scholarly journals Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

2020 ◽  
Author(s):  
Ruofan Wang ◽  
Camille R. Simoneau ◽  
Jessie Kulsuptrakul ◽  
Mehdi Bouhaddou ◽  
Katherine Travisano ◽  
...  
Keyword(s):  
Viral Entry ◽  
Common Cold ◽  
Distress Syndrome ◽  
Cholesterol Homeostasis ◽  
Host Factors ◽  
Phosphatidylinositol Phosphate ◽  
Genome Wide ◽  
Potential Development ◽  
Human Host Factors ◽  
Lysosomal Protein

AbstractThe Coronaviridae are a family of viruses that causes disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors that are common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted parallel genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E) and glycosaminoglycans (for OC43). Additionally, we discovered phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle as well as the potential development of host-directed therapies.

scholarly journals Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication

Nature ◽  
2010 ◽  
Vol 463 (7282) ◽  
pp. 818-822 ◽  
Author(s):  
Alexander Karlas ◽  
Nikolaus Machuy ◽  
Yujin Shin ◽  
Klaus-Peter Pleissner ◽  
Anita Artarini ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Replication ◽  
Rnai Screen ◽  
Host Factors ◽  
Human Host ◽  
Genome Wide ◽  
Influenza Virus Replication ◽  
Human Host Factors

scholarly journals Visual Genome-Wide RNAi Screening to Identify Human Host Factors Required for Trypanosoma cruzi Infection

PLoS ONE ◽  
2011 ◽  
Vol 6 (5) ◽  
pp. e19733 ◽  
Author(s):  
Auguste Genovesio ◽  
Miriam A. Giardini ◽  
Yong-Jun Kwon ◽  
Fernando de Macedo Dossin ◽  
Seo Yeon Choi ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Host Factors ◽  
Rnai Screening ◽  
Human Host ◽  
Genome Wide ◽  
Human Host Factors ◽  
Cruzi Infection

scholarly journals Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal coronaviruses

2021 ◽  
Author(s):  
Antoine Rebendenne ◽  
Priyanka Roy ◽  
Boris Bonaventure ◽  
Ana Luiza Chaves Valadão ◽  
Lowiese Desmarets ◽  
...  
Keyword(s):  
Viral Entry ◽  
Influenza A ◽  
Defense Mechanism ◽  
Meta Analysis ◽  
Lung Epithelial Cells ◽  
Host Factors ◽  
Therapeutic Interventions ◽  
Cell Type Specificity ◽  
Genome Wide ◽  
High Level

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.

scholarly journals Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2)

2018 ◽  
Vol 20 (2) ◽  
pp. 112-120 ◽  
Author(s):  
Sarah E. Kleinstein ◽  
Patrick R. Shea ◽  
Andrew S. Allen ◽  
David M. Koelle ◽  
Anna Wald ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Genome Wide Association Study ◽  
Host Factors ◽  
Genome Wide Association ◽  
Factors Influencing ◽  
Genome Wide ◽  
Simplex Virus ◽  
Human Host Factors

scholarly journals Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs

2021 ◽  
Author(s):  
Caroline Goujon ◽  
Antoine Rebendenne ◽  
Priyanka Roy ◽  
Boris Bonaventure ◽  
Ana Chaves Valadao ◽  
...  
Keyword(s):  
Viral Entry ◽  
Influenza A ◽  
Defense Mechanism ◽  
Meta Analysis ◽  
Lung Epithelial Cells ◽  
Host Factors ◽  
Therapeutic Interventions ◽  
Cell Type Specificity ◽  
Genome Wide ◽  
High Level

Abstract 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.

scholarly journals A genome-wide CRISPR screen identifies UFMylation and TRAMP-like complexes as host factors required for hepatitis A virus infection

Cell Reports ◽  
2021 ◽  
Vol 34 (11) ◽  
pp. 108859
Author(s):  
Jessie Kulsuptrakul ◽  
Ruofan Wang ◽  
Nathan L. Meyers ◽  
Melanie Ott ◽  
Andreas S. Puschnik
Keyword(s):  
Virus Infection ◽  
Hepatitis A ◽  
Hepatitis A Virus ◽  
Host Factors ◽  
Genome Wide ◽  
A Genome ◽  
Crispr Screen

scholarly journals Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection

Cell ◽  
2021 ◽  
Vol 184 (1) ◽  
pp. 76-91.e13 ◽  
Author(s):  
Jin Wei ◽  
Mia Madel Alfajaro ◽  
Peter C. DeWeirdt ◽  
Ruth E. Hanna ◽  
William J. Lu-Culligan ◽  
...  
Keyword(s):  
Host Factors ◽  
Genome Wide

scholarly journals Yersinia pestis Targets the Host Endosome Recycling Pathway during the Biogenesis of the Yersinia-Containing Vacuole To Avoid Killing by Macrophages

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Michael G. Connor ◽  
Amanda R. Pulsifer ◽  
Donghoon Chung ◽  
Eric C. Rouchka ◽  
Brian K. Ceresa ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Host Factors ◽  
Endocytic Recycling ◽  
Recycling Endosome ◽  
Independent Manner ◽  
Genome Wide ◽  
Type Three Secretion System ◽  
A Genome ◽  
Recycling Pathway ◽  
Bacterial Replication

ABSTRACTYersinia pestishas evolved many strategies to evade the innate immune system. One of these strategies is the ability to survive within macrophages. Upon phagocytosis,Y. pestisprevents phagolysosome maturation and establishes a modified compartment termed theYersinia-containing vacuole (YCV).Y. pestisactively inhibits the acidification of this compartment, and eventually, the YCV transitions from a tight-fitting vacuole into a spacious replicative vacuole. The mechanisms to generate the YCV have not been defined. However, we hypothesized that YCV biogenesis requiresY. pestisinteractions with specific host factors to subvert normal vesicular trafficking. In order to identify these factors, we performed a genome-wide RNA interference (RNAi) screen to identify host factors required forY. pestissurvival in macrophages. This screen revealed that 71 host proteins are required for intracellular survival ofY. pestis. Of particular interest was the enrichment for genes involved in endosome recycling. Moreover, we demonstrated thatY. pestisactively recruits Rab4a and Rab11b to the YCV in a type three secretion system-independent manner, indicating remodeling of the YCV byY. pestisto resemble a recycling endosome. While recruitment of Rab4a was necessary to inhibit YCV acidification and lysosomal fusion early during infection, Rab11b appeared to contribute to later stages of YCV biogenesis. We also discovered thatY. pestisdisrupts global host endocytic recycling in macrophages, possibly through sequestration of Rab11b, and this process is required for bacterial replication. These data provide the first evidence thatY. pestistargets the host endocytic recycling pathway to avoid phagolysosomal maturation and generate the YCV.IMPORTANCEYersinia pestiscan infect and survive within macrophages. However, the mechanisms that the bacterium use to subvert killing by these phagocytes have not been defined. To provide a better understanding of these mechanisms, we used an RNAi approach to identify host factors required for intracellularY. pestissurvival. This approach revealed that the host endocytic recycling pathway is essential forY. pestisto avoid clearance by the macrophage. We further demonstrate thatY. pestisremodels the phagosome to resemble a recycling endosome, allowing the bacterium to avoid the normal phagolysosomal maturation pathway. Moreover, we show that infection withY. pestisdisrupts normal recycling in the macrophage and that disruption is required for bacterial replication. These findings provide the first evidence thatY. pestistargets the host endocytic recycling pathway in order to evade killing by macrophages.

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