Ameliorative effect of anti-complement factor antibody on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected macaque

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces severe pneumonia and acute respiratory distress syndrome (ARDS), leading to death. Therefore, the therapeutic focus is mainly on respiratory disorders. Recently, it was reported that SARS-CoV-2-infected patients also showed thrombosis through overactivation of coagulation factors, leading to multiple tissue disorders [1,2,3,4]. The coagulation and complement pathways are closely connected (Fig. 1). In addition, complement activation by SARS-CoV-2 infection affected COVID-19 severity and outcomes [5, 6]. Therefore, we hypothesized that SARS-CoV-2 infection occurs via the ACE2 receptor in endothelial cells and induces endothelial cell damage. Damaged endothelial cells secrete clotting factors and stimulate complement pathways. The activation of both complement and coagulation pathways might induce a vicious cycle that involves not only thrombosis but also a cytokine storm (Fig. 2). Thus, the suppression of complement after infection can improve disease progression. In this study, we evaluated the coagulation and complement activation phenotypes of SARS-CoV-2-infected macaques, determined the appropriate anti-complement factor antibody treatment timing, and evaluated the ameliorative effect of our anti-complement factor antibody on COVID-19.

Fig. 1.

Relationship between coagulation, fibrinolysis, and complement pathways.

Fig. 2.

Hypothesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activation on complement pathways leading to the activation of coagulation and fibrinolysis pathways (Red; activated by SARS-CoV-2 infection).

Results

Evaluation of complement, coagulation, and endothelial injury marker phenotypes in SARS-CoV-2-infected macaques

SARS-CoV-2 J (WK-521) [7] was inoculated into macaques. X-ray analysis revealed pneumonia in all infected macaques, and their body temperature increased. Moreover, a decrease in the platelet count and complement factors and an increase in inflammation, coagulation, and endothelial injury markers were observed in the blood. After seven days, pneumonia and lung scarring were observed. There are some limitations to studying SARS-CoV-2 in macaques: they show mild or moderate phenotypes, without a significant decrease in blood oxygen levels, and immediately recovered within one week post-infection. To establish a severe COVID-19 macaque model, additive endothelial injury derived from obesity and injury-related compounds might be needed before SARS-CoV-2 infection. Based on these SARS-CoV-2-infected macaque phenotypes, we decided to treat them with the anti-complement factor antibody after SARS-CoV-2 inoculation. SARS-CoV2 WK521 was inoculated into these macaques, and phosphate-buffered saline (PBS) and the anti-complement factor antibody (n=3 in each group) were administered post-infection. Unfortunately, one PBS-treated macaque died approximately 2 hr after inoculation. Therefore, we compared the results of anti-complement factor antibody between the PBS-treated group (n=2) and anti-complement factor antibody-treated group (n=3) but could not determine statistical significance due to the lack of macaque numbers, which is statistically satisfied, in the PBS-treated group. In conclusion, although only a few SARS-CoV-2-infected macaques were investigated in this study, we observed an ameliorative effect of the anti-complement factor antibody (Fig. 3). Thus, complement suppression could lead to severe human COVID-19 phenotypes (Fig. 4).

Fig. 3.

Amelioration of the COVID-19 phenotype through anti-complement factor antibody treatment.

Fig. 4.

Ameliorative effect of the anti-complement factor antibody on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected macaques.

Animal Studies Ethics

This study was carried out in strict accordance with the Guidelines for the Husbandry and Management of Laboratory Animals of the Research Center for Animal Life Science at the Shiga University of Medical Science and Standards Relating to the Care and Fundamental Guidelines for the Proper Conduct of Animal Experiments and Related Activities in Academic Research Institutions under the jurisdiction of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Potential Conflicts of Interest

The authors have nothing to disclose.

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