Biology subjects

Bamford, C.

Publications and source records attributed to Bamford, C..

5 recordsLinked to original sources

bioRxiv2026

ISG15-USP18 signaling restrains viperin-dependent metabolic antiviral restriction

Type I interferon (IFN-I) responses are tightly regulated to balance antiviral defense with cellular homeostasis. In humans, interferon-stimulated gene 15 (ISG15) functions as a critical negative regulator of IFN-I signaling by stabilizing the IFN negative regulator USP18, yet the functional consequences of ISG15 deficiency remain elusive. Here, we show that the loss of ISG15 exaggerates the JAK-STAT activation and, downstream, amplifies multiple ISGs including the nucleotide-modifying enzyme RSAD2 (viperin). Our quantitative proteomics, genetic reconstitution, and signaling analyses establish that defective USP18 stabilization skews the IFN response towards viperin expression. This amplified ISG network promotes viperin-catalyzed accumulation of the antiviral nucleotide analog ddhCTP, resulting in enhanced inhibition of viral RNA synthesis and the replication of Crimean-Congo hemorrhagic fever virus and SARS-CoV-2. Together, these findings demonstrate an ISG15-USP18-viperin axis that can be targeted to boost the metabolic antiviral restriction.

microbiology↗

bioRxiv2025

Serological evidence of SARS-CoV-2 infection in red and fallow deer in Great Britain.

SARS-CoV-2 is the viral agent of COVID-19 disease in humans and has been shown to infect a wide range of mammals, including white-tailed deer in North America and fallow deer in the Republic of Ireland. There are six species of deer in the UK which inhabit both urban and rural areas, providing a broad interface for human-deer interaction. Little is known if British deer species act as a reservoir for zoonotic spread of consequence to human health. Here, we report a high seroprevalence of SARS-CoV-2 neutralising antibodies in British deer, adding native red deer to the list of susceptible species. 62% of fallow and 25% of red deer sampled between 2024 and 2025 from one British deer park were positive for SARS-CoV-2 infection by serology. Data suggest that deer may function as permissive, reservoir-capable hosts and highlight the risks of anthroponosis and zoonosis from unregulated human-deer contact. While there is currently no evidence to suggest that these viruses are persisting within deer populations in Great Britain, the animal origins of SARS-CoV-2 highlight the importance of appropriate and limited interactions with wildlife, to minimise transmission risks and safeguard both animal and human health.

microbiology↗

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↗

bioRxiv2021

Conserved induction of distinct antiviral signalling kinetics by primate interferon lambda 4 proteins

Interferon lambdas (IFN{lambda}) (also known as type III IFNs) are critical cytokines that combat infection predominantly at barrier tissues, such as the lung, liver and gastrointestinal tract. Humans have four IFN{lambda}s (1-4) where IFN{lambda}1-3 show [~]80-95% homology and IFN{lambda}4 is the most divergent displaying only [~]30% sequence identity. Variants in IFN{lambda}4 in humans are associated with the outcome of infection, such as with hepatitis C virus. However, how IFN{lambda}4 variants impact cytokine signalling in other tissues and how well this is conserved is largely unknown. In this study we address whether differences in antiviral signalling exist between IFN{lambda}4 variants in human hepatocyte and intestinal cells, comparing them to IFN{lambda}3. We demonstrate that compared to IFN{lambda}3, wild-type human IFN{lambda}4 induces a signalling response with distinct magnitudes and kinetics, which is modified by naturally-occurring variants P70S and K154E in both cell types. IFN{lambda}4s distinct antiviral response was more rapid yet transient compared to IFN{lambda}1 and 3. Additionally, divergent antiviral kinetics were also observed using non-human primate IFN{lambda}s and cell lines. Furthermore, an IFN{lambda}4-like receptor-interacting interface failed to alter IFN{lambda}1s kinetics. Together our data provide further evidence that major functional differences exist within the IFN{lambda} gene family. These results highlight the possible tissue specialisation of IFN{lambda}s and encourage further investigation of the divergent, non-redundant activities of IFN{lambda}4 and other IFN{lambda}s. Contribution to the FieldViral infections remain major causes of death and disease in humans and other animals. Interferons (IFNs) are a diverse group of host signalling proteins that can induce a potent antiviral state in cells and are intimately involved in the outcome of infection. Genetic variants within one IFN (interferon lambda 4, IFN{lambda}4) are associated with the outcome of hepatitis C infection in humans. However, how IFN{lambda}4 functions - and how natural variants affect its activity - remains poorly understood. Comparing how the antiviral activity changes over time following stimulation with different IFN{lambda}s, we identified that IFN{lambda}4 induces a more rapid antiviral state compared to other IFN{lambda}s in liver and intestinal cells. Importantly, this response was conserved within human variants and between humans and non-human primates (chimpanzee and Rhesus macaque). Our results shed light on the unique functions of the divergent IFN{lambda}4 protein.

immunology↗

bioRxiv2018

Differential induction of interferon stimulated genes between type I and type III interferons is independent of interferon receptor abundance

It is currently believed that type I and III interferons (IFNs) have redundant functions. However, the preferential distribution of type III IFN receptor on epithelial cells suggests functional differences at epithelial surfaces. Here, using human intestinal epithelial cells we could show that although both type I and type III IFNs confer an antiviral state to the cells, they do so with distinct kinetics. Type I IFN signaling is characterized by an acute strong induction of interferon stimulated genes (ISGs) and confers fast antiviral protection. On the contrary, the slow acting type III IFN mediated antiviral protection is characterized by a weaker induction of ISGs in a delayed manner compared to type I IFN. Moreover, while transcript profiling revealed that both IFNs induced a similar set of ISGs, their temporal expression strictly depended on the IFNs, thereby leading to unique antiviral environments. Using a combination of data-driven mathematical modeling and experimental validation, we addressed the molecular reason for this differential kinetic of ISG expression. We could demonstrate that these kinetic differences are intrinsic to each signaling pathway and not due to different expression levels of the corresponding IFN receptors. We report that type III IFN is specifically tailored to act in specific cell types not only due to the restriction of its receptor but also by providing target cells with a distinct antiviral environment compared to type I IFN. We propose that this specific environment is key at surfaces that are often challenged with the extracellular environment.\n\nAuthor summaryThe human intestinal tract plays two important roles in the body: first it is responsible for nutrient absorption and second it is the primary barrier which protects the human body from the outside environment. This complex tissue is constantly exposed to commensal bacteria and is often exposed to both bacterial and viral pathogens. To protect itself, the gut produces, among others, secreted agents called interferons which help to fight against pathogen attacks. There are several varieties (type I, II, and III) of interferons and our work aims at understanding how type I and III interferon act to protect human intestinal epithelial cells (hIECs) during viral infection. In this study, we confirmed that both interferons can protect hIECs against viral infection but with different kinetics. We determined that type I confer an antiviral state to hIECs faster than type III interferons. We uncovered that these differences were intrinsic to each pathway and not the result of differential abundance of the respective interferon receptors. The results of this study suggest that type III interferon may provide a different antiviral environment to the epithelium target cells which is likely critical for maintaining gut homeostasis. Our findings will also help us to design therapies to aid in controlling and eliminating viral infections of the gut.

immunology↗