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The Pirbright Institute publication directory contains details of selected publications written by our researchers.

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Carter T, Iqbal M (2024)

The Influenza A Virus Replication Cycle: A Comprehensive Review

viruses 16 (2)
Publisher’s version: https://doi.org/10.3390/v16020316

Abstract

Influenza A virus (IAV) is the primary causative agent of influenza, colloquially called the flu. Each year, it infects up to a billion people, resulting in hundreds of thousands of human deaths, and causes devastating avian outbreaks with worldwide losses worth billions of dollars. Always present is the possibility that a highly pathogenic novel subtype capable of direct human-to-human transmission will spill over into humans, causing a pandemic as devastating if not more so than the 1918 influenza pandemic. While antiviral drugs for influenza do exist, they target very few aspects of IAV replication and risk becoming obsolete due to antiviral resistance. Antivirals targeting other areas of IAV replication are needed to overcome this resistance and combat the yearly epidemics, which exact a serious toll worldwide. This review aims to summarise the key steps in the IAV replication cycle, along with highlighting areas of research that need more focus.

Gubbins S (2024)

Quantifying the relationship between within-host dynamics and transmission for viral diseases of livestock

Journal of Royal Society Interface
Publisher’s version: https://doi.org/10.1098/rsif.2023.0445

Abstract

Understanding the population dynamics of an infectious disease requires linking within-host dynamics and between-host transmission in a quantitative manner, but this is seldom done in practice. Here a simple phenomenological model for viral dynamics within a host is linked to between-host transmission by assuming that the probability of transmission is related to log viral titre. Data from transmission experiments for two viral diseases of livestock, foot-and-mouth disease virus in cattle and swine influenza virus in pigs, are used to parametrize the model and, importantly, test the underlying assumptions. The model allows the relationship between within-host parameters and transmission to be determined explicitly through their influence on the reproduction number and generation time. Furthermore, these critical within-host parameters (time and level of peak titre, viral growth and clearance rates) can be computed from more complex within-host models, raising the possibility of assessing the impact of within-host processes on between-host transmission in a more detailed quantitative manner.

Morales SV, Coelho GM, Ricciadi-Jorge T, Dorl GG, Zanluca C, Santos CNDC (2024)

Development of a quantitative NS1 antigen enzyme-linked immunosorbent assay (ELISA) for Zika virus detection using a novel virus-specific mAb

Scientific reports 14 (1)
Publisher’s version: https://doi.org/10.1038/s41598-024-52123-2

Abstract

Viruses from the Flaviviridae family, such as Dengue virus (DENV), Yellow fever virus (YFV), and Zika virus (ZIKV) are notorious global public health problems. ZIKV emergence in Polynesia and the Americas from 2013 to 2016 raised concerns as new distinguishing features set it apart from previous outbreaks, including its association with neurological complications and heightened disease severity. Virus detection is impaired as cross-reactivity to other closely related orthoflaviviruses is common among commercially available diagnostic kits. While non-structural protein 1 (NS1) has been used as an early marker of DENV and West Nile virus (WNV) infection, little is known about NS1 expression during ZIKV infection. In the present work, we developed a NS1 capture ELISA using a novel ZIKV-specific monoclonal antibody to study NS1 expression dynamics in vitro in mosquito and human cell lines. While detectable in culture supernatants, higher concentrations of NS1 were predominantly cell-associated. To our knowledge, this is the first report of NS1 detection in human cells despite viral clearance over time. Tests with human samples need to be conducted to validate the applicability of NS1 detection for diagnosis, but overall, the tools developed in this work are promising for specific detection of acute ZIKV infection.

Keep S, Stevenson-Leggett P, Webb I, Fones A, Kirk J, Britton P, Bickerton E (2024)

The spike protein of the apathogenic Beaudette strain of avian coronavirus can elicit a protective immune response against a virulent M41 challenge

PLOS ONE 19 (1)
Publisher’s version: https://doi.org/10.1371/journal.pone.0297516

Abstract

The avian Gammacoronavirus infectious bronchitis virus (IBV) causes major economic losses in the poultry industry as the aetiological agent of infectious bronchitis, a highly contagious respiratory disease in chickens. IBV causes major economic losses to poultry industries across the globe and is a concern for global food security. IBV vaccines are currently produced by serial passage, typically 80 to 100 times in chicken embryonated eggs (CEE) to achieve attenuation by unknown molecular mechanisms. Vaccines produced in this manner present a risk of reversion as often few consensus level changes are acquired. The process of serial passage is cumbersome, time consuming, solely dependent on the supply of CEE and does not allow for rapid vaccine development in response to newly emerging IBV strains. Both alternative rational attenuation and cell culture-based propagation methods would therefore be highly beneficial. The majority of IBV strains are however unable to be propagated in cell culture proving a significant barrier to the development of cell-based vaccines. In this study we demonstrate the incorporation of a heterologous Spike (S) gene derived from the apathogenic Beaudette strain of IBV into a pathogenic M41 genomic backbone generated a recombinant IBV denoted M41K-Beau(S) that exhibits Beaudette's unique ability to replicate in Vero cells, a cell line licenced for vaccine production. The rIBV M41K-Beau(S) additionally exhibited an attenuated in vivo phenotype which was not the consequence of the presence of a large heterologous gene demonstrating that the Beaudette S not only offers a method for virus propagation in cell culture but also a mechanism for rational attenuation. Although historical research suggested that Beaudette, and by extension the Beaudette S protein was poorly immunogenic, vaccination of chickens with M41K-Beau(S) induced a complete cross protective immune response in terms of clinical disease and tracheal ciliary activity against challenge with a virulent IBV, M41-CK, belonging to the same serogroup as Beaudette. This implies that the amino acid sequence differences between the Beaudette and M41 S proteins have not distorted important protective epitopes. The Beaudette S protein therefore offers a significant avenue for vaccine development, with the advantage of a propagation platform less reliant on CEE.

Zhang Z, Gallo G, Sharma Pa, Ha J, Magri A, Borrmann H, Harris JM, Tsudkuda S, Bentley E, Kirby A, de Neck S, Yang H, Balfe P, Wing PAC, Matthews D, Harris AL, Kipar A, Stewart JP, Bailey D, McKeating JA (2024)

Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression

iScience 27 (1), 108763
Publisher’s version: https://doi.org/10.1016/j.isci.2023.108763

Abstract

Respiratory syncytial virus (RSV) is a global healthcare problem, causing respiratory illness in young children and elderly individuals. Our knowledge of the host pathways that define susceptibility to infection and disease severity are limited. Hypoxia inducible factors (HIFs) define metabolic responses to low oxygen and regulate inflammatory responses in the lower respiratory tract. We demonstrate a role for HIFs to suppress RSV entry and RNA replication. We show that hypoxia and HIF prolyl-hydroxylase inhibitors reduce the expression of the RSV entry receptor nucleolin and inhibit viral cell-cell fusion. We identify a HIF regulated microRNA, miR-494, that regulates nucleolin expression. In RSV-infected mice, treatment with the clinically approved HIF prolyl-hydroxylase inhibitor, Daprodustat, reduced the level of infectious virus and infiltrating monocytes and neutrophils in the lung. This study highlights a role for HIF-signalling to limit multiple aspects of RSV infection and associated inflammation and informs future therapeutic approaches for this respiratory pathogen.

Elahir YM, Ishag HZA, Wadsworth J, Hicks HM, Knowles NJ, Mioulet V, King DP, Mohamed MS, Bensalah OK, Yusof MF, Gasim EFM, Hammadi ZMA, Shah AAM, Abdelmagid YA, El Gahlan MAM, Kassim MF, Kayaf K, Zahran A, Nuaimat MMA (2024)

Molecular Epidemiology of Foot-and-Mouth Disease Viruses in the Emirate of Abu Dhabi, United Arab Emirates

veterinary sciences 11 (1)
Publisher’s version: https://doi.org/10.3390/vetsci11010032

Abstract

Foot-and-mouth disease (FMD) is an endemic disease in the United Arab Emirates (UAE) in both wild and domestic animals. Despite this, no systematic FMD outbreak investigation accompanied by molecular characterisation of FMD viruses (FMDVs) in small ruminants or cattle has been performed, and only a single report that describes sequences for FMDVs in wildlife from the Emirate has been published. In this study, FMD outbreaks that occurred in 2021 in five animal farms and one animal market in the Emirate of Abu Dhabi were investigated. Cases involved sheep, goats, and cattle, as well as Arabian oryx (Oryx leucoryx). Twelve samples were positive for FMDV via RT-qPCR, and four samples (Arabian oryx n = 1, goat n = 2, and sheep n = 1) were successfully genotyped using VP1 nucleotide sequencing. These sequences shared 88~98% identity and were classified within the serotype O, Middle East-South Asia topotype (O/ME-SA). Phylogenetic analysis revealed that the Arabian oryx isolate (UAE/2/2021) belonged to the PanAsia-2 lineage, the ANT-10 sublineage, and was closely related to the FMDVs recently detected in neighbouring countries. The FMDV isolates from goats (UAE/10/2021 and UAE/11/2021) and from sheep (UAE/14/2021) formed a monophyletic cluster within the SA-2018 lineage that contained viruses from Bangladesh, India, and Sri Lanka. This is the first study describing the circulation of the FMDV O/ME-SA/SA-2018 sublineage in the UAE. These data shed light on the epidemiology of FMD in the UAE and motivate further systematic epidemiological studies and genomic sequencing to enhance the ongoing national animal health FMD control plan.

Ellis J, Brown E, Colenutt C, Schley D, Gubbins S (2024)

Inferring transmission routes for foot-and-mouth disease virus within a cattle herd using approximate Bayesian computation

Epidemics 46
Publisher’s version: https://doi.org/10.1016/j.epidem.2024.100740

Abstract

To control an outbreak of an infectious disease it is essential to understand the different routes of transmission and how they contribute to the overall spread of the pathogen. With this information, policy makers can choose the most efficient methods of detection and control during an outbreak. Here we assess the contributions of direct contact and environmental contamination to the transmission of foot-and-mouth disease virus (FMDV) in a cattle herd using an individual-based model that includes both routes. Model parameters are inferred using approximate Bayesian computation with sequential Monte Carlo sampling (ABC-SMC) applied to data from transmission experiments and the 2007 epidemic in Great Britain. This demonstrates that the parameters derived from transmission experiments are applicable to outbreaks in the field, at least for closely related strains. Under the assumptions made in the model we show that environmental transmission likely contributes a majority of infections within a herd during an outbreak, although there is a lot of variation between simulated outbreaks. The accumulation of environmental contamination not only causes infections within a farm, but also has the potential to spread between farms via fomites. We also demonstrate the importance and effectiveness of rapid detection of infected farms in reducing transmission between farms, whether via direct contact or the environment.

Al-Rawahi WA, Elshafie EI, Baqir S, Al-Ansari A, Wadsworth J, Hicks HM, Knowles NJ, Nardo AD, King DP, Zientara S, Salloom FA, Sangula A, Bernelin-Cottet C, Bakka-Kassimi L, Riyami BA (2024)

Detection of foot-and-mouth disease viruses from the A/AFRICA/G-I genotype in the Sultanate of Oman

Preventive Veterinary Medicine 223
Publisher’s version: https://doi.org/10.1016/j.prevetmed.2023.106113

Abstract

Rapid identification and characterization of circulating foot-and-mouth disease virus (FMDV) strains is crucial for effective disease control. In Oman, a few serological and molecular studies have been conducted to identify the strains of FMDV responsible for the outbreaks that have been occurring within the country. In this study, 13 oral epithelial tissue samples from cattle were collected from suspected cases of FMD in Ash Sharqiyah North, Al Batinah North, Dhofar and Ad Dhakhyilia governorates of Oman between 2018 and 2021. FMDV RNA was detected in all samples by real-time RT-PCR and viruses were isolated after one- or two-blind passages in the porcine Instituto Biologico-Rim Suino-2 cell line. Antigen capture ELISA characterized all isolates as serotype A and VP1 phylogenetic analysis placed all sequences within a single clade of the G-I genotype within the A/AFRICA topotype. These sequences shared the closest nucleotide identities to viruses circulating in Bahrain in 2021 (93.5% to 99.5%) and Kenya in 2017 (93.4% to 99.1%). To the best of our knowledge, this is the first time that A/AFRICA/G-I viruses have been detected in Oman. Together with the closely related viruses detected recently in Bahrain, these findings reinforce the importance of deploying effective quarantine control measures to minimize the risks of transboundary transmission of FMD associated with the importation of cattle from East Africa.

 

Newbrook K, Khan N, Fisher A, Chong K, Gubbins S, Davies WC, Sanders C, Busquets MG, Cooke L, Corla A, Ashby M, Flannery J, Batten C, Stokes JE, Sanz-Bernardo B, Carpenter S, Moffat K, Darpel KE (2024)

Specific T-cell subsets have a role in anti-viral immunity and pathogenesis but not viral dynamics or onwards vector transmission of an important livestock arbovirus

Frontiers in Immunology 15
Publisher’s version: https://doi.org/10.3389/fimmu.2024.1328820

Abstract

Introduction: Bluetongue virus (BTV) is an arthropod-borne Orbivirus that is almost solely transmitted by Culicoides biting midges and causes a globally important haemorrhagic disease, bluetongue (BT), in susceptible ruminants. Infection with BTV is characterised by immunosuppression and substantial lymphopenia at peak viraemia in the host.

Methods: In this study, the role of cell-mediated immunity and specific T-cell subsets in BTV pathogenesis, clinical outcome, viral dynamics, immune protection, and onwards transmission to a susceptible Culicoides vector is defined in unprecedented detail for the first time, using an in vivo arboviral infection model system that closely mirrors natural infection and transmission of BTV. Individual circulating CD4+, CD8+, or WC1+ γδ T-cell subsets in sheep were depleted through the administration of specific monoclonal antibodies.

Results: The absence of cytotoxic CD8+ T cells was consistently associated with less severe clinical signs of BT, whilst the absence of CD4+ and WC1+ γδ T cells both resulted in an increased clinical severity. The absence of CD4+ T cells also impaired both a timely protective neutralising antibody response and the production of IgG antibodies targeting BTV non-structural protein, NS2, highlighting that the CD4+ T-cell subset is important for a timely protective immune response. T cells did not influence viral replication characteristics, including onset/dynamics of viraemia, shedding, or onwards transmission of BTV to Culicoides. We also highlight differences in T-cell dependency for the generation of immunoglobulin subclasses targeting BTV NS2 and the structural protein, VP7.

Discussion: This study identifies a diverse repertoire of T-cell functions during BTV infection in sheep, particularly in inducing specific anti-viral immune responses and disease manifestation, and will support more effective vaccination strategies.

Wang L, Ganges L, Dixon LK, Bu Z, Zhao D, Truong QL, Richt JA, Jin M, Netherton CL, Benarafa C, Summerfield A, Weng C, Peng G, Reis AL, Han J, Penright ML, Mo Y, Su Z, Hoang DV, Pogranichniy RM, Balaban-Oglan DA, Li Y, Wang K, Cai X, Shi J (2023)

2023 International African Swine Fever Workshop: Critical Issues That Need to Be Addressed for ASF Control

viruses 16 (1)
Publisher’s version: https://doi.org/10.3390/v16010004

Abstract

The 2023 International African Swine Fever Workshop (IASFW) took place in Beijing, China, on 18-20 September 2023. It was jointly organized by the U.S.-China Center for Animal Health (USCCAH) at Kansas State University (KSU) and the Chinese Veterinary Drug Association (CVDA) and sponsored by the United States Department of Agriculture Foreign Agricultural Service (USDA-FAS), Harbin Veterinary Research Institute, and Zoetis Inc. The objective of this workshop was to provide a platform for ASF researchers around the world to unite and share their knowledge and expertise on ASF control and prevention. A total of 24 outstanding ASF research scientists and experts from 10 countries attended this meeting. The workshop included presentations on current ASF research, opportunities for scientific collaboration, and discussions of lessons and experiences learned from China/Asia, Africa, and Europe. This article summarizes the meeting highlights and presents some critical issues that need to be addressed for ASF control and prevention in the future.

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