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Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2

Guo, Xuanming, Cao, Jianli, Cai, Jian-Piao, Wu, Jiayan, Huang, Jiangang, Asthana, Pallavi, Wong, Sheung Kin Ken, Ye, Zi-Wei, Gurung, Susma, Zhang, Yijing, Wang, Sheng, Wang, Zening, Ge, Xin, Kwan, Hiu Yee, Lyu, Aiping, Chan, Kui Ming, Wong, Nathalie, Huang, Jiandong, Zhou, Zhongjun, Bian, Zhao-Xiang, Yuan, Shuofeng, Wong, Hoi Leong Xavier·2022·Nature Communications
DOI 10.1038/s41467-022-35590-xPMC PMC9780620
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung epithelium. Mechanistically, MT1-MMP directly cleaves memACE2 at M706-S to release solACE2 18-706 that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE2 18-706 enables SARS-CoV-2 infection in both non-permissive cells and naturally insusceptible C57BL/6 mice. Inhibition of MT1-MMP activities suppresses solACE2-directed entry of SARS-CoV-2 in human organoids and aged mice. Both solACE2 and circulating MT1-MMP are positively correlated in plasma of aged mice and humans. Our findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19.

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Fig. 1 The shedding of ACE2 by MT1-MMP. a Western blotting analyses on the expression of ACE2 in the total cell lysate (TCL) and conditioned medium (CM) derived from wild-type and Mmp14-/- mouse primary lung epithelial cells. Coomassie stained membrane served as a loading control for conditioned medium (n = 3). b Real-time quantitative PCR analyses on the relative mRNA expression of ACE2 in wild-type and Mmp14-/- mouse primary lung epithelial cells (n = 5). c HEK293T cells were co-transfected with human ACE2 and wild-type or E/A catalytic mutant MT1-MMP (MT1 E240A). Expression of full-length ACE2 in total cell lysates and conditioned medium was detected by western blotting. Coomassie stained membrane was a loading control for conditioned medium (n = 3). d Western blotting analyses on the expression of solACE2 and memACE2 in human cardiac organoids and human bronchial epithelial cells that were lentivirally transduced with either shRNA or shMMP14 (n = 3). e The recombinant full-length ACE2 (rACE2) was incubated with the catalytic domain of MT1-MMP (cMT1) and the protein mixture was analyzed by western blotting using specific antibodies (n = 3). f Endogenous interaction between MT1-MMP and ACE2. Co-immunoprecipitation was performed with the cell lysates of Caco2 cells and examined by western blotting analyses using specific antibodies. IgG immunoprecipitates were used as controls (n = 3). g A diagram illustrating the cleavage of ACE2 by MT1-MMP. Data are means ± S.E.M. of three independent repeats; two-tailed unpaired t-test for (b). Source data are provided as a Source Data file.
Fig. 1 The shedding of ACE2 by MT1-MMP. a Western blotting analyses on the expression of ACE2 in the total cell lysate (TCL) and conditioned medium (CM) derived from wild-type and Mmp14-/- mouse primary lung epithelial cells. Coomassie stained membrane served as a loading control for conditioned medium (n = 3). b Real-time quantitative PCR analyses on the relative mRNA expression of ACE2 in wild-type and Mmp14-/- mouse primary lung epithelial cells (n = 5). c HEK293T cells were co-transfected with human ACE2 and wild-type or E/A catalytic mutant MT1-MMP (MT1 E240A). Expression of full-length ACE2 in total cell lysates and conditioned medium was detected by western blotting. Coomassie stained membrane was a loading control for conditioned medium (n = 3). d Western blotting analyses on the expression of solACE2 and memACE2 in human cardiac organoids and human bronchial epithelial cells that were lentivirally transduced with either shRNA or shMMP14 (n = 3). e The recombinant full-length ACE2 (rACE2) was incubated with the catalytic domain of MT1-MMP (cMT1) and the protein mixture was analyzed by western blotting using specific antibodies (n = 3). f Endogenous interaction between MT1-MMP and ACE2. Co-immunoprecipitation was performed with the cell lysates of Caco2 cells and examined by western blotting analyses using specific antibodies. IgG immunoprecipitates were used as controls (n = 3). g A diagram illustrating the cleavage of ACE2 by MT1-MMP. Data are means ± S.E.M. of three independent repeats; two-tailed unpaired t-test for (b). Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 2 MT1-MMP+ACE2+ lung epithelial cells are susceptible to SARS-CoV-2 infection. a MT1-MMP+ cells were distributed across the indicated cell types in the human lung within UMAP. b Heat map analysis of MMP14 gene expression in various lung and airway cells. c The distribution of ACE2+ and ACE2+ MT1-MMP+ cells in the lung was assessed using human cellular profiles at the single cell level. Gene expression was visualized for each cell type using tSNE. d UMAP is depicted for ACE2+ (purple), ACE2+MT1-MMP+ cells (red) and viral RNA+ cells (yellow circles).
Fig. 2 MT1-MMP+ACE2+ lung epithelial cells are susceptible to SARS-CoV-2 infection. a MT1-MMP+ cells were distributed across the indicated cell types in the human lung within UMAP. b Heat map analysis of MMP14 gene expression in various lung and airway cells. c The distribution of ACE2+ and ACE2+ MT1-MMP+ cells in the lung was assessed using human cellular profiles at the single cell level. Gene expression was visualized for each cell type using tSNE. d UMAP is depicted for ACE2+ (purple), ACE2+MT1-MMP+ cells (red) and viral RNA+ cells (yellow circles).CC BY · PubMed Central
Fig. 3 MT1-MMP regulates the cell entry of SARS-CoV-2 by releasing solACE2. a Comparison of MMP14 expression levels in lung and airway cells from uninfected populations and patients infected with SARS-CoV-2. Boxplots show the median (central line), the 25–75% interquartile range (IQR) (box limits), the ±1.5 × IQR (whiskers). (n = 44 for healthy controls; n = 104 for infected patients) b MT1-MMP promotes the entry of SARS-CoV-2 viral pseudotypes in host cells. HEK293T cells expressing different ACE2 mutants (wild-type ACE2, ACE2 S707A & ACE2 I727A) were transfected with WT or E/A catalytic mutant MT1-MMP (MT1 E240A) and infected with SARS-CoV-2 viral pseudotypes for 72 h. Intracellular luciferase levels were measured. (n = 3) c ACE2-HEK293T cells were inoculated with various concentrations of conditioned media derived from HEK293T transfected with ACE2 with/without MT1-MMP, followed by infection with SARS-CoV-2 pseudotypes for 72 h. Intracellular luciferase levels were measured. (n = 3) d, e Huh-7 or Caco2 cells were transfected with either siRNA targeting MMP14 or control siRNA, followed by the infection with SARS-CoV-2 pseudotyped virus. Luciferase levels were detected by chemiluminescence at 72 h post-infection. (n = 3) (p=<2e-16) f Caco2 cells stably transduced with shMMP14 or control shRNA were infected with SARS-CoV-2 pseudotyped virus for 48 h. The expression levels of solACE2, memACE2 and MT1-MMP were subsequently detected by western blotting. (n = 3) g The HK-2 cells were inoculated with the conditioned media derived from HEK293T cells co-expressing either ACE2, ACE2 with MT1-MMP or ACE2 with catalytic mutant MT1-MMP (E240A), followed by SARS-CoV-2 infection. (n = 3) h The HK-2 cells pretreated with different concentrations of recombinant ACE2 and with or without incubation with catalytic domain of MT1-MMP were infected with SARS-CoV-2. Mock-treated HK-2 cells served as a control. (n = 3) i Primary human bronchial epithelial 3D cultures with an air-liquid interface (ALI) were lentivirally transduced with shRNA targeting MT1-MMP or control shRNA, following by the infection of SARS-CoV-2. (n = 3) The data are shown as the means ± SEM from three independent experiments. P values were calculated using one-way ANOVA for (b, e; g, h); two-way ANOVA for (i) and unpaired two -tailed t-test for (a). Source data are provided as a Source Data file.
Fig. 3 MT1-MMP regulates the cell entry of SARS-CoV-2 by releasing solACE2. a Comparison of MMP14 expression levels in lung and airway cells from uninfected populations and patients infected with SARS-CoV-2. Boxplots show the median (central line), the 25–75% interquartile range (IQR) (box limits), the ±1.5 × IQR (whiskers). (n = 44 for healthy controls; n = 104 for infected patients) b MT1-MMP promotes the entry of SARS-CoV-2 viral pseudotypes in host cells. HEK293T cells expressing different ACE2 mutants (wild-type ACE2, ACE2 S707A & ACE2 I727A) were transfected with WT or E/A catalytic mutant MT1-MMP (MT1 E240A) and infected with SARS-CoV-2 viral pseudotypes for 72 h. Intracellular luciferase levels were measured. (n = 3) c ACE2-HEK293T cells were inoculated with various concentrations of conditioned media derived from HEK293T transfected with ACE2 with/without MT1-MMP, followed by infection with SARS-CoV-2 pseudotypes for 72 h. Intracellular luciferase levels were measured. (n = 3) d, e Huh-7 or Caco2 cells were transfected with either siRNA targeting MMP14 or control siRNA, followed by the infection with SARS-CoV-2 pseudotyped virus. Luciferase levels were detected by chemiluminescence at 72 h post-infection. (n = 3) (p=<2e-16) f Caco2 cells stably transduced with shMMP14 or control shRNA were infected with SARS-CoV-2 pseudotyped virus for 48 h. The expression levels of solACE2, memACE2 and MT1-MMP were subsequently detected by western blotting. (n = 3) g The HK-2 cells were inoculated with the conditioned media derived from HEK293T cells co-expressing either ACE2, ACE2 with MT1-MMP or ACE2 with catalytic mutant MT1-MMP (E240A), followed by SARS-CoV-2 infection. (n = 3) h The HK-2 cells pretreated with different concentrations of recombinant ACE2 and with or without incubation with catalytic domain of MT1-MMP were infected with SARS-CoV-2. Mock-treated HK-2 cells served as a control. (n = 3) i Primary human bronchial epithelial 3D cultures with an air-liquid interface (ALI) were lentivirally transduced with shRNA targeting MT1-MMP or control shRNA, following by the infection of SARS-CoV-2. (n = 3) The data are shown as the means ± SEM from three independent experiments. P values were calculated using one-way ANOVA for (b, e; g, h); two-way ANOVA for (i) and unpaired two -tailed t-test for (a). Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 4 MT1-MMP-mediated ACE2 shedding mediates the SARS-CoV-2 cell entry in vitro and in vivo. a–c The A549 and HEK293T cells were inoculated with rACE21-706, followed by SARS-CoV-2 infection. Vehicle-treated cells served as a control. The viral antigens of these cells were detected by immunostaining of Nucleocapsid Protein (NP) (green) as shown in a. (One representative data was shown from three independently repeated experiments) (Scale bar: 20 μm) The viral gene copies of these cells were measured by qPCR analyses of the SARS-CoV-2 genes as shown in b and c. (n = 3 biologically independent experiments) d Experimental strategy to study the role of human solACE in mediating SARS-CoV-2 infection in mice. e Immunostaining of human ACE2 (red) and SARS-CoV-2 (green) Nucleocapsid Protein (NP) in lung sections of mice expressing solACE21-706/ solACE21-740/ACE2full length (FL) (n = 8 for AAV-control; n = 8 for AAV-hACE2(1-706); n = 8 for AAV-hACE2 (1-740); n = 8 for AAV-hACE2(full length)). (Scale bar: 20 μm) f The viral loads in the lungs of mice expressing solACE21-706/ solACE21-740/ ACE2full length (FL) were measured by qPCR analyses of the SARS-CoV-2 genes (n = 8 for AAV-control; n = 8 for AAV-hACE2(1-706); n = 8 for AAV-hACE2 (1-740); n = 8 for AAV-hACE2(full length)). g Summary histology scores determined in the lung tissues of mice expressing solACE21-706/ solACE21-740/ACE2full length (FL) (n = 8 for AAV-control; n = 8 for AAV-hACE2(1-706); n = 8 for AAV-hACE2 (1-740); n = 8 for AAV-hACE2(full length)) h Representative Hematoxylin-eosin (HE) staining of lungs of mice expressing solACE21-706/ solACE21-740/ACE2full length (FL) (n = 8 for AAV-control; n = 8 for AAV-hACE2(1-706); n = 8 for AAV-hACE2 (1-740); n = 8 for AAV-hACE2(full length)). (Scale bar: 50 μm) Data are means ± S.E.M. of three independent repeats. Statistical analyses were performed by one way ANOVA for (b, c; f, g) Source data are provided as a Source Data file.
Fig. 4 MT1-MMP-mediated ACE2 shedding mediates the SARS-CoV-2 cell entry in vitro and in vivo. a–c The A549 and HEK293T cells were inoculated with rACE21-706, followed by SARS-CoV-2 infection. Vehicle-treated cells served as a control. The viral antigens of these cells were detected by immunostaining of Nucleocapsid Protein (NP) (green) as shown in a. (One representative data was shown from three independently repeated experiments) (Scale bar: 20 μm) The viral gene copies of these cells were measured by qPCR analyses of the SARS-CoV-2 genes as shown in b and c. (n = 3 biologically independent experiments) d Experimental strategy to study the role of human solACE in mediating SARS-CoV-2 infection in mice. e Immunostaining of human ACE2 (red) and SARS-CoV-2 (green) Nucleocapsid Protein (NP) in lung sections of mice expressing solACE21-706/ solACE21-740/ACE2full length (FL) (n = 8 for AAV-control; n = 8 for AAV-hACE2(1-706); n = 8 for AAV-hACE2 (1-740); n = 8 for AAV-hACE2(full length)). (Scale bar: 20 μm) f The viral loads in the lungs of mice expressing solACE21-706/ solACE21-740/ ACE2full length (FL) were measured by qPCR analyses of the SARS-CoV-2 genes (n = 8 for AAV-control; n = 8 for AAV-hACE2(1-706); n = 8 for AAV-hACE2 (1-740); n = 8 for AAV-hACE2(full length)). g Summary histology scores determined in the lung tissues of mice expressing solACE21-706/ solACE21-740/ACE2full length (FL) (n = 8 for AAV-control; n = 8 for AAV-hACE2(1-706); n = 8 for AAV-hACE2 (1-740); n = 8 for AAV-hACE2(full length)) h Representative Hematoxylin-eosin (HE) staining of lungs of mice expressing solACE21-706/ solACE21-740/ACE2full length (FL) (n = 8 for AAV-control; n = 8 for AAV-hACE2(1-706); n = 8 for AAV-hACE2 (1-740); n = 8 for AAV-hACE2(full length)). (Scale bar: 50 μm) Data are means ± S.E.M. of three independent repeats. Statistical analyses were performed by one way ANOVA for (b, c; f, g) Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 5 MT1-MMP inhibition suppresses SARS-CoV-2 infection in human organoids. a–e The inhibitory effect of MT1-MMP knockdown on SARS-CoV-2 infectivity in primary cells and organoids. Primary human bronchial epithelial 3D cultures with an air-liquid interface (ALI) (n = 3 biologically independent experiments), human cardiac organoids formed by iPSC-derived cardiomyocytes (n = 3) and human liver organoids (n = 3) were lentivirally transduced with shRNA targeting MT1-MMP or control shRNA, following by the infection of SARS-CoV-2. d Air–liquid interface culture was pretreated with increasing dosages of 3A2 and infected with SARS-CoV-2. (n = 3 biologically independent experiments) e Human bronchial epithelial cells transduced with shMT1-MMP or shRNA control were infected with SARS-CoV-2 omicron variant. (n = 3 biologically independent experiments) Data are means ± S.E.M. of three independent repeats. Statistical analyses were performed by one way ANOVA for (d) and multiple unpaired two-tailed t-test for (a–c), e. Source data are provided as a Source Data file.
Fig. 5 MT1-MMP inhibition suppresses SARS-CoV-2 infection in human organoids. a–e The inhibitory effect of MT1-MMP knockdown on SARS-CoV-2 infectivity in primary cells and organoids. Primary human bronchial epithelial 3D cultures with an air-liquid interface (ALI) (n = 3 biologically independent experiments), human cardiac organoids formed by iPSC-derived cardiomyocytes (n = 3) and human liver organoids (n = 3) were lentivirally transduced with shRNA targeting MT1-MMP or control shRNA, following by the infection of SARS-CoV-2. d Air–liquid interface culture was pretreated with increasing dosages of 3A2 and infected with SARS-CoV-2. (n = 3 biologically independent experiments) e Human bronchial epithelial cells transduced with shMT1-MMP or shRNA control were infected with SARS-CoV-2 omicron variant. (n = 3 biologically independent experiments) Data are means ± S.E.M. of three independent repeats. Statistical analyses were performed by one way ANOVA for (d) and multiple unpaired two-tailed t-test for (a–c), e. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 6 The positive correlation between MT1-MMP and ACE2 in the elderly. a, b Expression levels of soluble ACE2 and MT1-MMP in the plasma of young human subjects and aged human subjects were measured by ELISA (n = 21 young people & 23 old people) (unpaired two-tailed t-test). The data are shown as the means ± SEM. c Comparison of MMP14 expression levels in young human subjects and elderly human subjects by analysis of single-cell transcriptome obtained from human lung and airway cells (unpaired two-tailed t-test). Boxplots show the median (central line), the 25–75% interquartile range (IQR) (box limits), the ±1.5 × IQR (whiskers). (n = 25 for young subjects; n = 11 for old subjects) d The positive correlation between plasma MT1-MMP and soluble ACE2 in human plasma (p = 000008, two-tailed; R = 0.4646, n = 43; Spearman’s correlation) Dashed lines represent the 95% confidence interval for the lines of regression presented in the figure. Source data are provided as a Source Data file.
Fig. 6 The positive correlation between MT1-MMP and ACE2 in the elderly. a, b Expression levels of soluble ACE2 and MT1-MMP in the plasma of young human subjects and aged human subjects were measured by ELISA (n = 21 young people & 23 old people) (unpaired two-tailed t-test). The data are shown as the means ± SEM. c Comparison of MMP14 expression levels in young human subjects and elderly human subjects by analysis of single-cell transcriptome obtained from human lung and airway cells (unpaired two-tailed t-test). Boxplots show the median (central line), the 25–75% interquartile range (IQR) (box limits), the ±1.5 × IQR (whiskers). (n = 25 for young subjects; n = 11 for old subjects) d The positive correlation between plasma MT1-MMP and soluble ACE2 in human plasma (p = 000008, two-tailed; R = 0.4646, n = 43; Spearman’s correlation) Dashed lines represent the 95% confidence interval for the lines of regression presented in the figure. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 7 Pharmacological inhibition of MT1-MMP confers protection against SARS-CoV-2 infection in aged mice. a Experimental strategy to study the beneficial effect of MT1-MMP inhibition on SARS-CoV-2 infection in aged mice. b The level of plasma ACE2 in 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 was detected by western blotting (n = 3 for IgG control; n = 3 for 3A2). c The viral loads in the lungs (left) and tracheas (right) from 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 were quantified by qPCR analyses of the SARS-CoV-2 viral genes (n = 5 for IgG control; n = 6 for 3A2). d Immunostaining of SARS-CoV-2 Nucleocapsid Protein (NP) (green) in lung sections of 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2. (n = 5 for IgG control; n = 6 for 3A2) Scale bar: 20 μm. e, f Survival rate and weight changes in 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 (n = 5 for IgG control; n = 6 for 3A2). g Histological examination of lung sections from 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 by hematoxylin and eosin staining (n = 5 for IgG control; n = 6 for 3A2) (Scale bar: 20 μm). h Summary histology scores determined in the lung tissues from 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 (n = 5 for IgG control; n = 6 for 3A2). Data are means ± S.E.M. of three independent repeats. Statistical analyses were performed by unpaired two-tailed t-test for (c, h); one way ANOVA for (f). Source data are provided as a Source Data file.
Fig. 7 Pharmacological inhibition of MT1-MMP confers protection against SARS-CoV-2 infection in aged mice. a Experimental strategy to study the beneficial effect of MT1-MMP inhibition on SARS-CoV-2 infection in aged mice. b The level of plasma ACE2 in 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 was detected by western blotting (n = 3 for IgG control; n = 3 for 3A2). c The viral loads in the lungs (left) and tracheas (right) from 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 were quantified by qPCR analyses of the SARS-CoV-2 viral genes (n = 5 for IgG control; n = 6 for 3A2). d Immunostaining of SARS-CoV-2 Nucleocapsid Protein (NP) (green) in lung sections of 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2. (n = 5 for IgG control; n = 6 for 3A2) Scale bar: 20 μm. e, f Survival rate and weight changes in 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 (n = 5 for IgG control; n = 6 for 3A2). g Histological examination of lung sections from 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 by hematoxylin and eosin staining (n = 5 for IgG control; n = 6 for 3A2) (Scale bar: 20 μm). h Summary histology scores determined in the lung tissues from 3A2/control IgG-treated mice challenged with mouse-adapted SARS-CoV-2 (n = 5 for IgG control; n = 6 for 3A2). Data are means ± S.E.M. of three independent repeats. Statistical analyses were performed by unpaired two-tailed t-test for (c, h); one way ANOVA for (f). Source data are provided as a Source Data file.CC BY · PubMed Central

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Metadata

Authors
Guo, X., Cao, J., Cai, J.-P., Wu, J., Huang, J., Asthana, P., Wong, S. K. K., Ye, Z.-W., Gurung, S., Zhang, Y., Wang, S., Wang, Z., Ge, X., Kwan, H. Y., Lyu, A., Chan, K. M., Wong, N., Huang, J., Zhou, Z., Bian, Z.-X., Yuan, S., & Wong, H. L. X.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-12-23
Volume
13
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-022-35590-x
PMC
PMC9780620
Cited by
25
References
13
Language
en
Licence
Funders
  • Research Grants Council, University Grants Committee (R4017-18, 12101019, 12102020)
  • Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (06170056, 08793626)
  • Natural Science Foundation of Guangdong Province (2021A1515011128)

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