Frontiers in Immunology (Oct 2022)

Levels of soluble complement regulators predict severity of COVID-19 symptoms

  • Anna L. Tierney,
  • Anna L. Tierney,
  • Wajd Mohammed Alali,
  • Thomas Scott,
  • Karen S. Rees-Unwin,
  • CITIID-NIHR BioResource COVID-19 Collaboration,
  • Simon J. Clark,
  • Simon J. Clark,
  • Simon J. Clark,
  • Richard D. Unwin,
  • Stephen Baker,
  • John Bradley,
  • Patrick Chinnery,
  • Daniel Cooper,
  • Gordon Dougan,
  • Ian Goodfellow,
  • Ravindra Gupta,
  • Nathalie Kingston,
  • Paul J. Lehner,
  • Paul A. Lyons,
  • Nicholas J. Matheson,
  • Caroline Saunders,
  • Kenneth G. C. Smith,
  • Charlotte Summers,
  • James Thaventhiran,
  • M. Estee Torok,
  • Mark R. Toshner,
  • Michael P. Weekes,
  • Gisele Alvio,
  • Sharon Baker,
  • Areti Bermperi,
  • Karen Brookes,
  • Ashlea Bucke,
  • Jo Calder,
  • Laura Canna,
  • Cherry Crucusio,
  • Isabel Cruz,
  • Ranalie de Jesus,
  • Katie Dempsey,
  • Giovanni Di Stephano,
  • Jason Domingo,
  • Anne Elmer,
  • Julie Harris,
  • Sarah Hewitt,
  • Heather Jones,
  • Sherly Jose,
  • Jane Kennet,
  • Yvonne King,
  • Jenny Kourampa,
  • Emily Li,
  • Caroline McMahon,
  • Anne Meadows,
  • Vivien Mendoza,
  • Criona O’Brien,
  • Charmain Ocaya,
  • Ciro Pasquale,
  • Marlyn Perales,
  • Jane Price,
  • Rebecca Rastall,
  • Carla Ribeiro,
  • Jane Rowlands,
  • Valentina Ruffolo,
  • Hugo Tordesillas,
  • Phoebe Vargas,
  • Bensi Vergese,
  • Laura Watson,
  • Jieniean Worsley,
  • Julie-Ann Zerrudo,
  • Laura Bergamashi,
  • Ariana Betancourt,
  • Georgie Bower,
  • Ben Bullman,
  • Chiara Cossetti,
  • Aloka De Sa,
  • Benjamin J. Dunmore,
  • Maddie Epping,
  • Stuart Fawke,
  • Stefan Gräf,
  • Richard Grenfell,
  • Andrew Hinch,
  • Josh Hodgson,
  • Christopher Huang,
  • Oisin Huhn,
  • Kelvin Hunter,
  • Isobel Jarvis,
  • Emma Jones,
  • Maša Josipović,
  • Ekaterina Legchenko,
  • Daniel Lewis,
  • Joe Marsden,
  • Jennifer Martin,
  • Federica Mescia,
  • Ciara O’Donnell,
  • Ommar Omarjee,
  • Marianne Perera,
  • Linda Pointon,
  • Nicole Pond,
  • Nathan Richoz,
  • Nika Romashova,
  • Natalia Savoinykh,
  • Rahul Sharma,
  • Joy Shih,
  • Mateusz Strezlecki,
  • Rachel Sutcliffe,
  • Tobias Tilly,
  • Zhen Tong,
  • Carmen Treacy,
  • Lori Turner,
  • Jennifer Wood,
  • Marta Wylot,
  • John Allison,
  • Heather Biggs,
  • John R. Bradley,
  • Helen Butcher,
  • Daniela Caputo,
  • Matt Chandler,
  • Patrick Chinnery,
  • Debbie Clapham-Riley,
  • Eleanor Dewhurst,
  • Christian Fernandez,
  • Anita Furlong,
  • Barbara Graves,
  • Jennifer Gray,
  • Sabine Hein,
  • Tasmin Ivers,
  • Emma Le Gresley,
  • Rachel Linger,
  • Mary Kasanicki,
  • Rebecca King,
  • Nathalie Kingston,
  • Sarah Meloy,
  • Alexei Moulton,
  • Francesca Muldoon,
  • Nigel Ovington,
  • Sofia Papadia,
  • Christopher J. Penkett,
  • Isabel Phelan,
  • Venkatesh Ranganath,
  • Roxana Paraschiv,
  • Abigail Sage,
  • Jennifer Sambrook,
  • Ingrid Scholtes,
  • Katherine Schon,
  • Hannah Stark,
  • Kathleen E. Stirrups,
  • Paul Townsend,
  • Neil Walker,
  • Jennifer Webster,
  • Mayurun Selvan,
  • Petra Polgarova,
  • Sarah L. Caddy,
  • Laura G. Caller,
  • Yasmin Chaudhry,
  • Martin D. Curran,
  • Theresa Feltwell,
  • Stewart Fuller,
  • Iliana Georgana,
  • Grant Hall,
  • William L. Hamilton,
  • Myra Hosmillo,
  • Charlotte J. Houldcroft,
  • Rhys Izuagbe,
  • Aminu S. Jahun,
  • Fahad A. Khokhar,
  • Anna G. Kovalenko,
  • Luke W. Meredith,
  • Surendra Parmar,
  • Malte L. Pinckert,
  • Anna Yakovleva,
  • Emily C. Horner,
  • Lucy Booth,
  • Alexander Ferreira,
  • Rebecca Boston,
  • Robert Hughes,
  • Juan Carlos Yam Puc,
  • Nonantzin Beristain-Covarrubias,
  • Maria Rust,
  • Thevinya Gurugama,
  • Lihinya Gurugama,
  • Thomas Mulroney,
  • Sarah Spencer,
  • Zhaleh Hosseini,
  • Kate Williamson

DOI
https://doi.org/10.3389/fimmu.2022.1032331
Journal volume & issue
Vol. 13

Abstract

Read online

The SARS-CoV-2 virus continues to cause significant morbidity and mortality worldwide from COVID-19. One of the major challenges of patient management is the broad range of symptoms observed. While the majority of individuals experience relatively mild disease, a significant minority of patients require hospitalisation, with COVID-19 still proving fatal for some. As such, there remains a desperate need to better understand what drives this severe disease, both in terms of the underlying biology, but also to potentially predict at diagnosis which patients are likely to require further interventions, thus enabling better outcomes for both patients and healthcare systems. Several lines of evidence have pointed to dysregulation of the complement cascade as a major factor in severe COVID-19 outcomes. How this is underpinned mechanistically is not known. Here, we have focussed on the role of the soluble complement regulators Complement Factor H (FH), its splice variant Factor H-like 1 (FHL-1) and five Factor H-Related proteins (FHR1-5). Using a targeted mass spectrometry approach, we quantified these proteins in a cohort of 188 plasma samples from controls and SARS-CoV-2 patients taken at diagnosis. This analysis revealed significant elevations in all FHR proteins, but not FH, in patients with more severe disease, particularly FHR2 and FHR5 (FHR2: 1.97-fold, p<0.0001; FHR5: 2.4-fold, p<0.0001). Furthermore, for a subset of 77 SARS-CoV-2 +ve patients we also analysed time course samples taken approximately 28 days post-diagnosis. Here, we see complement regulator levels drop in all individuals with asymptomatic or mild disease, but regulators remain high in those with more severe outcomes, with elevations in FHR2 over baseline levels in this group. These data support the hypothesis that elevation of circulating levels of the FHR family of proteins could predict disease severity in COVID-19 patients, and that the duration of elevation (or lack of immune activation resolution) may be partly responsible for driving poor outcomes in COVID-19.

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