SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity

Wuji Zhang; Brendon Y. Chua; Kevin J. Selva; Lukasz Kedzierski; Thomas M. Ashhurst; Ebene R. Haycroft; Suzanne K. Shoffner-Beck; Luca Hensen; David F. Boyd; Fiona James; Effie Mouhtouris; Jason C. Kwong; Kyra Y.L. Chua; George Drewett; Ana Copaescu; Julie E. Dobson; Louise C. Rowntree; Jennifer R. Habel; Lilith F. Allen; Hui Fern Koay; Jessica A. Neil; Matthew J. Gartner; Christina Y. Lee; Patiyan Andersson; Sadid F. Khan; Luke Blakeway; Jessica Wisniewski; James H. McMahon; Erica E. Vine; Anthony L. Cunningham; Jennifer Audsley; Irani Thevarajan; Torsten Seemann; Norelle L. Sherry; Fatima Amanat; Florian Krammer; Sarah L. Londrigan; Linda M. Wakim; Nicholas J.C. King; Dale I. Godfrey; Laura K. Mackay; Paul G. Thomas; Suellen Nicholson; Kelly B. Arnold; Amy W. Chung; Natasha E. Holmes; Olivia C. Smibert; Jason A. Trubiano; Claire L. Gordon; Thi H.O. Nguyen; Katherine Kedzierska

doi:10.1038/s41467-022-30088-y

SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity

Wuji Zhang, Brendon Y. Chua, Kevin J. Selva, Lukasz Kedzierski, Thomas M. Ashhurst, Ebene R. Haycroft, Suzanne K. Shoffner-Beck, Luca Hensen, David F. Boyd, Fiona James, Effie Mouhtouris, Jason C. Kwong, Kyra Y.L. Chua, George Drewett, Ana Copaescu, Julie E. Dobson, Louise C. Rowntree, Jennifer R. Habel, Lilith F. Allen, Hui Fern KoayJessica A. Neil, Matthew J. Gartner, Christina Y. Lee, Patiyan Andersson, Sadid F. Khan, Luke Blakeway, Jessica Wisniewski, James H. McMahon, Erica E. Vine, Anthony L. Cunningham, Jennifer Audsley, Irani Thevarajan, Torsten Seemann, Norelle L. Sherry, Fatima Amanat, Florian Krammer, Sarah L. Londrigan, Linda M. Wakim, Nicholas J.C. King, Dale I. Godfrey, Laura K. Mackay, Paul G. Thomas, Suellen Nicholson, Kelly B. Arnold, Amy W. Chung, Natasha E. Holmes, Olivia C. Smibert, Jason A. Trubiano, Claire L. Gordon, Thi H.O. Nguyen, Katherine Kedzierska

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

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Abstract

Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory samples from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory samples and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory samples, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory samples and blood, and shows how drug therapy affects immune responses during COVID-19.

Original language	English
Article number	2774
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30088-y
State	Published - Dec 2022

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Zhang, W., Chua, B. Y., Selva, K. J., Kedzierski, L., Ashhurst, T. M., Haycroft, E. R., Shoffner-Beck, S. K., Hensen, L., Boyd, D. F., James, F., Mouhtouris, E., Kwong, J. C., Chua, K. Y. L., Drewett, G., Copaescu, A., Dobson, J. E., Rowntree, L. C., Habel, J. R., Allen, L. F., ... Kedzierska, K. (2022). SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity. Nature Communications, 13(1), Article 2774. https://doi.org/10.1038/s41467-022-30088-y

@article{fd1c50d11d3b489e861de7f26d036fb4,

title = "SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity",

abstract = "Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory samples from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory samples and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory samples, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory samples and blood, and shows how drug therapy affects immune responses during COVID-19.",

author = "Wuji Zhang and Chua, {Brendon Y.} and Selva, {Kevin J.} and Lukasz Kedzierski and Ashhurst, {Thomas M.} and Haycroft, {Ebene R.} and Shoffner-Beck, {Suzanne K.} and Luca Hensen and Boyd, {David F.} and Fiona James and Effie Mouhtouris and Kwong, {Jason C.} and Chua, {Kyra Y.L.} and George Drewett and Ana Copaescu and Dobson, {Julie E.} and Rowntree, {Louise C.} and Habel, {Jennifer R.} and Allen, {Lilith F.} and Koay, {Hui Fern} and Neil, {Jessica A.} and Gartner, {Matthew J.} and Lee, {Christina Y.} and Patiyan Andersson and Khan, {Sadid F.} and Luke Blakeway and Jessica Wisniewski and McMahon, {James H.} and Vine, {Erica E.} and Cunningham, {Anthony L.} and Jennifer Audsley and Irani Thevarajan and Torsten Seemann and Sherry, {Norelle L.} and Fatima Amanat and Florian Krammer and Londrigan, {Sarah L.} and Wakim, {Linda M.} and King, {Nicholas J.C.} and Godfrey, {Dale I.} and Mackay, {Laura K.} and Thomas, {Paul G.} and Suellen Nicholson and Arnold, {Kelly B.} and Chung, {Amy W.} and Holmes, {Natasha E.} and Smibert, {Olivia C.} and Trubiano, {Jason A.} and Gordon, {Claire L.} and Nguyen, {Thi H.O.} and Katherine Kedzierska",

note = "Funding Information: We acknowledge all DRASTIC (The use of cytokines as a preDictoR of disease Severity in criTically Ill COVID-19) investigators from Austin Health, and thank the participants involved. This project obtained samples from the COVID-19 Biobank based at the Alfred Hospital and acknowledge all its investigators and the participants who contributed samples. We acknowledge Janine Roney{\textquoteright}s support for this work and funding from the Lord Mayor{\textquoteright}s Charitable Foundation and the Ray William Houston Trust. This research included samples and data from the Sentinel Travelers Research Preparedness Platform for Emerging Infectious Diseases (SETREP-ID). We acknowledge all SETREP-ID investigators and sites, and thank all participants involved. The authors thank Barbara Scher for setting up the ethics and governance for the SETREP-ID platform and the Australian Partnership for Preparedness Research for Infectious Disease Emergencies (APPRISE) for ongoing funding of SETREP-ID, Ajantha Rhodes, Judy Chang, Ashanti Dantanarayana and Rosalyn Cao who contributed to the SETREP-ID biobank. SETREP-ID is supported by funding through the National Health and Medical Research Council Centre of Research Excellence (NHMRC CRE), the Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE AppID 1116530). Funding Information: We acknowledge all DRASTIC (The use of cytokines as a preDictoR of disease Severity in criTically Ill COVID-19) investigators from Austin Health, and thank the participants involved. This project obtained samples from the COVID-19 Biobank based at the Alfred Hospital and acknowledge all its investigators and the participants who contributed samples. We acknowledge Janine Roney{\textquoteright}s support for this work and funding from the Lord Mayor{\textquoteright}s Charitable Foundation and the Ray William Houston Trust. This research included samples and data from the Sentinel Travelers Research Preparedness Platform for Emerging Infectious Diseases (SETREP-ID). We acknowledge all SETREP-ID investigators and sites, and thank all participants involved. The authors thank Barbara Scher for setting up the ethics and governance for the SETREP-ID platform and the Australian Partnership for Preparedness Research for Infectious Disease Emergencies (APPRISE) for ongoing funding of SETREP-ID, Ajantha Rhodes, Judy Chang, Ashanti Dantanarayana and Rosalyn Cao who contributed to the SETREP-ID biobank. SETREP-ID is supported by funding through the National Health and Medical Research Council Centre of Research Excellence (NHMRC CRE), the Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE AppID 1116530), the Snow Medical Foundation, the Jack Ma Foundation and the A2 Milk Company. We thank Austin Health Foundation for support of the study. We acknowledge Francesca L. Mordant and Kanta Subbarao for their contributions to the microneutralization assay. We acknowledge Adam K. Wheatley for kindly providing SARS-CoV-2 and HKU-1 spike trimers and Bruce D. Wines and P. Mark Hogarth for kindly providing FcγR dimers. The RBD proteins were produced under HHSN272201400008C and obtained through BEI Resources, NIAID, NIH: Spike Glycoprotein RBD from SARS-Related Coronavirus 2, Wuhan-Hu-1 with C-Terminal Histidine Tag, Recombinant from HEK293F Cells, NR-52366. We thank the staff at the diagnostic microbiology laboratories at Austin Pathology, Melbourne Pathology, Dorevitch Pathology, 4Cyte Pathology, Microbiological Diagnostic Unit Public Health Laboratory, Northern Pathology Victoria, Eastern Health Pathology for performing initial diagnostic testing for the detection of SARS-CoV-2 nucleic acid. We acknowledge Bridie Clemens for reviewing our manuscript. This work was supported by the NHMRC Leadership Investigator Grant to KK (#1173871), Research Grants Council of the Hong Kong Special Administrative Region, China (#T11-712/19-N) to KK, the MRFF Award (#1202445) to KK and AWC, NIH contract CIVC-HRP (HHS-NIH-NIAID-BAA2018) to PGT and KK, NHMRC Senior Principal Research Fellowship (#1117766) to DIG, NHMRC Emerging Leadership Level 1 Investigator Grant to THON (#1194036) and NHMRC Early Career Fellowships to HFK (#1160333), CLG (#1160963) and JAT (#1139902). PGT is supported by NIH NIAID R01 AI136514-03 and ALSAC at St. Jude. WZ and JRH are supported by the Melbourne Research Scholarship from The University of Melbourne. LH is supported by the Melbourne International Research Scholarship (MIRS) and the Melbourne International Fee Remission Scholarship (MIFRS) from The University of Melbourne. We acknowledge the Melbourne Cytometry Platform (Peter Doherty Institute and Melbourne Brain Centre nodes) for provision of flow cytometry services. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-30088-y",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Zhang, W, Chua, BY, Selva, KJ, Kedzierski, L, Ashhurst, TM, Haycroft, ER, Shoffner-Beck, SK, Hensen, L, Boyd, DF, James, F, Mouhtouris, E, Kwong, JC, Chua, KYL, Drewett, G, Copaescu, A, Dobson, JE, Rowntree, LC, Habel, JR, Allen, LF, Koay, HF, Neil, JA, Gartner, MJ, Lee, CY, Andersson, P, Khan, SF, Blakeway, L, Wisniewski, J, McMahon, JH, Vine, EE, Cunningham, AL, Audsley, J, Thevarajan, I, Seemann, T, Sherry, NL, Amanat, F, Krammer, F, Londrigan, SL, Wakim, LM, King, NJC, Godfrey, DI, Mackay, LK, Thomas, PG, Nicholson, S, Arnold, KB, Chung, AW, Holmes, NE, Smibert, OC, Trubiano, JA, Gordon, CL, Nguyen, THO & Kedzierska, K 2022, 'SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity', Nature Communications, vol. 13, no. 1, 2774. https://doi.org/10.1038/s41467-022-30088-y

TY - JOUR

T1 - SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity

AU - Zhang, Wuji

AU - Chua, Brendon Y.

AU - Selva, Kevin J.

AU - Kedzierski, Lukasz

AU - Ashhurst, Thomas M.

AU - Haycroft, Ebene R.

AU - Shoffner-Beck, Suzanne K.

AU - Hensen, Luca

AU - Boyd, David F.

AU - James, Fiona

AU - Mouhtouris, Effie

AU - Kwong, Jason C.

AU - Chua, Kyra Y.L.

AU - Drewett, George

AU - Copaescu, Ana

AU - Dobson, Julie E.

AU - Rowntree, Louise C.

AU - Habel, Jennifer R.

AU - Allen, Lilith F.

AU - Koay, Hui Fern

AU - Neil, Jessica A.

AU - Gartner, Matthew J.

AU - Lee, Christina Y.

AU - Andersson, Patiyan

AU - Khan, Sadid F.

AU - Blakeway, Luke

AU - Wisniewski, Jessica

AU - McMahon, James H.

AU - Vine, Erica E.

AU - Cunningham, Anthony L.

AU - Audsley, Jennifer

AU - Thevarajan, Irani

AU - Seemann, Torsten

AU - Sherry, Norelle L.

AU - Amanat, Fatima

AU - Krammer, Florian

AU - Londrigan, Sarah L.

AU - Wakim, Linda M.

AU - King, Nicholas J.C.

AU - Godfrey, Dale I.

AU - Mackay, Laura K.

AU - Thomas, Paul G.

AU - Nicholson, Suellen

AU - Arnold, Kelly B.

AU - Chung, Amy W.

AU - Holmes, Natasha E.

AU - Smibert, Olivia C.

AU - Trubiano, Jason A.

AU - Gordon, Claire L.

AU - Nguyen, Thi H.O.

AU - Kedzierska, Katherine

N1 - Funding Information: We acknowledge all DRASTIC (The use of cytokines as a preDictoR of disease Severity in criTically Ill COVID-19) investigators from Austin Health, and thank the participants involved. This project obtained samples from the COVID-19 Biobank based at the Alfred Hospital and acknowledge all its investigators and the participants who contributed samples. We acknowledge Janine Roney’s support for this work and funding from the Lord Mayor’s Charitable Foundation and the Ray William Houston Trust. This research included samples and data from the Sentinel Travelers Research Preparedness Platform for Emerging Infectious Diseases (SETREP-ID). We acknowledge all SETREP-ID investigators and sites, and thank all participants involved. The authors thank Barbara Scher for setting up the ethics and governance for the SETREP-ID platform and the Australian Partnership for Preparedness Research for Infectious Disease Emergencies (APPRISE) for ongoing funding of SETREP-ID, Ajantha Rhodes, Judy Chang, Ashanti Dantanarayana and Rosalyn Cao who contributed to the SETREP-ID biobank. SETREP-ID is supported by funding through the National Health and Medical Research Council Centre of Research Excellence (NHMRC CRE), the Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE AppID 1116530). Funding Information: We acknowledge all DRASTIC (The use of cytokines as a preDictoR of disease Severity in criTically Ill COVID-19) investigators from Austin Health, and thank the participants involved. This project obtained samples from the COVID-19 Biobank based at the Alfred Hospital and acknowledge all its investigators and the participants who contributed samples. We acknowledge Janine Roney’s support for this work and funding from the Lord Mayor’s Charitable Foundation and the Ray William Houston Trust. This research included samples and data from the Sentinel Travelers Research Preparedness Platform for Emerging Infectious Diseases (SETREP-ID). We acknowledge all SETREP-ID investigators and sites, and thank all participants involved. The authors thank Barbara Scher for setting up the ethics and governance for the SETREP-ID platform and the Australian Partnership for Preparedness Research for Infectious Disease Emergencies (APPRISE) for ongoing funding of SETREP-ID, Ajantha Rhodes, Judy Chang, Ashanti Dantanarayana and Rosalyn Cao who contributed to the SETREP-ID biobank. SETREP-ID is supported by funding through the National Health and Medical Research Council Centre of Research Excellence (NHMRC CRE), the Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE AppID 1116530), the Snow Medical Foundation, the Jack Ma Foundation and the A2 Milk Company. We thank Austin Health Foundation for support of the study. We acknowledge Francesca L. Mordant and Kanta Subbarao for their contributions to the microneutralization assay. We acknowledge Adam K. Wheatley for kindly providing SARS-CoV-2 and HKU-1 spike trimers and Bruce D. Wines and P. Mark Hogarth for kindly providing FcγR dimers. The RBD proteins were produced under HHSN272201400008C and obtained through BEI Resources, NIAID, NIH: Spike Glycoprotein RBD from SARS-Related Coronavirus 2, Wuhan-Hu-1 with C-Terminal Histidine Tag, Recombinant from HEK293F Cells, NR-52366. We thank the staff at the diagnostic microbiology laboratories at Austin Pathology, Melbourne Pathology, Dorevitch Pathology, 4Cyte Pathology, Microbiological Diagnostic Unit Public Health Laboratory, Northern Pathology Victoria, Eastern Health Pathology for performing initial diagnostic testing for the detection of SARS-CoV-2 nucleic acid. We acknowledge Bridie Clemens for reviewing our manuscript. This work was supported by the NHMRC Leadership Investigator Grant to KK (#1173871), Research Grants Council of the Hong Kong Special Administrative Region, China (#T11-712/19-N) to KK, the MRFF Award (#1202445) to KK and AWC, NIH contract CIVC-HRP (HHS-NIH-NIAID-BAA2018) to PGT and KK, NHMRC Senior Principal Research Fellowship (#1117766) to DIG, NHMRC Emerging Leadership Level 1 Investigator Grant to THON (#1194036) and NHMRC Early Career Fellowships to HFK (#1160333), CLG (#1160963) and JAT (#1139902). PGT is supported by NIH NIAID R01 AI136514-03 and ALSAC at St. Jude. WZ and JRH are supported by the Melbourne Research Scholarship from The University of Melbourne. LH is supported by the Melbourne International Research Scholarship (MIRS) and the Melbourne International Fee Remission Scholarship (MIFRS) from The University of Melbourne. We acknowledge the Melbourne Cytometry Platform (Peter Doherty Institute and Melbourne Brain Centre nodes) for provision of flow cytometry services. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory samples from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory samples and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory samples, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory samples and blood, and shows how drug therapy affects immune responses during COVID-19.

AB - Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory samples from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory samples and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory samples, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory samples and blood, and shows how drug therapy affects immune responses during COVID-19.

UR - http://www.scopus.com/inward/record.url?scp=85130320222&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-30088-y

DO - 10.1038/s41467-022-30088-y

M3 - Article

C2 - 35589689

AN - SCOPUS:85130320222

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2774

ER -

SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity

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