARS-CoV-2 infection. 5 ×ばつ 10⁹ copies of SARS-CoV-2 viral RNA from infected control and METTL3 KD Caco-2 cells were used for RIG-I RIP experiments. RIG-I IP efficiency was examined by western blotting. IgG serves as a negative control (left panel). RIG-I-bound RNAs were purified and quantified as described before. N = 4. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001. (right panel). See also Figure S3 and Table S4.

Figure 5

Figure 5

Mutagenesis of m6A-modified adenosine sites in SARS-CoV-2 RNA increases RIG-I recognition and inflammatory gene expression (A) Mutagenesis of putative m6A sites in the SARS-CoV-2 N region. (B) Equal amounts of wild-type (WT) and mutant (Mut) IVT-CoV-2 RNA were transfected into Caco-2 cells, and MeRIP-RT-qPCR was performed for WT and Mut IVT-CoV-2 RNA transfected group. N = 2. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05. (C) Equal amounts of WT and Mut IVT-CoV-2 RNA were transfected into Caco-2 cells. IVT-CoV-2, CCL5, TNF, and IL-8 mRNA expression was examined by qRT-PCR. N = 2. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001. (D) Equal amounts of WT and Mut IVT-CoV-2 RNA were transfected into Caco-2 cells. Cell lysates were collected, and RIG-I RIP experiments were performed by using IgG control and anti-RIG-I antibody. N = 2. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗∗∗p < 0.001. (E) Equal amounts of biotinylated WT (lane 1) or Mut (lane 4) RNA or a mixture of WT and Mut (1:1 ratio, lanes 2 and 3) IVT-CoV-2 RNA was transfected into Caco-2 cells. Cell lysates were collected, and biotinylated RNA pull-down experiments were performed. RNA-bound RIG-I proteins were examined by western blotting. See also Table S4.

Figure 6

Figure 6

METTL3 depletion leads to increased IRF3 and IκBα phosphorylation and inflammatory gene expression (A) Mock-transfected Caco-2 cells or Caco-2 cells (Caco-2, shControl, or shMETTL3) transfected with equal amounts of IVT-SARS-CoV-2-N RNA were collected for western blotting. (B) Phosphorylation levels of IκBα were determined in shControl and METTL3-depleted Caco-2 cells upon SARS-CoV-2 infection by western blotting. (C) shControl and METTL3-depleted Caco-2 cells were transfected with equal amounts of IVT-SARS-CoV-2-N RNA, and METTL3-depleted cells were treated with or without IκBα phosphorylation inhibitor Bay 11-7083. IκBα phosphorylation and METTL3 levels were examined by western blot. (D) shControl or METTL3 KD Caco-2 cells were infected with SARS-CoV-2 virus and treated with or without the IκBα phosphorylation inhibitor Bay 11-7083, and cells were then collected for RNA extraction. Expression levels of the inflammatory genes IL-8, CXCL1, CXCL3, and CCL20 were compared between control and METTL3 KD cells as well as cells treated with or without IκBα phosphorylation inhibitor upon SARS-CoV-2 infection (right panel). Two shRNAs were used to knock down METTL3, and KD efficacy was examined by qRT-PCR (left panel). N = 3. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001. (E) Significantly changed genes from lung samples of COVID-19 patients compared with healthy controls (Blanco-Melo et al., 2020). Inflammatory genes and ISGs, as well as METTL3 and METTL14, are shown as log2 (fold change). The genes shown have the p adj < 0.05 and pass the Wald test for the gene counts. (F) Bar graphs of METTL3, IL-8, and MX1 expression in healthy controls (HCs) and COVID-19 patients with moderate (M) or severe (S) disease (Liao et al., 2020). Single-cell RNA expression from epithelial cells of bronchoalveolar lavage fluid (BALF) from healthy donor and COVID-19-infected patients was analyzed, and the difference between each group was compared. Data are presented as the mean ± SEM. Group means were compared by Student’s t test. n.s., not significant; ^∗p < 0.05, ^∗∗p < 0.01, and ^∗∗∗p < 0.001. See also Table S4.

Figure 7

Figure 7

SARS-CoV-2 virus utilizes the host m6A methyltransferase METTL3 to modify viral RNA and evade host innate immune responses (Left) After entry into the host cell, the viral genome enters the replication phase, and 5′-phosphorylated viral RNA is generated, which is m6A modified by METTL3 and does not bind RIG-I to activate immune pathways. Viral infection also enhances METTL3-mediated proviral gene expression. (Right) When METTL3 is depleted, m6A levels of viral RNA are reduced, and RIG-I-bound viral RNA is increased, leading to enhanced RIG-I sensing and activation, which is followed by downstream activation of the NF-κB pathway and inflammatory gene expression. In addition, METTL3 depletion alters gene expression and m6A levels of several proviral host factors upon SARS-CoV-2 infection.

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References

1. Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801. - PubMed
1. Blanco-Melo D., Nilsson-Payant B.E., Liu W.C., Uhl S., Hoagland D., Møller R., Jordan T.X., Oishi K., Panis M., Sachs D. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181:1036–1045.e9. - PMC - PubMed
1. Bojkova D., Klann K., Koch B., Widera M., Krause D., Ciesek S., Cinatl J., Münch C. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature. 2020;583:469–472. - PMC - PubMed
1. Brubaker S.W., Bonham K.S., Zanoni I., Kagan J.C. Innate immune pattern recognition: a cell biological perspective. Annu. Rev. Immunol. 2015;33:257–290. - PMC - PubMed
1. Cantuti-Castelvetri L., Ojha R., Pedro L.D., Djannatian M., Franz J., Kuivanen S., van der Meer F., Kallio K., Kaya T., Anastasina M. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020;370:856–860. - PMC - PubMed

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[1] Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801. - PubMed

[2] Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801. - PubMed

[3] Blanco-Melo D., Nilsson-Payant B.E., Liu W.C., Uhl S., Hoagland D., Møller R., Jordan T.X., Oishi K., Panis M., Sachs D. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181:1036–1045.e9. - PMC - PubMed

[4] Blanco-Melo D., Nilsson-Payant B.E., Liu W.C., Uhl S., Hoagland D., Møller R., Jordan T.X., Oishi K., Panis M., Sachs D. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020;181:1036–1045.e9. - PMC - PubMed

[5] Bojkova D., Klann K., Koch B., Widera M., Krause D., Ciesek S., Cinatl J., Münch C. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature. 2020;583:469–472. - PMC - PubMed

[6] Bojkova D., Klann K., Koch B., Widera M., Krause D., Ciesek S., Cinatl J., Münch C. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature. 2020;583:469–472. - PMC - PubMed

[7] Brubaker S.W., Bonham K.S., Zanoni I., Kagan J.C. Innate immune pattern recognition: a cell biological perspective. Annu. Rev. Immunol. 2015;33:257–290. - PMC - PubMed

[8] Brubaker S.W., Bonham K.S., Zanoni I., Kagan J.C. Innate immune pattern recognition: a cell biological perspective. Annu. Rev. Immunol. 2015;33:257–290. - PMC - PubMed

[9] Cantuti-Castelvetri L., Ojha R., Pedro L.D., Djannatian M., Franz J., Kuivanen S., van der Meer F., Kallio K., Kaya T., Anastasina M. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020;370:856–860. - PMC - PubMed

[10] Cantuti-Castelvetri L., Ojha R., Pedro L.D., Djannatian M., Franz J., Kuivanen S., van der Meer F., Kallio K., Kaya T., Anastasina M. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020;370:856–860. - PMC - PubMed

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METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection

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METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection

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