Several genome-wide CRISPR knockout screens have been conducted to identify host factors regulating SARS-CoV-2 replication, but the models used have often relied on overexpression of ACE2 receptor. Additionally, such screens have yet to identify the protease TMPRSS2, known to be important for viral entry at the plasma membrane. Here, we conducted a meta-analysis of these screens and showed a high level of cell-type specificity of the identified hits, arguing for the necessity of additional models to uncover the full landscape of SARS-CoV-2 host factors. We performed genome-wide knockout and activation CRISPR screens in Calu-3 lung epithelial cells, as well as knockout screens in Caco-2 intestinal cells. In addition to identifying ACE2 and TMPRSS2 as top hits, our study reveals a series of so far unidentified and critical host-dependency factors, including the Adaptins AP1G1 and AP1B1 and the flippase ATP8B1. Moreover, new anti-SARS-CoV-2 proteins with potent activity, including several membrane-associated Mucins, IL6R, and CD44 were identified. We further observed that these genes mostly acted at the critical step of viral entry, with the notable exception of ATP8B1, the knockout of which prevented late stages of viral replication. Exploring the pro- and anti-viral breadth of these genes using highly pathogenic MERS-CoV, seasonal HCoV-NL63 and -229E and influenza A orthomyxovirus, we reveal that some genes such as AP1G1 and ATP8B1 are general coronavirus cofactors. In contrast, Mucins recapitulated their known role as a general antiviral defense mechanism. These results demonstrate the value of considering multiple cell models and perturbational modalities for understanding SARS-CoV-2 replication and provide a list of potential new targets for therapeutic interventions.
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http://dx.doi.org/10.21203/rs.3.rs-555275/v1 | DOI Listing |
Commun Biol
January 2025
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Aedes mosquitoes transmit pathogenic arthropod-borne (arbo) viruses, putting nearly half the world's population at risk. Blocking virus replication in mosquitoes is a promising approach to prevent arbovirus transmission, the development of which requires in-depth knowledge of virus-host interactions and mosquito immunity. By integrating multi-omics data, we find that heat shock factor 1 (Hsf1) regulates eight small heat shock protein (sHsp) genes within one topologically associated domain in the genome of the Aedes aegypti mosquito.
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January 2025
Department of Medical Biology, Albert Szent-Györgyi Medical School, University of Szeged, Somogyi u. 4, Szeged, 6720, Hungary.
In our research, we performed temporal transcriptomic profiling of host cells infected with Equid alphaherpesvirus 1 (EHV-1) by utilizing direct cDNA sequencing based on nanopore MinION technology. The sequencing reads were harnessed for transcript quantification at various time points. Viral infection-induced differential gene expression was identified through the edgeR package.
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January 2025
Department of Pathology, Division of Microbiology, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, 50-375, Wroclaw, Poland.
The process of viral entry into host cells is crucial for the establishment of infection and the determination of viral pathogenicity. A comprehensive understanding of entry pathways is fundamental for the development of novel therapeutic strategies. Standard techniques for investigating viral entry include confocal microscopy and flow cytometry, both of which provide complementary qualitative and quantitative data.
View Article and Find Full Text PDFNat Commun
January 2025
Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Multidrug resistance in the pathogenic fungus Candida glabrata is a growing global threat. Here, we study mechanisms of multidrug resistance in this pathogen. Exposure of C.
View Article and Find Full Text PDFInt J Biol Macromol
January 2025
College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University; Yangling, Shaanxi 712100, China. Electronic address:
Biofilms are complex adhesive structures that establish chronic infection and allow robust protection from external stressors such as antibiotics. Cellulose as one of the compositions of bacteria biofilm which protect bacteria from stress, host immune responses and resistance to antibiotics. Bacterial stress responses are regulated via guanosine pentaphosphate and tetraphosphate (p)ppGpp.
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