Comparison of infection and human immune responses of two SARS-CoV-2 strains in a humanized hACE2 NIKO mouse model.

The COVID-19 pandemic has sickened millions, cost lives and has devastated the global economy. Various animal models for experimental infection with SARS-CoV-2 have played a key role in many aspects of COVID-19 research. Here, we describe a humanized hACE2 (adenovirus expressing hACE2) NOD-SCID IL2Rγ-/- (NIKO) mouse model and compare infection with ancestral and mutant (SARS-CoV-2-∆382) strains of SARS-CoV-2. Immune cell infiltration, inflammation, lung damage and pro-inflammatory cytokines and chemokines was observed in humanized hACE2 NIKO mice. Humanized hACE2 NIKO mice infected with the ancestral and mutant SARS-CoV-2 strain had lung inflammation and production of pro-inflammatory cytokines and chemokines. This model can aid in examining the pathological basis of SARS-CoV-2 infection in a human immune environment and evaluation of therapeutic interventions.

Association of SARS-CoV-2 clades with clinical, inflammatory and virologic outcomes: An observational study.

BACKGROUND: Host determinants of severe coronavirus disease 2019 include advanced age, comorbidities and male sex. Virologic factors may also be important in determining clinical outcome and transmission rates, but limited patient-level data is available. METHODS: We conducted an observational cohort study at seven public hospitals in Singapore. Clinical and laboratory data were collected and compared between individuals infected with different SARS-CoV-2 clades. Firth's logistic regression was used to examine the association between SARS-CoV-2 clade and development of hypoxia, and quasi-Poisson regression to compare transmission rates. Plasma samples were tested for immune mediator levels and the kinetics of viral replication in cell culture were compared. FINDINGS: 319 patients with PCR-confirmed SARS-CoV-2 infection had clinical and virologic data available for analysis. 29 (9%) were infected with clade S, 90 (28%) with clade L/V, 96 (30%) with clade G (containing D614G variant), and 104 (33%) with other clades 'O' were assigned to lineage B.6. After adjusting for age and other covariates, infections with clade S (adjusted odds ratio (aOR) 0·030 (95% confidence intervals (CI): 0·0002-0·29)) or clade O (B·6) (aOR 0·26 (95% CI 0·064-0·93)) were associated with lower odds of developing hypoxia requiring supplemental oxygen compared with clade L/V. Patients infected with clade L/V had more pronounced systemic inflammation with higher concentrations of pro-inflammatory cytokines, chemokines and growth factors. No significant difference in the severity of clade G infections was observed (aOR 0·95 (95% CI: 0·35-2·52). Though viral loads were significantly higher, there was no evidence of increased transmissibility of clade G, and replicative fitness in cell culture was similar for all clades. INTERPRETATION: Infection with clades L/V was associated with increased severity and more systemic release of pro-inflammatory cytokines. Infection with clade G was not associated with changes in severity, and despite higher viral loads there was no evidence of increased transmissibility.