Abstract MP43: Liposome-human ACE2 Complex As An Engineered Decoy To Abrogate SARS-CoV-2-induced Inflammatory Responses In Macrophages

Abstract

Introduction: Innate immune cells such as macrophages have been implicated in pathological inflammation in COVID-19 patients. As many immune cells express low levels of human angiotensin-converting enzyme 2 (hACE2), the mechanisms underlying SARS-CoV-2-mediated macrophage inflammatory responses remain elusive. Further, neutralizing SARS-CoV-2 prior to their binding to the host cells was proposed as a therapeutic approach to ameliorate SARS-CoV-2-stimulated inflammation. This study aims to investigate whether an engineered decoy receptor can affect SARS-CoV-2-induced macrophage inflammation. Hypothesis: Liposome-based hACE2 complex acts as a molecular decoy to abrogate SARS-CoV-2-induced macrophage inflammation. Methods: Rhodamine incapsulated liposome-based nanoparticles were used to generated Liposome-human ACE2 complex (Liposome-hACE2). Liposome-hACE2 was used as a decoy receptor or competitive inhibitor to inhibit SARS-CoV-2 or Spike protein-induced macrophage inflammation in vitro and in vivo. Results and Conclusions: SARS-CoV-2 or Spike protein induces strong inflammatory responses in murine macrophages in a hACE2-independent manner. Liposome-hACE2 can efficiently abrogated SARS-CoV-2 or Spike protein-induced inflammatory responses in murine macrophages in vitro and in vivo. Mechanistically, Spike protein stimulated macrophage inflammation by activating canonical IKKβ/NF-κB signaling, and deficiency of IKKβ abolished Spike protein-elicited inflammatory responses in macrophages. The use of Liposome-hACE2 as a molecular decoy was further recapitulated in human macrophages. SARS-CoV-2 or Spike protein-induced inflammatory responses in human peripheral blood mononuclear cells and differentiated THP-1 macrophages were also abolished by Liposome-hACE2 treatment. These results suggest that neutralizing SARS-CoV-2 by liposomes may present an innovative therapeutic strategy treating COVID-19.