Comparative Transcriptomic Response of Primary and Immortalized Macrophages to Murine Norovirus Infection

Levenson, Eric A.; Martens, Craig; Kanakabandi, Kishore; Turner, Charles V.; Virtaneva, Kimmo; Paneru, Monica; Ricklefs, Stacy M.; Sosnovtsev, Stanislav V.; Johnson, Jamlik-Omari; Porcella, Stephen F.; Green, Kim Y.

doi:10.4049/jimmunol.1700384

Cited by 21 publications

(21 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We and others have shown that MNV-infected cells increase the transcription of cytokine (IFN-β, TNF-α, and IL-6) mRNAs (Fig. 4) (56, 57), indicating that pattern recognition receptors (PRRs) such as MDA5 (58) have successfully detected the viral infection and activated an antiviral response against it. Intriguingly, MNV-infected cells do not secrete significant levels of cytokines which would help to overcome and contain the acute infection (Fig.…”

Section: Discussionmentioning

confidence: 93%

Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis

Fritzlar

Aktepe

Chao

et al. 2019

mBio

View full text Add to dashboard Cite

The integrated stress response (ISR) is a cellular response system activated upon different types of stresses, including viral infection, to restore cellular homeostasis. However, many viruses manipulate this response for their own advantage. In this study, we investigated the association between murine norovirus (MNV) infection and the ISR and demonstrate that MNV regulates the ISR by activating and recruiting key ISR host factors. We observed that during MNV infection, there is a progressive increase in phosphorylated eukaryotic initiation factor 2α (p-eIF2α), resulting in the suppression of host translation, and yet MNV translation still progresses under these conditions. Interestingly, the shutoff of host translation also impacts the translation of key signaling cytokines such as beta interferon, interleukin-6, and tumor necrosis factor alpha. Our subsequent analyses revealed that the phosphorylation of eIF2α was mediated via protein kinase R (PKR), but further investigation revealed that PKR activation, phosphorylation of eIF2α, and translational arrest were uncoupled during infection. We further observed that stress granules (SGs) are not induced during MNV infection and that MNV can restrict SG nucleation and formation. We observed that MNV recruited the key SG nucleating protein G3BP1 to its replication sites and intriguingly the silencing of G3BP1 negatively impacts MNV replication. Thus, it appears that MNV utilizes G3BP1 to enhance replication but equally to prevent SG formation, suggesting an anti-MNV property of SGs. Overall, this study highlights MNV manipulation of SGs, PKR, and translational control to regulate cytokine translation and to promote viral replication. IMPORTANCE Viruses hijack host machinery and regulate cellular homeostasis to actively replicate their genome, propagate, and cause disease. In retaliation, cells possess various defense mechanisms to detect, destroy, and clear infecting viruses, as well as signal to neighboring cells to inform them of the imminent threat. In this study, we demonstrate that the murine norovirus (MNV) infection stalls host protein translation and the production of antiviral and proinflammatory cytokines. However, virus replication and protein translation still ensue. We show that MNV further prevents the formation of cytoplasmic RNA granules, called stress granules (SGs), by recruiting the key host protein G3BP1 to the MNV replication complex, a recruitment that is crucial to establishing and maintaining virus replication. Thus, MNV promotes immune evasion of the virus by altering protein translation. Together, this evasion strategy delays innate immune responses to MNV infection and accelerates disease onset.

show abstract

Section: Discussionmentioning

confidence: 93%

Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis

Fritzlar

Aktepe

Chao

et al. 2019

mBio

View full text Add to dashboard Cite

show abstract

“…We validated DE TE dynamics with the data obtained from four virus strains from two independent studies: a 20-h mouse norovirus (MNV) infection time course in mouse RAW 264.7 cells (GSE96586, Fig S9) (Levenson et al, 2018) and a 24-h IAV time course comparing IAV (H3N2) Brisbane, Udorn, and Perth strains in a human cell line (GSE61517) (Fabozzi et al, 2018) (Fig S10). We witnessed dramatic changes in numbers of TEs changing expression by the first time point across all time courses (Figs S9A-F and S10A-C).…”

Section: Dynamics Of Te Up-regulation During Virus Infectionmentioning

confidence: 99%

“…The 7-d influenza A (GSE49933), 20-h norovirus time course (GSE96586), and three 24-h influenza A (H3N2) strain time courses (Brisbane, Udorn, and Perth; GSE61517) were downloaded from GEO and mapped and quantified identically to other mouse and human virus data sets (Altboum et al, 2014;Levenson et al, 2018). The 7-d IAV time course did not have biological replicates for each time point, so time points that were 1-2 h apart were grouped together as biological replicates for DE analysis using a less stringent significance cutoff (FDR < 0.25) for gene and TE-calling against the uninfected (0 h) time point.…”

Section: -D Influenza 20-h Norovirus and 24-h Iav Strain Infectionmentioning

confidence: 99%

Virus-induced transposable element expression up-regulation in human and mouse host cells

2020

View full text Add to dashboard Cite

Virus–host cell interactions initiate a host cell–defensive response during virus infection. How transposable elements in the host cell respond to viral stress at the molecular level remains largely unclear. By reanalyzing next generation sequencing data sets from dozens of virus infection studies from the Gene Expression Omnibus database, we found that genome-wide transposon expression up-regulation in host cells occurs near antiviral response genes and exists in all studies regardless of virus, species, and host cell tissue types. Some transposons were found to be up-regulated almost immediately upon infection and before increases in virus replication and significant increases in interferon β expression. These findings indicate that transposon up-regulation is a common phenomenon during virus infection in human and mouse and that early up-regulated transposons are part of the first wave response during virus infection.

show abstract

“…We and others have shown that MNV infected cells increase the transcription of cytokine (IFNβ, TNFα and IL-6) mRNAs (Fig. 4) (56, 57) indicating that PRRs like MDA5 (58) have successfully detected the viral infection and activated an antiviral response against it. Intriguingly, MNV infected cells do not secrete significant levels cytokines which would help to overcome and contain the acute infection (Fig.…”

Section: Discussionmentioning

confidence: 86%

Mouse Norovirus infection arrests host cell translation uncoupled from the stress granule-PKR-eIF2α axis

Fritzlar

Aktepe

Chao

et al. 2019

Preprint

View full text Add to dashboard Cite

1 8 1 9 ¶ These authors contributed equally to this work. SF and TEA are Joint Authors 2 0 2 1 Abstract 2 5The integrated stress response (ISR) is a cellular response system activated upon different 2 6 types of stresses, including viral infection, to restore cellular homeostasis. However, many viruses 2 7 manipulate this response for their own advantage. In this study we investigated the association 2 8between murine norovirus (MNV) infection and the ISR and demonstrate that MNV regulates the 2 9ISR by activating and recruiting key ISR host factors. We observed that during MNV infection, 3 0there is a progressive increase in phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) 3 1 resulting in the suppression of host translation, yet MNV translation still progresses under these 3 2 conditions. Interestingly, the shutoff of host translation also impacts the translation of key signalling 3 3 cytokines such as IFNβ, IL-6 and TNFα. Our subsequent analyses revealed that the phosphorylation 3 4 of eIF2α was mediated via Protein kinase-R (PKR), but further investigation revealed that PKR 3 5 activation, phosphorylation of eIF2α and translational arrest were uncoupled during infection. We 3 6 further observed that stress granules (SGs) are not induced during MNV infection, and MNV has 3 7the capacity to restrict SG nucleation and formation. We observed that MNV recruited the key SG 3 8nucleating protein G3BP1 to its replication sites and intriguingly the silencing of G3BP1 negatively 3 9impacts MNV replication. Thus, it appears, MNV utilises G3BP1 to enhance replication, but 4 0 equally to prevent SG formation, intimating an anti-MNV property of SGs. Overall, thus study 4 1

show abstract

Comparative Transcriptomic Response of Primary and Immortalized Macrophages to Murine Norovirus Infection

Cited by 21 publications

References 79 publications

Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis

Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis

Virus-induced transposable element expression up-regulation in human and mouse host cells

Mouse Norovirus infection arrests host cell translation uncoupled from the stress granule-PKR-eIF2α axis

Contact Info

Product

Resources

About