SARS‐CoV‐2 evades immune detection in alveolar macrophages

Dalskov, Louise; Møhlenberg, Michelle; Thyrsted, Jacob; Blay-Cadanet, Julia; Poulsen, Ebbe Toftgaard; Folkersen, Birgitte Holst; Skaarup, Søren Helbo; Olagnier, David; Reinert, Line S.; Enghild, Jan J.; Hoffmann, Hans Jürgen; Holm, Christian K.; Hartmann, Rune

doi:10.15252/embr.202051252

Cited by 78 publications

(98 citation statements)

References 37 publications

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“…Using immunolabeling, we detected CD169 1 alveolar macrophages (AMs) and Ly6G 1 neutrophils in the lungs of infected mice. AMs have been shown to play a critical role in the initiation of a cytokine storm in severe COVID-19, and reports have shown that they are susceptible to infection with SARS-CoV-2 (19)(20)(21). Neutrophils, which have also been shown to play a role in lung inflammation during SARS-CoV-2 infection through the release of neutrophil extracellular traps (NETs) were detected in the parenchyma, although in lower numbers, and were more sparsely distributed than AMs (22,23).…”

Section: Resultsmentioning

confidence: 99%

Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice

Liu

Zaid

Freitas

et al. 2021

mBio

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Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 toolkit containing user-friendly reverse genetic (RG) infectious clones of SARS-CoV-2. Here, using K18-human ACE2 (hACE2) mice, we confirmed the validity of RG-rescued SARS-CoV-2 viruses to reproduce the infection profile, clinical disease, and pathogenesis already established in mice infected with natural SARS-CoV-2 isolates, often patient derived. RG-rescued SARS-CoV-2-infected K18-hACE2 mice developed substantial clinical disease and weight loss by day 6 postinfection. RG-rescued SARS-CoV-2 was recovered from the lungs and brains of infected K18-hACE2 mice, and infection resulted in viral pneumonia with considerable changes in lung pathology, as seen previously with natural SARS-CoV-2 infection. In mice infected with RG-rescued SARS-CoV-2-mCherry, mCherry was detected in areas of lung consolidation and colocalized with clinically relevant SARS-CoV-2-assocated immunopathology. RG-rescued SARS-CoV-2 viruses successfully recapitulated many of the features of severe COVID-19 associated with the K18-hACE2 model of SARS-CoV-2 infection. With utility in vivo, the RG-rescued SARS-CoV-2 viruses will be valuable resources to advance numerous areas of SARS-CoV-2 basic research and COVID-19 vaccine development. IMPORTANCE To develop COVID-19 countermeasures, powerful research tools are essential. We produced a SARS-COV-2 reverse genetic (RG) infectious clone toolkit that will benefit a variety of investigations. In this study, we further prove the toolkit’s value by demonstrating the in vivo utility of RG-rescued SARS-CoV-2 isolates. RG-rescued SARS-CoV-2 isolates reproduce disease signs and pathology characteristic of the K18-hACE2 mouse model of severe COVID-19 in infected mice. Having been validated as a model of severe COVID-19 previously using only natural SARS-CoV-2 isolated from patients, this is the first investigation of RG-rescued SARS-CoV-2 viruses in K18-hACE2 mice. The RG-rescued SARS-CoV-2 viruses will facilitate basic understanding of SARS-CoV-2 and the preclinical development of COVID-19 therapeutics.

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Section: Resultsmentioning

confidence: 99%

Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice

Liu

Zaid

Freitas

et al. 2021

mBio

View full text Add to dashboard Cite

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“…Several immune cell populations in the lungs have been found to play vital roles in the response to respiratory virus infection (Channappanavar et al, 2016;Dalskov et al, 2020;LeMessurier et al, 2020). We therefore sought to determine if any of the genetic loci identified in our study showed an association with influenza A virus (IAV)-induced disease phenotypes.…”

Section: Relationships Between Baseline Immune Lung Qtl and Respiratomentioning

confidence: 94%

Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice

Hampton

et al. 2021

Preprint

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Variation in immune homeostasis, immune system stability, in organ systems such as the lungs is likely to shape the host response to infection at these exposed tissues. We evaluated immune homeostasis in immune cell populations in the lungs of the Collaborative Cross (CC) mouse genetic reference population. We found vast heritable variation in leukocyte populations with the frequency of many of these cell types showing distinct patterns relative to classic inbred strains C57BL/6J and BALB/cJ. We identified 28 quantitative trait loci (QTL) associated with variation in baseline lung immune cell populations, including several loci that broadly regulate the abundance of immune populations from distinct developmental lineages, and found that many of these loci have predictive value for influenza disease outcomes, demonstrating that genetic determinants of homeostatic immunity in the lungs regulate susceptibility to virus-induced disease. All told, we highlight the need to assess diverse mouse strains in understanding immune homeostasis and resulting immune responses.

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“…Assessment of Avo1 expression was performed by re-searching LC-MS/MS data from two previously published SARS-CoV-2 studies looking at the infection of human alveolar macrophages [26] and green monkey Vero E6 cells [27]. Data were either search against the human or green monkey SWISS-PROT [28] reference proteomes (Human db: 09-2020, 20609 sequences; Green monkey: 08-2020, 19229 sequences) and the UNIPROT [29] SARS-CoV-2 database (12-2020, 16 sequences) to which the putative Avo1 protein sequence had been included.…”

Section: Methodsmentioning

confidence: 99%

Unheeded SARS-CoV-2 proteins? A deep look into negative-sense RNA

Bartas

Volná

Brázda

et al. 2020

Preprint

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SARS-CoV-2 is a novel ssRNA+ virus from the Coronaviridae family, which has caused the global COVID-19 pandemic. The genome of SARS-CoV-2 is one of the largest of RNA viruses, comprising of 26 known protein-coding loci. This study aimed to explore the coding potential of negative-strand RNA intermediate for its potential to contain additional protein coding-loci. Surprisingly, we have found several putative ORFs and one brandt new functional SARS-CoV-2 protein-coding loci and called it Avo1 (Ambient viral ORF1). This sequence is located on negative-sense RNA intermediate and bona fide coding for 81 amino acid residues long protein and contains strong Kozak sequence for translation on eukaryotic ribosomes. In silico translated protein Avo1 has a predominantly alpha-helical structure. The existence of Avo1 gene is supported also by its evolutionarily and structural conservation in RaTG13 bat coronavirus. The nucleotide sequence of Avo1 also contains a unique SREBP2 binding site which is closely related to the so-called “cytokine storm” in severe COVID-19 patients. Altogether, our results suggest the existence of still undescribed SARS-CoV-2 protein, which may play an important role in the viral lifecycle and COVID-19 pathogenesis.

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SARS‐CoV‐2 evades immune detection in alveolar macrophages

Cited by 78 publications

References 37 publications

Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice

Infectious Clones Produce SARS-CoV-2 That Causes Severe Pulmonary Disease in Infected K18-Human ACE2 Mice

Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice

Unheeded SARS-CoV-2 proteins? A deep look into negative-sense RNA

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