Determinants of susceptibility to SARS-CoV-2 infection in murine ACE2

Journal of Virology, Journal Year: 2025, Volume and Issue: unknown

Published: May 12, 2025

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme (ACE2) as a receptor to enter host cells, and primary recognition of the spike protein is major determinant range SARS-CoV-2. Since emergence SARS-CoV-2, considerable number variants have emerged. However, determinants tropism SARS-CoV-2 remain elusive. We conducted infection assays with chimeric recombinant carrying from 10 viral variants, assessing their entry efficiency using mammalian ACE2 orthologs species that close contact humans. found only murine exhibited different susceptibilities variants. Moreover, we revealed mutation N501Y in has crucial role determining infectivity cells expressing mice vivo . Next, identified six amino acid substitutions at 24, 30, 31, 82, 83, 353 allowed for which was previously resistant. Furthermore, showed closely related mice, Mus caroli , capable supporting could not use ACE2. These results suggest few susceptibility observed Collectively, our study reveals critical acids are involved shedding light on interspecies infection. IMPORTANCE can infect many besides humans, leading evolution virus adaptation other animal hosts, trigger new COVID-19 wave. The into cells. interaction determines In this study, viruses humans come with, confirmed alone residues restrict entry. an ortholog genetically mediated incapable infecting mice. This research highlights uniquely limited provides invaluable insights

Language: Английский

Mutations in nonstructural proteins essential for pathogenicity in SARS-CoV-2-infected mice

Journal of Virology, Journal Year: 2024, Volume and Issue: 98(7)

Published: June 18, 2024

ABSTRACT Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has resulted in substantial morbidity and mortality. The basis of humans is difficult to determine without the use experimental animal models. Mice are resistant infection with ancestral strains SARS-CoV-2, although many variants that arose later pandemic were able directly infect mice. In almost all cases, viruses naturally infected mice or engineered enable mouse required passage become virulent. most changes structural nonstructural occurred during adaptation. However, mechanism increased virulence not understood. Here, using a recently described strain mouse-adapted SARS-CoV-2 (rSARS2-MA30 N501Y ), we series recombinant expressed subset mutations present rSARS2-MA30 . Mutations detected spike protein three proteins (nsp4, nsp8, nsp9). We found expressing only S very mild infection. Addition nsp4 nsp8 was for complete virulence. Of note, these replicated equivalently cultured cells. innate immune response delayed after virulent compared attenuated viruses. Further, lineage tracking system, virus highly inhibited ability parenchyma, but airway Together, results indicate both maximal IMPORTANCE Understanding pathogenesis coronavirus (COVID-19) requires study animals (SARS-CoV-2). For this purpose, several have been developed. causes range diseases ranging from severe, show [spike (S) protein] Thus, protein, widely studied viral while adaptation, sufficient result virus.

Language: Английский

The Y498T499-SARS-CoV-2 spike (S) protein interacts poorly with rat ACE2 and does not affect the rat lung

Access Microbiology, Journal Year: 2024, Volume and Issue: 6(9)

Published: Sept. 1, 2024

The rat is a useful laboratory model for respiratory diseases. SARS-CoV-2 proteins, such as the spike (S) protein, can induce inflammation. This study has investigated ability of Q498Y, P499T (QP-YT) amino acid change, described in S-protein mouse-adapted MA strain, to interact with angiotensin converting enzyme-2 (ACE2) and stimulate responses lungs. A real-time S–ACE2 quantitative fusion assay shows that ancestral L452R S-proteins fuse human but not ACE2 expressed on HEK293 (human embryonic kidney-293) cells. QP-YT retains increases binding ACE2. Although lower lung contains both TMPRSS2 (transmembrane serine protease 2) target cells, intratracheal delivery or pseudotyped lentivirus did measurable changes, inflammatory infiltration innate mRNA responses. Isolation primary cells from alveoli demonstrated presence expressing TMPRSS2. Infection these however, was observed, poorly infected Analysis changes across interface highlights only Y498 interaction H353 likely facilitator also other acids could improve this interaction. Thus, lungs contain receptors SARS-CoV-2, variant bind ACE2, does result infection lung. Further, may enhance utility defining role driving

Language: Английский