ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

Abstract

In silico modelling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNg and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

Evidence in favor of the essentiality of human cell membrane-bound ACE2 and against soluble ACE2 for SARS-CoV-2 infectivity

“…Importantly, in the absence of membrane-bound full-length ACE2, kidney organoids cannot be infected with SARS-CoV-2. A faithful model of severe SARS-CoV-2 infection in mice using ACE2 mutant animals, moreover, supports the evidence for the essentiality of ACE2 as the SARS-CoV-2 receptor here reported ( Gawish et al., 2022 ). Based on our findings, including the use of the kidney organoid model of ACE2 deficiency to reduce experimental bias, we conclude that full-length membrane-bound ACE2 is the essential determinant for infectivity by SARS-CoV-2 and that the low levels of soluble ACE2 protein, that may correspond roughly to those present in vivo , cannot promote infectivity.…”

Genetic Diversity and Evolutionary Convergence of Cryptic SARS-CoV-2 Lineages Detected Via Wastewater Sequencing

“…In several cases both Q498H and Q498Y were seen in association with particular lineage classes including in NY2, 11, and 14 (Fig.2B, 4, 5A) as well as a lineage class from California detected by the University of California, Berkeley wastewater monitoring laboratory (COVID-WEB) (Fig.6). Changes at this position directly affect receptor binding and can affect the binding of multiple classes of neutralizing antibodies[19,29,30].Notably, Q498H and Q498Y have been associated with mouse adapted SARS-CoV-2 lineages[31][32][33]. Both of these amino acid changes are very rare, appearing in less than 0.01% of sequences in GISAID submitted byMarch 15, 2022.…”

Characterization of entry pathways, species-specific ACE2 residues determining entry, and antibody neutralization evasion of Omicron BA.1, BA.1.1, BA.2, and BA.3 variants

“…Alternatively, the K35 residue in horseshoe bat ACE2 interacts with Q493 residue in D614G spike (Figure 5L). On the other hand, substitutions similar to Q498R were previously observed in mouse-adapted SARS-CoV-2 (Q498H, Q498Y/P499T) to strengthen interaction with D38 of mouse ACE2, which otherwise forms an intramolecular salt bridge with H353 [50][51][52] (Table 2) (Figure 5M). The interactions between R498 in Omicron spike and D38 and H353 in mouse ACE2 likely plays an important role for infection.…”