Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection.
Feargal J Ryan, Christopher M Hope, Makutiro G Masavuli, Miriam A Lynn, Zelalem A Mekonnen, Arthur Eng Lip Yeow, Pablo Garcia-Valtanen, Zahraa Al-Delfi, Jason Gummow, Catherine Ferguson, Stephanie O'Connor, Benjamin A J Reddi, Pravin Hissaria, David Shaw, Chuan Kok-Lim, Jonathan M Gleadle, Michael R Beard, Simon C Barry, Branka Grubor-Bauk, David J Lynn
Author Information
Feargal J Ryan: Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5001, Australia.
Christopher M Hope: Women's and Children's Health Network, North Adelaide, SA, Australia.
Makutiro G Masavuli: Viral Immunology Group, Adelaide Medical School, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, SA, Australia.
Miriam A Lynn: Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5001, Australia.
Zelalem A Mekonnen: Viral Immunology Group, Adelaide Medical School, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, SA, Australia.
Arthur Eng Lip Yeow: Viral Immunology Group, Adelaide Medical School, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, SA, Australia.
Pablo Garcia-Valtanen: Viral Immunology Group, Adelaide Medical School, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, SA, Australia.
Zahraa Al-Delfi: Viral Immunology Group, Adelaide Medical School, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, SA, Australia.
Jason Gummow: Gene Silencing and Expression Core Facility, Adelaide Health and Medical Sciences, Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
Catherine Ferguson: Infectious Diseases Department, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia.
Stephanie O'Connor: Intensive Care Unit, Royal Adelaide Hospital, Central Adelaide Local Health Network and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
Benjamin A J Reddi: Intensive Care Unit, Royal Adelaide Hospital, Central Adelaide Local Health Network and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
Pravin Hissaria: Infectious Diseases Department, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia.
David Shaw: Infectious Diseases Department, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia.
Chuan Kok-Lim: Infectious Diseases Department, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, SA, Australia.
Jonathan M Gleadle: Department of Renal Medicine, Flinders Medical Centre, Flinders University, Bedford Park, SA, 5042, Australia.
Michael R Beard: Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, SA, 5005, Australia.
Simon C Barry: Women's and Children's Health Network, North Adelaide, SA, Australia. simon.barry@adelaide.edu.au.
Branka Grubor-Bauk: Viral Immunology Group, Adelaide Medical School, University of Adelaide and Basil Hetzel Institute for Translational Health Research, Adelaide, SA, Australia. branka.grubor@adelaide.edu.au.
David J Lynn: Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5001, Australia. david.lynn@sahmri.com.
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious respiratory virus which is responsible for the coronavirus disease 2019 (COVID-19) pandemic. It is increasingly clear that recovered individuals, even those who had mild COVID-19, can suffer from persistent symptoms for many months after infection, a condition referred to as "long COVID", post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. However, despite the plethora of research on COVID-19, relatively little is known about the molecular underpinnings of these long-term effects. METHODS: We have undertaken an integrated analysis of immune responses in blood at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 patients recovering from mild, moderate, severe, or critical COVID-19 in comparison to healthy uninfected controls. Twenty-one of these patients were referred to a long COVID clinic and > 50% reported ongoing symptoms more than 6 months post-infection. RESULTS: Anti-Spike and anti-RBD IgG responses were largely stable up to 24 wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper, and regulatory T cells) in convalescent individuals compared to healthy controls, which were most strongly evident at 12 and 16 wpi. RNA sequencing revealed significant perturbations to gene expression in COVID-19 convalescents until at least 6 months post-infection. We also uncovered significant differences in the transcriptome at 24 wpi of convalescents who were referred to a long COVID clinic compared to those who were not. CONCLUSIONS: Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.
