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Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2- mediated complement over-activation

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

Research Highlights 

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.

Summary 

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).

Study Type

· 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.

Main limitations:

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.