ACE2 nanoparticles prevent cell entry of SARS-CoV-2 (preprint)

We have now been in the grip of the COVID-19 pandemic for over two years with devastating consequences. The continual evolution of the virus has challenged the efficacy of many vaccines and treatment options based on immunotherapies are compromised by this viral escape. One treatment strategy that averts viral escape is the use of constructs based on its entry receptor Angiotensin-Converting Enzyme 2 (ACE2) acting as decoys. Here, we combined full-length human ACE2 with viral vectors commonly used for gene therapy to form nanoparticles that present ACE2 on their surface analogous to human cells. Using cell-based assays and direct, multiscale imaging including cryogenic cellular tomography, we show that these ACE2 nanoparticles are highly efficient in preventing entry of SARS-CoV-2, the virus causing COVID-19, in model cell systems as well as human respiratory tract ex-vivo cultures. Thus, ACE2 nanoparticles have high potential as the next generation therapeutics for addressing the immediate needs of the current pandemic and possible future outbreaks.

Tropism of the Novel Coronavirus SARS-CoV-2 in Human Respiratory Tract: An Analysis in Ex Vivo and In Vitro Cultures (preprint)

Background: A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, to cause a respiratory disease (COVID-19) of varying severity in Wuhan China, subsequently spreading to other parts of China and beyond. Methods: We infected ex vivo explant cultures of the human conjunctiva, bronchus and lung, and in vitro cultures of primary human alveolar epithelial cells and macrophages with SARS-CoV-2, and assessed viral tropism, replication competence and innate immune responses, in comparison with SARS-CoV, MERS-CoV, and the 2009 pandemic influenza H1N1 (pdmH1N1) virus.Findings: SARS-CoV-2 infected ciliated, mucus secreting and club cells of bronchial epithelium, spindled morphologically type I pneumocytes in the lung, and the conjunctival mucosa. Virus replication competence of SARS-CoV-2 in the bronchus was higher than that of SARS-CoV but lower than pdmH1N1. SARS-CoV-2 replication was comparable with SARS-CoV and pdmH1N1 in the lung but was lower than MERS-CoV. SARS-CoV-2 virus was a less potent inducer of pro-inflammatory cytokines compared with H5N1 and MERS-CoV. Influenza virus infection of alveolar epithelial cells increased ACE2 expression.Interpretation: The conjunctival epithelium and the conducting airways appear to be potential portals of infection of SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated comparably in the alveolar epithelium explaining the progression of infection to a primary viral pneumonia.Funding Statement: US National Institute of Allergy and Infectious Diseases (NIAID) under Centers of Excellence for Influenza Research and Surveillance (CEIRS) contract no. HHSN272201400006C and the Theme Based Research Scheme (Ref: T11-705/14N), Hong Kong Special Administrative Region.Declaration of Interests: There is no conflict of interest for all authors.Ethics Approval Statement: All experiments were carried out in a Bio-safety level 3 (BSL-3) facility. Informed consent was obtained from all subjects and approval was granted by the Institutional Review Board (IRB) of the University of Hong Kong and the Hospital Authority (Hong Kong West) (approval no: UW 20-167).