Back to Search
Start Over
Murine Norovirus Infection Results in Anti-inflammatory Response Downstream of Amino Acid Depletion in Macrophages
- Source :
- Journal of Virology
- Publication Year :
- 2021
- Publisher :
- American Society for Microbiology, 2021.
-
Abstract
- Murine norovirus (MNV) infection results in a late translation shutoff that is proposed to contribute to the attenuated and delayed innate immune response observed both in vitro and in vivo. Recently, we further demonstrated the activation of the α subunit of eukaryotic initiation factor 2 (eIF2α) kinase GCN2 during MNV infection, which has been previously linked to immunomodulation and resistance to inflammatory signaling during metabolic stress. While viral infection is usually associated with activation of double-stranded RNA (dsRNA) binding pattern recognition receptor PKR, we hypothesized that the establishment of a metabolic stress in infected cells is a proviral event, exploited by MNV to promote replication through weakening the activation of the innate immune response. In this study, we used multi-omics approaches to characterize cellular responses during MNV replication. We demonstrate the activation of pathways related to the integrated stress response, a known driver of anti-inflammatory phenotypes in macrophages. In particular, MNV infection causes an amino acid imbalance that is associated with GCN2 and ATF2 signaling. Importantly, this reprogramming lacks the features of a typical innate immune response, with the ATF/CHOP target GDF15 contributing to the lack of antiviral responses. We propose that MNV-induced metabolic stress supports the establishment of host tolerance to viral replication and propagation. IMPORTANCE During viral infection, host defenses are typically characterized by the secretion of proinflammatory autocrine and paracrine cytokines, potentiation of the interferon (IFN) response, and induction of the antiviral response via activation of JAK and Stat signaling. To avoid these and propagate, viruses have evolved strategies to evade or counteract host sensing. In this study, we demonstrate that murine norovirus controls the antiviral response by activating a metabolic stress response that activates the amino acid response and impairs inflammatory signaling. This highlights novel tools in the viral countermeasures arsenal and demonstrates the importance of the currently poorly understood metabolic reprogramming occurring during viral infections.
- Subjects :
- Eukaryotic Initiation Factor-2
Immunology
ved/biology.organism_classification_rank.species
translation
Protein Serine-Threonine Kinases
Viral Nonstructural Proteins
Biology
Virus Replication
Antiviral Agents
Microbiology
Cell Line
Proinflammatory cytokine
Mice
03 medical and health sciences
Interferon
Virology
medicine
Animals
Integrated stress response
Autocrine signalling
Caliciviridae Infections
RNA, Double-Stranded
030304 developmental biology
Inflammation
0303 health sciences
Innate immune system
Activating Transcription Factor 2
ved/biology
Macrophages
Norovirus
030302 biochemistry & molecular biology
stress response
Protein kinase R
Immunity, Innate
Virus-Cell Interactions
3. Good health
Cell biology
RAW 264.7 Cells
Viral replication
Insect Science
Interferons
Signal Transduction
Murine norovirus
medicine.drug
Subjects
Details
- ISSN :
- 10985514 and 0022538X
- Volume :
- 95
- Database :
- OpenAIRE
- Journal :
- Journal of Virology
- Accession number :
- edsair.doi.dedup.....66fc6cdcf39ec62685c0460b66061717