Protecting mucosal innate immunity against SARS-CoV-2 variant of concern

The current SARS-CoV-2 Omicron variant is distinct, compared to parental SARS-CoV-2 and other variant of concern (VOC), in at least two notable extents: 1) is a master of immune evasion but maintains robust angiotensin-converting enzyme 2 (ACE2) binding; and 2) depends more on cell endocytic pathway than other VOC to promote cell entry, leading to significant loss of endogenous mucosal ACE2 for lung protection as well as escape from neutralization antibodies and thus higher infectivity. The Omicron variant is more likely than other VOCs to cause upper airway infection and affects much less in lung distal tissue. People with weakened immune systems and those who had underlying conditions are considered high risk. Taken together the Omicron variant underscores the urgency of exploring effective prophylactic and therapeutic interventions to boost mucosal immunity against Omicron cell entry in upper airways. The study is to offer the potential prophylactic and therapeutic strategies protecting mucosal immunity against breakthrough infections. Patients and methods Based on the viral structure and the mechanisms of its interaction with host cells, we are testing several potential strategies against SARS-CoV-2 infection and its VOC in human lung organoids and humanized mice. The approaches include, but not limited to, using decoy viral particles, decoy host receptors and blockage of host receptor complex, as well as targeting the SARS-CoV-2 conserved non-structured protein regions and interrupting viral genome from which VOC with mutative spike proteins may escape. Results We have observed significant preservation of mucosal ACE2, decreases in viral load, clinical manifestation scores, lung injury scores using recombinant human ACE2 in humanized mice infected with SARS-CoV-2. We also demonstrated a potential prophylactic role of recombinant ACE2 and SARS-CoV-2 varus-like particles as decoys to attenuate the numbers of viral gene copy and cytopathic effects in human lung organoids infected with Delta and Omicron (BA.2) variants. Conclusion The decoy host receptor and decoy virus-like particles have shown promising results that will preserve mucosal host immunity and facilitate the development of effective prophylactic and treatment capability against breakthrough SARS-CoV-2 infections. Grant acknowledgement This work was supported by the Canadian Institutes of Health Research (OV3–170344, SBC-171482 and VS1–175560) to HZ.