Cell-intrinsic and -extrinsic effects of SARS-CoV-2 RNA on pathogenesis: single-cell meta-analysis

Abstract

Single-cell RNA-seq has been used to characterize human COVID-19. To determine if preclinical models successfully mimic the cell-intrinsic and -extrinsic effects of severe disease, we conducted a meta-analysis of single-cell data across five model species. To assess whether dissemination of viral RNA in lung cells tracks pathology and results in cell‐intrinsic and ‐extrinsic transcriptomic changes in COVID-19. We conducted a meta-analysis by analyzing six publicly available, scRNA-seq data sets. We used dual mapping (host and virus) and differential gene expression analyses to compare viral + and viral − cell populations. We conducted a principal component analysis to identify successful models of human COVID-19. We found expression of viral RNA in many non-epithelial cell types. Fibroblasts, macrophages, and endothelial cells exhibit clear evidence of viral-intrinsic and -extrinsic effects on host gene expression. Using viral RNA expression, we found that K18-hACE2 mice most closely modeled severe human COVID-19, followed by hamsters. Ferrets and macaques are poor models of human disease due to the low presence of viral RNA. Moreover, we found that increased transcripts of certain key inflammatory genes such as IL1B, IL18 , and CXCL10 are not restricted to virally infected cells, suggesting these genes are regulated in a paracrine or autocrine fashion. These data affirm widespread dissemination of viral RNA in the lung, which may be key in the pathogenesis of severe COVID-19 and demonstrate ferrets and Rhesus macaques are poor models of human COVID-19. IMPORTANCE We conducted a high-resolution meta-analysis of scRNA-seq data from humans and five animal models of COVID-19. This study reports viral RNA dissemination in several cell types in human data as well as in some of the pre-clinical models. Using this metric, the K18-hACE2 mouse model, followed by the hamster model, most closely resembled human COVID-19. We observed clear evidence of viral-intrinsic effects within cells (e.g., IRF5 expression) as well as viral-extrinsic cytokine modulation (e.g., IL1B, IL18, CXCL10 ). We observed proinflammatory chemokine expression in cells devoid of viral RNA expression, suggesting autocrine/paracrine interferon regulation. This report serves as a resource-synthesizing data from COVID-19 humans and animal models and suggesting improvements for relevant pre-clinical models that may aid future diagnostic and therapeutic development projects.

Natural Killer Cells Do Not Attenuate a Mouse-Adapted SARS-CoV-2-Induced Disease in Rag2−/− Mice

“…We investigated the infection pattern of MA30 in B6 mice and compared them with the well-established human transgenic K18-hACE2 mouse model exposed to the original CoV-2-WA1 strain, USA-WA1/2020. SARS-CoV-2-infected K18-hACE2 mice is a severe COVID-19 mouse model that has been widely used for testing therapeutic countermeasures and vaccines, as well as investigating the pathogenesis of severe COVID-19 [ 24 , 31 , 32 , 33 , 34 ]. We examined the nasal cavity and lung compartments at 3 DPI using a matched lethal dose (LD90) for MA30 in B6 mice (5 × 10 4 TCID 50 , IN) and WA1-infected K18 (1 × 10 4 TCID 50 , IN), respectively.…”

Tissue-Specific Metabolomic Reprogramming Determines the Disease Pathophysiology of Sars-Cov-2 Variants in Hamster Model

“…While numerous studies have focused on unraveling the pathogenesis of SARS-CoV-2 and the pathophysiology of COVID-19 (12,(44)(45)(46)(47), the impact of SARS-CoV-2 variants on metabolic regulations in diverse host tissues during acute infection remains elusive. Our study profiled metabolites in different tissues from GSHs infected with delta and omicron at acute infection.…”

Emerging role of complement in COVID-19 and other respiratory virus diseases

“…SARS-CoV-2-infected K18 mice recapitulate various COVID-19 phenotypes seen in humans, ranging from moderate to severe disease and even death [ 124 – 126 ]. The meta-analysis of single-cell data across five model species showed that the K18-hACE2 mouse model, followed by the hamster model, most closely resembled human COVID-19 lung pathology [ 127 ]. The severity of the disease in this model is dependent on the infectious dose of the SARS-CoV-2 virus [ 128 ].…”