Genetic diversity of Collaborative Cross mice controls viral replication, clinical severity and brain pathology induced by Zika virus infection, independently of Oas1b
Open accessPreprint — published as 10.1128/jvi.01034-19
Abstract
The explosive spread of Zika virus (ZIKV) has been associated with major variations in severe disease and congenital afflictions among infected populations, suggesting an influence of host genes. We investigated how genome-wide variants could impact susceptibility to ZIKV infection in mice. We first describe that the susceptibility of Ifnar1 knockout mice is largely influenced by their genetic background. We then show that the broad genetic diversity of Collaborative Cross mice, which receptor to type I interferon (IFNAR) was blocked by anti-IFNAR antibody, expressed phenotypes ranging from complete resistance to severe symptoms and death with large variations in the peak and rate of decrease of plasma viral load, in brain viral load, in brain histopathology and in viral replication rate in infected cells. Differences of susceptibility between CC strains were correlated between Zika, Dengue and West Nile viruses. We identified highly susceptible and resistant mouse strains as new models to investigate the mechanisms of human ZIKV disease and other flavivirus infections. Genetic analyses revealed that phenotypic variations are driven by multiple genes with small effects, reflecting the complexity of ZIKV disease susceptibility in human population. Notably, our results rule out a role of the Oas1b gene in the susceptibility to ZIKV. Altogether, this study emphasizes the role of host genes in the pathogeny of ZIKV infection and lays the foundation for further genetic and mechanistic studies. IMPORTANCE: In recent outbreaks, ZIKV has infected millions of people and induced rare but potentially severe complications, including Guillain-Barré syndrome and encephalitis in adults. While several viral sequence variants were proposed to enhance the pathogenicity of ZIKV, the influence of host genetic variants in the clinical heterogeneity remains mostly unexplored. We have addressed this question using a mouse panel which models the genetic diversity of human population and a ZIKV strain from a recent clinical isolate. Through a combination of in vitro and in vivo approaches, we demonstrate that multiple host genetic variants determine viral replication in infected cells, and clinical severity, kinetics of blood viral load and brain pathology in mice. We describe new mouse models expressing high susceptibility or resistance to ZIKV and to other flaviviruses. These models will facilitate the identification and mechanistic characterization of host genes that influence ZIKV pathogenesis.
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QTL mapping in multiparent populations has identified genetic modifiers for viral response, kidney disease, atherosclerosis, and heart size.
“For example, QTL mapping in these multiparent populations resulted in the identi cation of genetic modi ers for the viral response [13,14], kidney disease [15], atherosclerosis [16] and heart size [17].”
From Identification of Genetic Variants Regulating the Abundance of Clinically Relevant Plasma Proteins using the Diversity Outbred Mouse Model (2021) · cites this paper as [14]
For this citation, the relevant claim is that QTL mapping identified a modifier of viral response, not the separately cited claims about kidney disease, atherosclerosis, or heart size. In “Genetic analysis suggests a polygenic control of susceptibility to ZIKV in CC mice” (page unavailable), the paper reports that its genome scan found no significant loci for the viral-load traits; the Discussion likewise says no genomic region was significantly associated with viral-load variation. (LLM, conf=0.89)
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References 92 · Cited by 40
Research works printed but not linked: 19
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- Authors
- Manet, C., Simon-Lorière, E., Jouvion, G., Hardy, D., Prot, M., Flamand, M., Panthier, J.-J., Sakuntabhai, A., & Montagutelli, X.
- Affiliations
- Institut Pasteur (FR)
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Journal of Virology
- Publisher
- openRxiv
- Published
- 2019-06-21
- Volume
- 94
- Issue
- 3
- ISSN
- 0022-538X (ISSN-L)
- PMC
- PMC7000970
- OpenAlex
- W2984120059
- Cited by
- 40
- References
- 92
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 8 · 2022: 3 · 2021: 10 · 2020: 6 · 2019: 3
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- Journal of Virology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Agence Nationale de la Recherche (ANR‐10‐LABX‐62‐IBEID, ANR-10-LABX-0062)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Vectors
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Outbreaks Research
- Keywords
- Zika virus, Collaborative Cross mice, host genetic variation, viral replication, clinical severity, neuropathology, blood viral load, Guillain-Barré syndrome, encephalitis
- MeSH terms
- Zika Virus Infection, Zika Virus, Collaborative Cross Mice, Animals, Brain, Chlorocebus aethiops, Disease Models, Animal, Female, Humans, Male, Genetic Variation, Vero Cells, Virus Replication, West Nile virus, 2',5'-Oligoadenylate Synthetase, Mice, Knockout, Viral Load, Mice, Receptor, Interferon alpha-beta
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