SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice

Abstract

The COVID-19 pandemic has been fueled by SARS-CoV-2 novel variants of concern (VOC) that have increased transmissibility, receptor binding affinity, and other properties that enhance disease. The goal of this study is to characterize unique pathogenesis of the Delta VOC strain in the K18-hACE2-mouse challenge model. Challenge studies suggested that the lethal dose of Delta was higher than Alpha or Beta strains. To characterize the differences in the Delta strain’s pathogenesis, a time-course experiment was performed to evaluate the overall host response to Alpha or Delta variant challenge. qRT-PCR analysis of Alpha- or Delta-challenged mice revealed no significant difference between viral RNA burden in the lung, nasal wash or brain. However, histopathological analysis revealed high lung tissue inflammation and cell infiltration following Delta- but not Alpha-challenge at day 6. Additionally, pro-inflammatory cytokines were highest at day 6 in Delta-challenged mice suggesting enhanced pneumonia. Total RNA-sequencing analysis of lungs comparing challenged to no challenge mice revealed that Alpha-challenged mice have more total genes differentially activated. Conversely, Delta-challenged mice have a higher magnitude of differential gene expression. Delta-challenged mice have increased interferon-dependent gene expression and IFN-γ production compared to Alpha. Analysis of TCR clonotypes suggested that Delta challenged mice have increased T-cell infiltration compared to Alpha challenged. Our data suggest that Delta has evolved to engage interferon responses in a manner that may enhance pathogenesis. The in vivo and in silico observations of this study underscore the need to conduct experiments with VOC strains to best model COVID-19 when evaluating therapeutics and vaccines.

Genomic and structural mechanistic insight to reveal the differential infectivity of omicron and other variants of concern

“…The maximum negative binding energy was observed for delta variant (−152.13 kcal/mol) as compared to wild type (−145.09 kcal/mol). Previous concordant findings indicated that the delta spike protein has better binding affinity than the wild type and causes severe illness due to its higher affinity towards the hACE2 receptor [ 59 , 71 , 72 ]. For other variants, namely alpha, beta, gamma and omicron, the binding energy was observed to be −132.20, −138.94, −137.89 and −140.06 kcal/mol, respectively.…”

A SARS-CoV-2-Related Virus from Malayan Pangolin Causes Lung Infection without Severe Disease in Human ACE2-Transgenic Mice

“…Most SARSr-CoVs, including SARS-CoV and SARS-CoV-2, cannot infect or have limited infection potential in wild-type mice ( 29 – 32 ). Therefore, human ACE2-transgenic mice have been widely used to evaluate the pathogenicity of this group of viruses instead ( 32 – 35 ). In this study, we demonstrated that MpCoV-GX successfully infected three mouse models, including wild-type BALB/c mice, human ACE2-transgenic mice, and human ACE2 knock-in mice, though the infected animals presented no obvious clinical symptoms ( Fig.…”

Mouse-Adapted SARS-CoV-2 MA10 Strain Displays Differential Pulmonary Tropism and Accelerated Viral Replication, Neurodissemination, and Pulmonary Host Responses in K18-hACE2 Mice

“…As an alternative approach, Leist et al developed a mouse-adapted SARS-CoV-2 strain (namely, MA10) engineered to bind mACE2 and to which conventional mouse strains are permissive ( 34 ). To date, the vast majority of the studies in the literature have evaluated the pathogenicity of Wuhan-like SARS-CoV-2 and VOCs (i.e., Alpha, Beta, Delta, and Omicron variants) in K18-hACE2 mice ( 35 , 53 – 55 ), with only a single study evaluating the replication of the mouse-adapted MA10 strain in this specific mouse model ( 39 ). Thus, far, no in-depth characterization of the differences in infection dynamics and pathophysiology between the mouse-adapted MA10 strain and the counterpart USA-WA1/2020 in K18-hACE2 mice has been undertaken.…”