Integrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection DOI Creative Commons
Jiakai Hou, Yanjun Wei, Jing Zou

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses multi-omics data screen, association studies, single-cell RNA-Seq, host-virus proteins or protein/RNA interactome. This study uncovers many that currently underappreciated, including components V-ATPases, ESCRT, N-glycosylation pathways modulate viral entry and/or replication. The cohesin complex is also identified as an pathway, suggesting important role three-dimensional chromatin organization mediating host-viral interaction. Furthermore, discover another regulator KLF5, transcriptional factor involved sphingolipid metabolism, which up-regulated, harbors genetic variations linked COVID-19 patients with severe symptoms. Anti-viral effects three candidates (DAZAP2/VTA1/KLF5) confirmed individually. Molecular characterization DAZAP2/VTA1/KLF5-knockout cells highlights involvement genes related coagulation system determining severity COVID-19. Together, our results provide further resources understanding network during may help develop new countermeasure strategies.

Language: Английский

Spike mutations contributing to the altered entry preference of SARS-CoV-2 omicron BA.1 and BA.2 DOI Creative Commons
Bingjie Hu, Jasper Fuk‐Woo Chan, Huan Liu

et al.

Emerging Microbes & Infections, Journal Year: 2022, Volume and Issue: 11(1), P. 2275 - 2287

Published: Aug. 30, 2022

SARS-CoV-2 B.1.1.529.1 (Omicron BA.1) emerged in November 2021 and quickly became the predominant circulating variant globally. Omicron BA.1 contains more than 30 mutations spike protein, which contribute to its altered virological features when compared ancestral or previous variants. Recent studies by us others demonstrated that is less dependent on transmembrane serine protease 2 (TMPRSS2), efficient cleavage, fusogenic, adopts an propensity utilize plasma membrane endosomal pathways for virus entry. Ongoing suggest these of are part retained subsequent sublineages. However, exact determinants remain incompletely understood. In this study, we investigated observed characteristics Omicron. By screening individual changes BA.2 spike, identify 69-70 deletion, E484A, H655Y reduced TMPRSS2 usage while 25-27 S375F, T376A result cleavage. Among shared BA.2, S375F reduce spike-mediated fusogenicity. Interestingly, change consistently reduces increases use proteases. keeping with findings, substitution alone entry facilitates WT. Overall, our study identifies key contributes understanding determinant pathogenicity

Language: Английский

Citations

72
White-tailed deer ( Odocoileus virginianus ) may serve as a wildlife reservoir for nearly extinct SARS-CoV-2 variants of concern DOI Creative Commons
Leonardo C. Caserta, Mathias Martins, Salman L. Butt

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(6)

Published: Jan. 31, 2023

The spillover of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to white-tailed deer (WTD) and its ability transmit raised concerns about the role WTD in epidemiology ecology virus. Here, we present a comprehensive cross-sectional study assessing prevalence, genetic diversity, evolution SARS-CoV-2 State New York (NY). A total 5,462 retropharyngeal lymph node samples collected free-ranging hunter-harvested during hunting seasons 2020 (Season 1, September December 2020, n = 2,700) 2021 2, 2021, 2,762) were tested by real-time RT–PCR (rRT-PCR). RNA was detected 17 (0.6%) Season 1 583 (21.1%) 2. Hotspots infection identified multiple confined geographic areas NY. Sequence analysis genomes 164 demonstrated presence lineages cocirculation three major variants concern (VOCs) (Alpha, Gamma, Delta) WTD. Our suggests occurrence events (human deer) Alpha Delta with subsequent deer-to-deer transmission adaptation viruses. Detection Gamma long after their broad circulation NY that may serve as wildlife reservoir for VOCs no longer circulating humans. Thus, implementation continuous surveillance programs monitor dynamics is warranted, measures minimize virus between animals are urgently needed.

Language: Английский

Citations

69
SARS-CoV-2 and innate immunity: the good, the bad, and the “goldilocks” DOI Creative Commons
Benjamín L. Sievers, Mark T. K. Cheng,

Kata Csiba

et al.

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 21(2), P. 171 - 183

Published: Nov. 20, 2023

Abstract An ancient conflict between hosts and pathogens has driven the innate adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that be leveraged therapeutically. The humoral response to SARS-CoV-2 infection been focus intense research, role immune system received significantly less attention. Here, we review current knowledge various means employs evade defense systems. We consider immunity in vaccines phenomenon long COVID.

Language: Английский

Citations

51
Comparison of SARS-CoV-2 variants of concern in primary human nasal cultures demonstrates Delta as most cytopathic and Omicron as fastest replicating DOI Creative Commons
Nikhila S. Tanneti,

Anant K. Patel,

Li Tan

et al.

mBio, Journal Year: 2024, Volume and Issue: 15(4)

Published: March 13, 2024

ABSTRACT The SARS-CoV-2 pandemic was marked with emerging viral variants, some of which were designated as variants concern (VOCs) due to selection and rapid circulation in the human population. Here, we elucidate functional features each VOC linked variations replication rate. Patient-derived primary nasal cultures grown at air-liquid interface used model upper respiratory infection compared cell lines derived from lung epithelia. All VOCs replicated higher titers than ancestral virus, suggesting a for efficiency. In cultures, Omicron highest early time points, followed by Delta, paralleling comparative studies population sampling. viruses entered primarily via transmembrane serine protease 2 (TMPRSS2)-dependent pathway, more likely use an endosomal route entry. activated overcame dsRNA-induced cellular responses, including interferon (IFN) signaling, oligoadenylate ribonuclease L degradation, protein kinase R activation. Among VOCs, induced expression most IFN IFN-stimulated genes. Infections resulted damage, compromise barrier integrity loss cilia ciliary beating function, especially during Delta infection. Overall, optimized tract least favorable lower line, cytopathic both cells. Our findings highlight differences among level imply distinct mechanisms pathogenesis infected individuals. IMPORTANCE Comparative analysis infections virus concern, Alpha, Beta, Omicron, indicated that selected efficiency replication. patient-derived infection, reached finding confirmed parallel sampling studies. While all dsRNA-mediated host strongest interferon-stimulated gene response. damaging cells syncytia formation, integrity, function.

Language: Английский

Citations

20
Integrated multi-omics analyses identify anti-viral host factors and pathways controlling SARS-CoV-2 infection DOI Creative Commons
Jiakai Hou, Yanjun Wei, Jing Zou

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses multi-omics data screen, association studies, single-cell RNA-Seq, host-virus proteins or protein/RNA interactome. This study uncovers many that currently underappreciated, including components V-ATPases, ESCRT, N-glycosylation pathways modulate viral entry and/or replication. The cohesin complex is also identified as an pathway, suggesting important role three-dimensional chromatin organization mediating host-viral interaction. Furthermore, discover another regulator KLF5, transcriptional factor involved sphingolipid metabolism, which up-regulated, harbors genetic variations linked COVID-19 patients with severe symptoms. Anti-viral effects three candidates (DAZAP2/VTA1/KLF5) confirmed individually. Molecular characterization DAZAP2/VTA1/KLF5-knockout cells highlights involvement genes related coagulation system determining severity COVID-19. Together, our results provide further resources understanding network during may help develop new countermeasure strategies.

Language: Английский

Citations

19