Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern

Yu Onodera; Jady Liang; Yuchong Li; Bryan Griffin; Thenuka Thanabalasingam; Cong Lu; Jia Yi Zhu; Mingyao Liu; Theo Moraes; Wenhua Zheng; Jasmin Khateeb; Julie Khang; Yongbo Huang; Mirjana Jerkic; Masaki Nakane; Andrew Baker; Beverley Orser; Ya Wen Chen; Gerald Wirnsberger; Josef M. Penninger; Ori D. Rotstein; Arthur S. Slutsky; Yimin Li; Samira Mubareka; Haibo Zhang

doi:10.1016/j.isci.2023.107470

Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern

Yu Onodera, Jady Liang, Yuchong Li, Bryan Griffin, Thenuka Thanabalasingam, Cong Lu, Jia Yi Zhu, Mingyao Liu, Theo Moraes, Wenhua Zheng, Jasmin Khateeb, Julie Khang, Yongbo Huang, Mirjana Jerkic, Masaki Nakane, Andrew Baker, Beverley Orser, Ya Wen Chen, Gerald Wirnsberger, Josef M. PenningerOri D. Rotstein, Arthur S. Slutsky, Yimin Li, Samira Mubareka, Haibo Zhang

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Abstract

Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. To understand the underlying mechanisms behind this sex-biased difference in disease severity, we infected K18-human angiotensin converting enzyme 2 (ACE2) mice of both sexes with SARS-CoV-2. Our study revealed a unique protein expression profile in the lung microenvironment of female mice. As a result, they were less vulnerable to severe infection, with higher ACE2 expression and a higher estrogen receptor α (ERα)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ERα/AR ratio, thereby protecting the lungs. Our findings suggest that inhaling recombinant ACE2 could serve as a decoy receptor against SARS-CoV-2 and protect male mice by offsetting ERα-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant.

Original language	English
Article number	107470
Journal	iScience
Volume	26
Issue number	8
DOIs	https://doi.org/10.1016/j.isci.2023.107470
State	Published - 18 Aug 2023

Keywords

Biological sciences
Biology of gender
Immune response
Virology

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10.1016/j.isci.2023.107470

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Onodera, Y., Liang, J., Li, Y., Griffin, B., Thanabalasingam, T., Lu, C., Zhu, J. Y., Liu, M., Moraes, T., Zheng, W., Khateeb, J., Khang, J., Huang, Y., Jerkic, M., Nakane, M., Baker, A., Orser, B., Chen, Y. W., Wirnsberger, G., ... Zhang, H. (2023). Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern. iScience, 26(8), Article 107470. https://doi.org/10.1016/j.isci.2023.107470

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title = "Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern",

abstract = "Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. To understand the underlying mechanisms behind this sex-biased difference in disease severity, we infected K18-human angiotensin converting enzyme 2 (ACE2) mice of both sexes with SARS-CoV-2. Our study revealed a unique protein expression profile in the lung microenvironment of female mice. As a result, they were less vulnerable to severe infection, with higher ACE2 expression and a higher estrogen receptor α (ERα)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ERα/AR ratio, thereby protecting the lungs. Our findings suggest that inhaling recombinant ACE2 could serve as a decoy receptor against SARS-CoV-2 and protect male mice by offsetting ERα-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant.",

keywords = "Biological sciences, Biology of gender, Immune response, Virology",

author = "Yu Onodera and Jady Liang and Yuchong Li and Bryan Griffin and Thenuka Thanabalasingam and Cong Lu and Zhu, {Jia Yi} and Mingyao Liu and Theo Moraes and Wenhua Zheng and Jasmin Khateeb and Julie Khang and Yongbo Huang and Mirjana Jerkic and Masaki Nakane and Andrew Baker and Beverley Orser and Chen, {Ya Wen} and Gerald Wirnsberger and Penninger, {Josef M.} and Rotstein, {Ori D.} and Slutsky, {Arthur S.} and Yimin Li and Samira Mubareka and Haibo Zhang",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = aug,

day = "18",

doi = "10.1016/j.isci.2023.107470",

language = "English",

volume = "26",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier Inc.",

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Onodera, Y, Liang, J, Li, Y, Griffin, B, Thanabalasingam, T, Lu, C, Zhu, JY, Liu, M, Moraes, T, Zheng, W, Khateeb, J, Khang, J, Huang, Y, Jerkic, M, Nakane, M, Baker, A, Orser, B, Chen, YW, Wirnsberger, G, Penninger, JM, Rotstein, OD, Slutsky, AS, Li, Y, Mubareka, S & Zhang, H 2023, 'Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern', iScience, vol. 26, no. 8, 107470. https://doi.org/10.1016/j.isci.2023.107470

TY - JOUR

T1 - Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern

AU - Onodera, Yu

AU - Liang, Jady

AU - Li, Yuchong

AU - Griffin, Bryan

AU - Thanabalasingam, Thenuka

AU - Lu, Cong

AU - Zhu, Jia Yi

AU - Liu, Mingyao

AU - Moraes, Theo

AU - Zheng, Wenhua

AU - Khateeb, Jasmin

AU - Khang, Julie

AU - Huang, Yongbo

AU - Jerkic, Mirjana

AU - Nakane, Masaki

AU - Baker, Andrew

AU - Orser, Beverley

AU - Chen, Ya Wen

AU - Wirnsberger, Gerald

AU - Penninger, Josef M.

AU - Rotstein, Ori D.

AU - Slutsky, Arthur S.

AU - Li, Yimin

AU - Mubareka, Samira

AU - Zhang, Haibo

PY - 2023/8/18

Y1 - 2023/8/18

N2 - Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. To understand the underlying mechanisms behind this sex-biased difference in disease severity, we infected K18-human angiotensin converting enzyme 2 (ACE2) mice of both sexes with SARS-CoV-2. Our study revealed a unique protein expression profile in the lung microenvironment of female mice. As a result, they were less vulnerable to severe infection, with higher ACE2 expression and a higher estrogen receptor α (ERα)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ERα/AR ratio, thereby protecting the lungs. Our findings suggest that inhaling recombinant ACE2 could serve as a decoy receptor against SARS-CoV-2 and protect male mice by offsetting ERα-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant.

AB - Despite similar infection rates, COVID-19 has resulted in more deaths in men than women. To understand the underlying mechanisms behind this sex-biased difference in disease severity, we infected K18-human angiotensin converting enzyme 2 (ACE2) mice of both sexes with SARS-CoV-2. Our study revealed a unique protein expression profile in the lung microenvironment of female mice. As a result, they were less vulnerable to severe infection, with higher ACE2 expression and a higher estrogen receptor α (ERα)/androgen receptor (AR) ratio that led to increased antiviral factor levels. In male mice, inhaling recombinant ACE2 neutralized the virus and maintained the ERα/AR ratio, thereby protecting the lungs. Our findings suggest that inhaling recombinant ACE2 could serve as a decoy receptor against SARS-CoV-2 and protect male mice by offsetting ERα-associated protective mechanisms. Additionally, our study supports the potential effectiveness of recombinant ACE2 therapy in human lung organoids infected with the Delta variant.

KW - Biological sciences

KW - Biology of gender

KW - Immune response

KW - Virology

UR - http://www.scopus.com/inward/record.url?scp=85167516312&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2023.107470

DO - 10.1016/j.isci.2023.107470

M3 - Article

AN - SCOPUS:85167516312

SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 8

M1 - 107470

ER -

Inhalation of ACE2 as a therapeutic target on sex-bias differences in SARS-CoV-2 infection and variant of concern

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Keywords

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