Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

Maritza Puray-Chavez; Kyle M. LaPak; Travis P. Schrank; Jennifer L. Elliott; Dhaval P. Bhatt; Megan J. Agajanian; Ria Jasuja; Dana Q. Lawson; Keanu Davis; Paul W. Rothlauf; Zhuoming Liu; Heejoon Jo; Nakyung Lee; Kasyap Tenneti; Jenna E. Eschbach; Christian Shema Mugisha; Emily M. Cousins; Erica W. Cloer; Hung R. Vuong; Laura A. VanBlargan; Adam L. Bailey; Pavlo Gilchuk; James E. Crowe; Michael S. Diamond; D. Neil Hayes; Sean P.J. Whelan; Amjad Horani; Steven L. Brody; Dennis Goldfarb; M. Ben Major; Sebla B. Kutluay

doi:10.1016/j.celrep.2021.109364

Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

Maritza Puray-Chavez, Kyle M. LaPak, Travis P. Schrank, Jennifer L. Elliott, Dhaval P. Bhatt, Megan J. Agajanian, Ria Jasuja, Dana Q. Lawson, Keanu Davis, Paul W. Rothlauf, Zhuoming Liu, Heejoon Jo, Nakyung Lee, Kasyap Tenneti, Jenna E. Eschbach, Christian Shema Mugisha, Emily M. Cousins, Erica W. Cloer, Hung R. Vuong, Laura A. VanBlarganAdam L. Bailey, Pavlo Gilchuk, James E. Crowe, Michael S. Diamond, D. Neil Hayes, Sean P.J. Whelan, Amjad Horani, Steven L. Brody, Dennis Goldfarb, M. Ben Major, Sebla B. Kutluay

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97 Scopus citations

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type I interferon signaling. These findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.

Original language	English
Article number	109364
Journal	Cell Reports
Volume	36
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2021.109364
State	Published - Jul 13 2021

Keywords

ACE2-independent
COVID-19
RIG-I-like receptors
SARS-CoV-2
clathrin-mediated endocytosis
heparan sulfate
proteomics
spike variants
type I interferon
virus-host interactions

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10.1016/j.celrep.2021.109364

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Puray-Chavez, M., LaPak, K. M., Schrank, T. P., Elliott, J. L., Bhatt, D. P., Agajanian, M. J., Jasuja, R., Lawson, D. Q., Davis, K., Rothlauf, P. W., Liu, Z., Jo, H., Lee, N., Tenneti, K., Eschbach, J. E., Shema Mugisha, C., Cousins, E. M., Cloer, E. W., Vuong, H. R., ... Kutluay, S. B. (2021). Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell. Cell Reports, 36(2), Article 109364. https://doi.org/10.1016/j.celrep.2021.109364

@article{37bbdc9a1529417cb980fab26dabd4b6,

title = "Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell",

abstract = "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type I interferon signaling. These findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.",

keywords = "ACE2-independent, COVID-19, RIG-I-like receptors, SARS-CoV-2, clathrin-mediated endocytosis, heparan sulfate, proteomics, spike variants, type I interferon, virus-host interactions",

author = "Maritza Puray-Chavez and LaPak, {Kyle M.} and Schrank, {Travis P.} and Elliott, {Jennifer L.} and Bhatt, {Dhaval P.} and Agajanian, {Megan J.} and Ria Jasuja and Lawson, {Dana Q.} and Keanu Davis and Rothlauf, {Paul W.} and Zhuoming Liu and Heejoon Jo and Nakyung Lee and Kasyap Tenneti and Eschbach, {Jenna E.} and {Shema Mugisha}, Christian and Cousins, {Emily M.} and Cloer, {Erica W.} and Vuong, {Hung R.} and VanBlargan, {Laura A.} and Bailey, {Adam L.} and Pavlo Gilchuk and Crowe, {James E.} and Diamond, {Michael S.} and Hayes, {D. Neil} and Whelan, {Sean P.J.} and Amjad Horani and Brody, {Steven L.} and Dennis Goldfarb and Major, {M. Ben} and Kutluay, {Sebla B.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = jul,

day = "13",

doi = "10.1016/j.celrep.2021.109364",

language = "English",

volume = "36",

journal = "Cell Reports",

issn = "2639-1856",

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Puray-Chavez, M, LaPak, KM, Schrank, TP, Elliott, JL, Bhatt, DP, Agajanian, MJ, Jasuja, R, Lawson, DQ, Davis, K, Rothlauf, PW, Liu, Z, Jo, H, Lee, N, Tenneti, K, Eschbach, JE, Shema Mugisha, C, Cousins, EM, Cloer, EW, Vuong, HR, VanBlargan, LA, Bailey, AL, Gilchuk, P, Crowe, JE, Diamond, MS, Hayes, DN, Whelan, SPJ , Horani, A, Brody, SL, Goldfarb, D , Major, MB & Kutluay, SB 2021, 'Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell', Cell Reports, vol. 36, no. 2, 109364. https://doi.org/10.1016/j.celrep.2021.109364

TY - JOUR

T1 - Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

AU - Puray-Chavez, Maritza

AU - LaPak, Kyle M.

AU - Schrank, Travis P.

AU - Elliott, Jennifer L.

AU - Bhatt, Dhaval P.

AU - Agajanian, Megan J.

AU - Jasuja, Ria

AU - Lawson, Dana Q.

AU - Davis, Keanu

AU - Rothlauf, Paul W.

AU - Liu, Zhuoming

AU - Jo, Heejoon

AU - Lee, Nakyung

AU - Tenneti, Kasyap

AU - Eschbach, Jenna E.

AU - Shema Mugisha, Christian

AU - Cousins, Emily M.

AU - Cloer, Erica W.

AU - Vuong, Hung R.

AU - VanBlargan, Laura A.

AU - Bailey, Adam L.

AU - Gilchuk, Pavlo

AU - Crowe, James E.

AU - Diamond, Michael S.

AU - Hayes, D. Neil

AU - Whelan, Sean P.J.

AU - Horani, Amjad

AU - Brody, Steven L.

AU - Goldfarb, Dennis

AU - Major, M. Ben

AU - Kutluay, Sebla B.

PY - 2021/7/13

Y1 - 2021/7/13

N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type I interferon signaling. These findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.

AB - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type I interferon signaling. These findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.

KW - ACE2-independent

KW - COVID-19

KW - RIG-I-like receptors

KW - SARS-CoV-2

KW - clathrin-mediated endocytosis

KW - heparan sulfate

KW - proteomics

KW - spike variants

KW - type I interferon

KW - virus-host interactions

UR - http://www.scopus.com/inward/record.url?scp=85109439930&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.109364

DO - 10.1016/j.celrep.2021.109364

M3 - Article

C2 - 34214467

AN - SCOPUS:85109439930

SN - 2639-1856

VL - 36

JO - Cell Reports

JF - Cell Reports

IS - 2

M1 - 109364

ER -

Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

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