Biology subjects

Aranday-Cortes, E.

Publications and source records attributed to Aranday-Cortes, E..

3 recordsLinked to original sources

bioRxiv2022

A human and rhesus macaque interferon-stimulated gene screen reveals ARHGEF3/XPLN as an antiviral gene against hepatitis C virus and other flaviviruses

Natural hepatitis C virus (HCV) infection is restricted to humans whereas in other primates such as rhesus macaques, the virus is non-permissive. To identify human and rhesus macaque genes that differ or share the ability to inhibit HCV replication, we conducted a medium-throughput screen of lentivirus-expressed host genes that disrupt replication of HCV subgenomic replicon RNA expressing secreted Gaussia luciferase. A combined total of >800 interferon-stimulated genes (ISGs) were screened. Our findings confirmed established anti-HCV ISGs, such as IRF1, PKR and DDX60. Novel species-specific inhibitors were also identified and independently validated. Using a cell-based system that recapitulates productive HCV infection, we identified the Rho Guanine Nucleotide Exchange Factor 3 gene (ARHGEF3) from both species as a restriction factor for full-length virus replication. Mechanistically, ARHGEF3-mediated inhibition was ablated by mutating a critical GEF active site residue and deleting the N-terminal portion of the protein. Additionally, replication of two mosquito-borne flaviviruses, yellow fever virus (YFV) and Zika virus (ZIKV), were reduced in ARHGEF3-expressing cell lines compared to controls. In conclusion, we ascribe novel antiviral activity to the cellular gene ARHGEF3 that inhibits replication of HCV and other important human viral pathogens belonging to the Flaviviridae, and is conserved between humans and rhesus macaques.

microbiology↗

bioRxiv2018

Interferon lambda 4 impacts broadly on hepatitis C virus diversity.

Type III interferons (IFN-{lambda}) are part of the innate immune response to hepatitis C virus (HCV) infection however the specific role of IFN-{lambda}4 and the nature of the viral adaption to this pressure have not been defined. Here we use paired genome-wide human and viral genetic data in 485 patients infected with HCV genotype 3a to explore the role of IFN-{lambda}4 on HCV evolution during chronic infection. We show that genetic variations within the host IFNL4 locus have a broad and systematic impact on HCV amino acid diversity. We also demonstrate that this impact is larger in patients producing a more active form of IFN-{lambda}4 protein compared to the less active form. A similar observation was noted for viral load. We conclude that IFN-{lambda}4 protein is a likely causal agent driving widespread HCV amino acid changes and associated with viral load and possibly other clinical and biological outcomes of HCV infection.

genomics↗

bioRxiv2017

A Polymorphic Residue That Attenuates Interferon Lambda 4 Activity in Hominid Lineages

As antimicrobial signalling molecules, type III or lambda interferons (IFN{lambda}s) are critical for defence against infection by diverse pathogens. Counter-intuitively, expression of one member of the family, IFN{lambda}4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural in-frame nucleotide insertion that abrogates IFN{lambda}4 production improves viral clearance. To further understand how genetic variation between and within species affects IFN{lambda}4 function, we screened a panel of extant coding variants of human IFN{lambda}4 and identified three variants that substantially affect antiviral activity (P70S, L79F and K154E). The most notable variant was K154E, which enhanced in vitro activity in a range of antiviral and interferon stimulated gene (ISG) assays. This more active E154 variant of IFN{lambda}4 was found only in African Congo rainforest Pygmy hunter-gatherers. Remarkably, E154 was highly conserved as the ancestral residue in mammalian IFN{lambda}4s yet K154 is the dominant variant throughout evolution of the hominid genus Homo. Compared to chimpanzee IFN{lambda}4, the human orthologue had reduced activity due to amino acid substitution of glutamic acid with lysine at position 154. Meta-analysis of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFN{lambda}4 is consistent with differences in antiviral gene expression in vivo during HCV infection. Mechanistically, our data suggest that human-specific K154 likely affects IFN{lambda}4 activity by reducing secretion and potency. We postulate that evolution of an IFN{lambda}4 with attenuated activity in humans (K154) likely contributes to distinct host-specific responses to and outcomes of infection, such as HCV.

immunology↗