Mouse models of COVID-19 recapitulate inflammatory pathways rather than gene expression

Abstract

BACKGROUND: How well mouse models recapitulate the transcriptional profiles seen in humans remains debatable, with both conservation and diversity identified in various settings. The K18-hACE2 mouse model has been widely used for evaluation of new interventions for COVID-19. METHOD. Herein we use RNA-Seq data and bioinformatics approaches to compare the transcriptional responses in the SARS-CoV-2 infected lungs of K18-hACE2 mice with those seen in humans. RESULTS: Overlap in differentially expressed genes was generally poor (≈20-30%), even when multiple studies were combined. The overlap was not substantially improved when a second mouse model was examined wherein hACE was expressed from the mouse ACE2 promoter. In contrast, analyses of immune signatures and inflammatory pathways illustrated highly significant concordances between the species. CONCLUSION: As immunity and immunopathology are the focus of most studies, these hACE2 transgenic mouse models can thus be viewed as representative and relevant models of COVID-19.

Evolution of ACE2-independent SARS-CoV-2 infection and mouse adaption after passage in cells expressing human and mouse ACE2

“…: 034860) ( McCray et al. 2007 ) were purchased from The Jackson Laboratory, USA, and bred and maintained in-house at QIMRB Berghofer Medical Research Institute as heterozygotes by crossing with C57BL/6J mice ( Bishop et al. 2022 ).…”

ACE2-independent SARS-CoV-2 infection and mouse adaption emerge after passage in cells expressing human and mouse ACE2

“…Left lungs were fixed in 10% formalin for histology. K18-hACE2 mice (strain B6.Cg-Tg(K18-ACE2)2Prlmn/J, JAX Stock No: 034860) 60 were purchased from The Jackson Laboratory, USA, and bred and maintained in-house at QIMRB as heterozygotes by crossing with C57BL/6J mice 10 . Mice were genotyped using Extract-N-Amp Tissue PCR Kit (Sigma Aldrich) according to manufacturers' instructions with the following primers; Forward 5'-CTTGGTGATATGTGGGGTAGA-3' and Reverse 5'-CGCTTCATCTCCCACCACTT-3' (recommended by NIOBIOHN, Osaka, Japan).…”

“…The original isolates of SARS-CoV-2 (Wuhan strain) are unable to bind mouse ACE2 (mACE2) for infection 2 , therefore, to study these viruses a series of mouse models were developed that express hACE2 2,[7][8][9][10] . Some subsequent SARS-CoV-2 variants of concern emerged to be able to use mACE2, including Alpha, Beta, Gamma, and Omicron, but not Delta 6,11 .…”

An S1-Nanoparticle Vaccine Protects against SARS-CoV-2 Challenge in K18-hACE2 Mice

“…We have now undertaken a vaccination and challenge study in K18-hACE2 transgenic mice ( Fig. 1B ), which provide a robust and lethal model of SARS-CoV-2 infection ( 5 – 7 ); ethics statements and regulatory compliance and detailed methods are available in Rawle et al ( 8 ). Female K18-hACE2 mice ( n = 6/group) received two intramuscular vaccinations 5 weeks apart with 2 μg S1 (no adjuvant), 2 μg S1-VLP (no adjuvant), or phosphate-buffered saline (PBS).…”

“…At 11 weeks after the first vaccination ( Fig. 1B ), the mice received an intrapulmonary challenge delivered intranasally with 5 × 10 4 50% cell culture infectious dose (CCID 50 )/mouse (in 50 μL) SARS-CoV-2 UK strain, B1.1.7; hCoV-19/Australia/QLD1517/2021 ( 10 ), and disease scores (quantitating overt clinical signs [ 6 ]) and weight change were monitored over 5 days. Mice that received the S1 subunit vaccine or PBS developed clear signs of disease ( Fig.…”