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

Abstract

The COVID-19 pandemic has been fueled by 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 infected to uninfected 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.

The Delta SARS-CoV-2 Variant of Concern Induces Distinct Pathogenic Patterns of Respiratory Disease in K18-hACE2 Transgenic Mice Compared to the Ancestral Strain from Wuhan

“…The viral RNA level in the brain of Delta-infected mice was ∼10 5 -fold higher than that of ancestral strain-infected mice. However, our observations differ from the study by Lee et al that showed low levels (below detection limit) of Delta viral RNA in mouse brain at 6 dpi ( 33 ). Further studies on the brain tropism of Delta are therefore recommended.…”

“…Histopathological analysis of ancestral strain- and Delta-infected lung tissue revealed moderate to severe alveolar damage and inflammation in the parenchyma. Similar pathology has been observed in small-animal models ( 33 , 38 ). The brain has been shown to be another important organ involved in COVID-19 pathology in both clinical patients ( 37 ) and K18-hACE2 mice following infection with SARS-CoV-2 clinical isolate USA-WA1/2020 ( 39 – 41 ).…”

“…Notably, the analysis shows that Delta has the highest risk of ICU admission and mortality compared to the Alpha, Beta, and Gamma variants. A recent study to determine pathogenicity of the Delta variant conducted by Lee et al showed a higher disease score in K18-hACE2 mice infected with Delta compared with the Alpha variant (hCoV19/England/204820464/2020, GISAID: EPI_ISL_683466) ( 33 ). We observed comparable disease severity and weight loss over 6 days in K18-hACE2 mice infected with ancestral or Delta SARS-CoV-2.…”

Diet induced obesity and type 2 diabetes drives exacerbated sex-associated disease profiles in K18-hACE2-mice challenged with SARS-CoV-2

“…In our experiment, we only evaluated one SARS-CoV-2 challenge strain, Alpha, and there have now been three VOC strain surges (Beta, Delta, Omicron) since Alpha was dominantly circulating. In additional studies since then, we have observed enhanced airway inflammation due to challenge with the Delta variant (68). We anticipate that different strains would result in variable host responses to what was identified using Alpha; however, additional studies will need to be performed.…”

“…The Alpha strain was intranasally administered at 10 3 , 10 4 , and 10 5 PFU per dose. Using a previously established disease scoring system (55,68,69), we determined that the 10 3 PFU dose caused lethality but postponed the time to morbidity compared to higher doses (Fig. 2A) and caused disease phenotypes that increase in severity over time (Fig.…”