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

Abstract

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.

Unbiased plasma profiling using pre-selected RNA aptamer pools predicts mortality in COVID-19 and identifies protein risk factors

“… 29 Complement dysregulation is reported to be central in COVID-19 pathophysiology. 30 , 31 In line with this, the plasma concentration of factor H is reported to be increased by 2-fold in ICU patients compared to non-ICU patients. 32 In addition to complement factor H, the factor H protein family consists of 6 other highly homologous proteins controlling the complement alternative pathway associated with susceptibility to various diseases.…”

The human factor H protein family – an update

“…In a recent study, serum levels of all FH family proteins in COVID-19 patients and controls were quantified using a targeted mass spectrometry approach; while no elevation in FH level was found, the serum levels of all other FH protein family members were increased, with FHR-2 and FHR-5 showing the highest elevation in severe COVID cases compared to controls ( 230 ). The authors raised the hypothesis that the elevated circulating FHR levels could predict disease severity of COVID-19 patients ( 230 ). These studies suggest that complement dysregulation associated with SARS-CoV-2 infection involves the disbalance among FH family proteins.…”

Control of complement-induced inflammatory responses to SARS-CoV-2 infection by anti-SARS-CoV-2 antibodies

“…The complement system constitutes an important innate immune response and acts as a first line of defense against viruses and might have a critical role in COVID-19 pathogenesis (Afzali et al, 2022 ; Lim et al, 2023 ; Tierney et al, 2022 ; Yu et al, 2022 ). Complement activation limits SARS-CoV-2 infection but uncontrolled activity leads to aberrant inflammatory responses observed during severe COVID-19 (Afzali et al, 2022 ; Ma et al, 2021 ; Mastellos et al, 2020 ).…”