Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses

Jordan A. Hartmann; Marcella R. Cardoso; Maria Cecilia Ramiro Talarico; Devin J. Kenney; Madison R. Leone; Dagny C. Reese; Jacquelyn Turcinovic; Aoife K. O'Connell; Hans P. Gertje; Caitlin Marino; Pedro E. Ojeda; Erich V. De Paula; Fernanda A. Orsi; Licio Augusto Velloso; Thomas R. Cafiero; John H. Connor; Alexander Ploss; Angelique Hoelzemer; Mary Carrington; Amy K. Barczak; Nicholas A. Crossland; Florian Douam; Julie Boucau; Wilfredo F. Garcia-Beltran

doi:10.1016/j.cell.2024.03.026

Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses

Jordan A. Hartmann, Marcella R. Cardoso, Maria Cecilia Ramiro Talarico, Devin J. Kenney, Madison R. Leone, Dagny C. Reese, Jacquelyn Turcinovic, Aoife K. O'Connell, Hans P. Gertje, Caitlin Marino, Pedro E. Ojeda, Erich V. De Paula, Fernanda A. Orsi, Licio Augusto Velloso, Thomas R. Cafiero, John H. Connor, Alexander Ploss, Angelique Hoelzemer, Mary Carrington, Amy K. BarczakNicholas A. Crossland, Florian Douam, Julie Boucau, Wilfredo F. Garcia-Beltran

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.

Original language	English (US)
Pages (from-to)	2393-2410.e14
Journal	Cell
Volume	187
Issue number	10
DOIs	https://doi.org/10.1016/j.cell.2024.03.026
State	Published - May 9 2024

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

Keywords

COVID-19
MIC-A/B
NK cells
NKG2D
SARS-CoV-2
cytotoxic
lymphocytes
sarbecoviruses

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10.1016/j.cell.2024.03.026

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Hartmann, J. A., Cardoso, M. R., Talarico, M. C. R., Kenney, D. J., Leone, M. R., Reese, D. C., Turcinovic, J., O'Connell, A. K., Gertje, H. P., Marino, C., Ojeda, P. E., De Paula, E. V., Orsi, F. A., Velloso, L. A., Cafiero, T. R., Connor, J. H., Ploss, A., Hoelzemer, A., Carrington, M., ... Garcia-Beltran, W. F. (2024). Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses. Cell, 187(10), 2393-2410.e14. https://doi.org/10.1016/j.cell.2024.03.026

@article{ececba7810da4984bca18e5d31859f0b,

title = "Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses",

abstract = "SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.",

keywords = "COVID-19, MIC-A/B, NK cells, NKG2D, SARS-CoV-2, cytotoxic, lymphocytes, sarbecoviruses",

author = "Hartmann, {Jordan A.} and Cardoso, {Marcella R.} and Talarico, {Maria Cecilia Ramiro} and Kenney, {Devin J.} and Leone, {Madison R.} and Reese, {Dagny C.} and Jacquelyn Turcinovic and O'Connell, {Aoife K.} and Gertje, {Hans P.} and Caitlin Marino and Ojeda, {Pedro E.} and {De Paula}, {Erich V.} and Orsi, {Fernanda A.} and Velloso, {Licio Augusto} and Cafiero, {Thomas R.} and Connor, {John H.} and Alexander Ploss and Angelique Hoelzemer and Mary Carrington and Barczak, {Amy K.} and Crossland, {Nicholas A.} and Florian Douam and Julie Boucau and Garcia-Beltran, {Wilfredo F.}",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2024",

month = may,

day = "9",

doi = "10.1016/j.cell.2024.03.026",

language = "English (US)",

volume = "187",

pages = "2393--2410.e14",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

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Hartmann, JA, Cardoso, MR, Talarico, MCR, Kenney, DJ, Leone, MR, Reese, DC, Turcinovic, J, O'Connell, AK, Gertje, HP, Marino, C, Ojeda, PE, De Paula, EV, Orsi, FA, Velloso, LA, Cafiero, TR, Connor, JH, Ploss, A, Hoelzemer, A, Carrington, M, Barczak, AK, Crossland, NA, Douam, F, Boucau, J & Garcia-Beltran, WF 2024, 'Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses', Cell, vol. 187, no. 10, pp. 2393-2410.e14. https://doi.org/10.1016/j.cell.2024.03.026

TY - JOUR

T1 - Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses

AU - Hartmann, Jordan A.

AU - Cardoso, Marcella R.

AU - Talarico, Maria Cecilia Ramiro

AU - Kenney, Devin J.

AU - Leone, Madison R.

AU - Reese, Dagny C.

AU - Turcinovic, Jacquelyn

AU - O'Connell, Aoife K.

AU - Gertje, Hans P.

AU - Marino, Caitlin

AU - Ojeda, Pedro E.

AU - De Paula, Erich V.

AU - Orsi, Fernanda A.

AU - Velloso, Licio Augusto

AU - Cafiero, Thomas R.

AU - Connor, John H.

AU - Ploss, Alexander

AU - Hoelzemer, Angelique

AU - Carrington, Mary

AU - Barczak, Amy K.

AU - Crossland, Nicholas A.

AU - Douam, Florian

AU - Boucau, Julie

AU - Garcia-Beltran, Wilfredo F.

PY - 2024/5/9

Y1 - 2024/5/9

N2 - SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.

AB - SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.

KW - COVID-19

KW - MIC-A/B

KW - NK cells

KW - NKG2D

KW - SARS-CoV-2

KW - cytotoxic

KW - lymphocytes

KW - sarbecoviruses

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UR - http://www.scopus.com/inward/citedby.url?scp=85192193649&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2024.03.026

DO - 10.1016/j.cell.2024.03.026

M3 - Article

C2 - 38653235

AN - SCOPUS:85192193649

SN - 0092-8674

VL - 187

SP - 2393-2410.e14

JO - Cell

JF - Cell

IS - 10

ER -

Evasion of NKG2D-mediated cytotoxic immunity by sarbecoviruses

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