Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2- mediated complement over-activation
clinical immunology/immunity therapeutics
Authors: Ting Gao….. Cheng Cao Link to paper: https://www.medrxiv.org/content/10.1101/2020.03.29.20041962v2.full.pdf
Journal/ Pre-Print: medRxiv
Key Words: SARS-CoV-2; COVID-19; complement; C5; innate immune
1. The N protein of SARS-CoV-2 interacts with MASP-2 enhancing complement (C4b) deposition.
2. Serum levels of the anaphylatoxin C5a is significantly increased in SARS-CoV2 patients with severe disease compared to mild cases or healthy individuals.
3. Two SARS-CoV2 patients treated with recombinant C5a antibody show clinical improvement form the point of administration.
The authors show the highly homologous N proteins from SARS-CoV, SARS-CoV2 and MERS interact with MASP-2. MASP-2 is a protease critical to complement activation by the lectin pathway. In an in vivo murine infection model the N protein of SARS-CoV expressed from an adenoviral vector enhances LPS induced lung injury; a phenotype lost by blocking N protein: MASP2 interaction and by suppressing complement activation. Serum C5a levels were significantly increased in severe COVID-19 patients. 2 of these COVID-19 patients treated with recombinant anti-C5a antibody show clinical improvement. This indicates that targeting complement pathways offers therapeutic potential for pneumonia induced by coronaviruses.
IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS
Understand the immune response to SARS-CoV2/COVID19
Clinical symptoms and pathogenesis of SARS-Cov2/COVID19
Treatment of SARS-CoV2/COVID19 positive individuals
(antibody therapeutics targeting C5 could potentially be used to treat SARS-CoV2 infection. These are already available in the clinic for example eculizumab although they are very expensive).
· In vitro study
· In vivo study (e.g. mouse, NHP)
· Patient Case study
STRENGTHS AND LIMITATIONS OF THE PAPER
Novelty: SARS-CoV2 enhances the lection pathway of complement activation.
Standing in the field: Previously known SARS-CoV interacts with MAP-19 an alternative splice form of MASP-2.
Appropriate statistics: Broadly yes according to methods. Individual figure legends do not describe tests used on each graph.
Viral model used: Strain SARS-CoV2 N protein cloned from not stated.
Translatability: Yes, but larger clinical cohort needed.
Tissue sections from COVID-19 patients showing enhanced complement deposition are not compared to healthy controls. Only two patients were treated with the C5 targeting antibody and so a larger cohort would be needed to prove it is effective.