William James

William James
University of Oxford | OX · Sir William Dunn School of Pathology

DPhil

About

253
Publications
38,294
Reads
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8,847
Citations
Citations since 2016
116 Research Items
5463 Citations
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Introduction
The macrophage is a key cell in AIDS pathogenesis, and HIV has developed a number of “stealth” mechanisms to circumvent their innate antiviral defences, only some of which are understood. In order to elucidate these mechanisms, we have developed stem cell-based technologies, which enable us to test biological hypotheses in ways that have not been possible before. We have identified a novel endocytic pathway in macrophages that is absolutely required for HIV infection, and are investigating its detailed molecular machinery. We are also probing the subsequent steps of the life cycle, in which virus and host cell factors engage in a struggle for dominance. The stem cell research in our lab is supervised by Dr Sally Cowley, who heads the James Martin Stem See www.wsjlab.com for more details.
Additional affiliations
October 1984 - present
University of Oxford
Position
  • Professor of Virology
Education
October 1981 - July 1984
University of Oxford
Field of study
  • Biochemistry
October 1978 - June 1981
University of Birmingham
Field of study
  • Biological Sciences

Publications

Publications (253)
Article
Full-text available
The SARS-CoV-2 pandemic continues despite the presence of effective vaccines, and novel vaccine approaches may help to reduce viral spread and associated COVID-19 disease. Current vaccine administration modalities are based on systemic needle-administered immunisation which may be suboptimal for mucosal pathogens. Here we demonstrate in a mouse mod...
Preprint
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SAMHD1 is a key regulator of dNTP metabolism, being activated by dGTP and converting dNTPs into their respective nucleosides. As a result, it plays a significant role in several distinct diseases. Not only is SAMHD1 a restriction factor for HIV-1 replication, which requires dNTPs for replication, but it is also required for genome stability, is mut...
Preprint
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Neuronal progenitor subtypes have distinct fate restrictions regulated by time-dependent activation of energetic pathways during development. Thus, the hijacking of cellular metabolism by Zika virus (ZIKV) to support its replication may contribute to damage in the developing fetal brain. Here, we showed that 2D in vitro differentiation of human ind...
Preprint
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There is increasing genetic evidence for the role of microglia in neurodegenerative diseases, including Alzheimers, Parkinsons, and motor neuron disease. Therefore, there is a need to generate authentic in vitro models to study human microglial physiology. Various methods have been developed using human induced Pluripotent Stem Cells (iPSC) to gene...
Article
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Motor neuron diseases such as amyotrophic lateral sclerosis are primarily characterized by motor neuron degeneration with additional involvement of non-neuronal cells, in particular, microglia. In previous work, we have established protocols for the differentiation of iPSC-derived spinal motor neurons and microglia. Here, we combine both cell linea...
Article
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Flaviviruses have caused large epidemics and ongoing outbreaks for centuries. They are now distributed in every continent infecting up to millions of people annually and may emerge to cause future epidemics. Some of the viruses from this group cause severe illnesses ranging from hemorrhagic to neurological manifestations. Despite decades of researc...
Article
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Background Evaluation of susceptibility to emerging SARS-CoV-2 variants of concern (VOC) requires rapid screening tests for neutralising antibodies which provide protection. Methods Firstly, we developed a receptor-binding domain-specific haemagglutination test (HAT) to Wuhan and VOC (alpha, beta, gamma and delta) and compared to pseudotype, micro...
Preprint
The role of the human type I interferon (IFN-I) system in restricting Zika virus (ZIKV) is uncertain. Here, genetic and pharmacological ablation of IFN-I signalling enhanced ZIKV replication and cytopathicity in macrophages and microglia, key cells in ZIKV transmission and pathogenesis. Thus, despite the extensive IFN-I countermeasures employed by...
Article
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The trajectories of acquired immunity to severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We present a detailed longitudinal cohort study of UK healthcare workers prior to vaccination, presenting April-June 2020 with asymptomatic or symptomatic infection. Here we show a highly variable range of responses, some of...
Article
Full-text available
Zika virus (ZIKV) is a mosquito-borne, single-stranded RNA virus belonging to the genus Flavivirus. Although ZIKV infection is usually known to exhibit mild clinical symptoms, intrauterine ZIKV infections have been associated with severe neurological manifestations, including microcephaly and Guillain Barre syndrome (GBS). Therefore, it is imperati...
Article
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Zika virus (ZIKV), despite being discovered six decades earlier, became a major health concern only after an epidemic in French Polynesia and an increase in the number of microcephaly cases in Brazil. Substantial evidence has been found to support the link between ZIKV and neurological complications in infants. The virus targets various cells in th...
Article
Background Inflammatory phenomena such as hyperinflammation or hemophagocytic lymphohistiocytosis are a frequent yet paradoxical accompaniment to viral susceptibility in patients with impairment of type I interferon (IFN-I) signaling caused by deficiency of STAT2 or IRF9. Objective We hypothesized that altered and/or prolonged IFN-I signaling cont...
Article
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Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single-molecule fluorescence in situ hybridisat...
Article
Full-text available
Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has prompted a wider application of this technology to meet the public health challenge of pandem...
Article
Full-text available
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new beta coronavirus that emerged at the end of 2019 in the Hubei province of China. SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) and was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. Herd or community immunity has been proposed as a strategy t...
Article
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NP105–113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105–113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assess...
Article
Background: Administration of potent anti-receptor-binding domain (RBD) monoclonal antibodies has been shown to curtail viral shedding and reduce hospitalization in patients with SARS-CoV-2 infection. However, the structure-function analysis of potent human anti-RBD monoclonal antibodies and its links to the formulation of antibody cocktails remain...
Article
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Background Previous infection with SARS-CoV-2 affects the immune response to the first dose of the SARS-CoV-2 vaccine. We aimed to compare SARS-CoV-2-specific T-cell and antibody responses in health-care workers with and without previous SARS-CoV-2 infection following a single dose of the BNT162b2 (tozinameran; Pfizer–BioNTech) mRNA vaccine. Method...
Article
Full-text available
Background: Previous infection with SARS-CoV-2 affects the immune response to the first dose of the SARS-CoV-2 vaccine. We aimed to compare SARS-CoV-2-specific T-cell and antibody responses in health-care workers with and without previous SARS-CoV-2 infection following a single dose of the BNT162b2 (tozinameran; Pfizer-BioNTech) mRNA vaccine. Met...
Article
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Zika virus (ZIKV) received worldwide attention over the past decade when outbreaks of the disease were found to be associated with severe neurological syndromes and congenital abnormalities. Unlike most other flaviviruses, ZIKV can spread through sexual and transplacental transmission, adding to the complexity of Zika pathogenesis and clinical outc...
Article
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Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in the fluid has important uses in biotechnology, and is integral to many point-of-care SARS-CoV-2 diagnostics. Sandwich enzyme-linked immunosorbent assays (ELISAs) are a sensitive, well-established method of measuring antigens in solutions. They use one ligand to ca...
Article
Full-text available
SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We rep...
Preprint
Full-text available
Evaluation of susceptibility to emerging SARS-CoV-2 variants of concern (VOC) requires rapid screening tests for neutralising antibodies which provide protection. We developed a receptor-binding domain specific hemagglutination test (HAT) which correlated with neutralising antibodies (R=0.74-0.82) in two independent cohorts from 798 convalescents....
Article
Full-text available
The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from nat...
Article
Full-text available
Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified viral components and inactivated viruses. However, structural and ultrastructural evidence on how the SARS-CoV-2 infection progresses in the native cellular context is scarce, and there is a lack of comprehensive knowledge on the SARS-CoV-2 replica...
Preprint
Full-text available
NP 105-113 -B*07:02 specific CD8 ⁺ T-cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP 105-113 -B*07:02 specific T-cell clones and single cell sequencing were performed concurrently, with functional avidity and anti-viral efficacy...
Preprint
Full-text available
Despite an unprecedented global research effort on SARS-CoV-2, early replication events remain poorly understood. Given the clinical importance of emergent viral variants with increased transmission, there is an urgent need to understand the early stages of viral replication and transcription. We used single molecule fluorescence in situ hybridisat...
Preprint
Full-text available
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is normally controlled by effective host immunity including innate, humoral and cellular responses. However, the trajectories and correlates of acquired immunity, and the capacity of memory responses months after infection to neutralise variants of concern - which has important...
Article
Full-text available
Human induced pluripotent stem cells (iPSCs) and macrophages derived from them are increasingly popular tools for research into both infectious and degenerative diseases. However, as the field strives for greater modeling accuracy, it is becoming ever more challenging to justify the use of undefined and proprietary media for the culture of these ce...
Preprint
Full-text available
SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We rep...
Article
Full-text available
Background: Following a single dose of BNT162b2 mRNA vaccine, higher antibody titres are observed following prior SARS-CoV-2 infection than in infection-naive individuals, but T-cell responses are less well defined. Methods: We sampled healthcare workers (HCWs) enrolled in the UK PITCH study, before and after BNT162b2 mRNA vaccination. We measured...
Article
Full-text available
COVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 2 million fatalities to date. Viral replication is shaped by the cellular microenvironment and one important factor to consider is oxygen tension, where hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily inf...
Preprint
Full-text available
The ability of acquired immune responses against SARS-CoV-2 to protect after subsequent exposure to emerging variants of concern (VOC) such as B1.1.7 and B1.351 is currently of high significance. Here, we use a hamster model of COVID-19 to show that prior infection with a strain representative of the original circulating lineage B of SARS-CoV-2 ind...
Article
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A Correction to this paper has been published: https://doi.org/10.1038/s41594-021-00566-w.
Article
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Serological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral...
Article
Microglia orchestrate neuroimmune responses in several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Microglia clear up dead and dying neurons through the process of efferocytosis, a specialized form of phagocytosis. The phagocytosis function can be disrupted by environmental or genetic risk factors that affect...
Preprint
Full-text available
Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK,...
Preprint
Full-text available
Both natural infection with SARS-CoV-2 and immunization with vaccines induce protective immunity. However, the extent to which such immune responses protect against emerging variants is of increasing importance. Such variants of concern (VOC) include isolates of lineage B.1.1.7, first identified in the UK, and B.1.351, first identified in South Afr...
Preprint
Full-text available
Both natural infection with SARS-CoV-2 and immunization with a number of vaccines induce protective immunity. However, the ability of such immune responses to recognize and therefore protect against emerging variants is a matter of increasing importance. Such variants of concern (VOC) include isolates of lineage B1.1.7, first identified in the UK,...
Article
Full-text available
Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike, and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data driven method to map RBD binding sites. We find that althoug...
Article
Full-text available
SARS-CoV-2 has caused over 2M deaths in little over a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of the pandemic and error-prone virus replication is leading to the appearance of mutant viruses and potentially escape from antibody responses. Variant B.1.1.7, now dominant in the UK, wi...
Article
Full-text available
The race to produce vaccines against SARS-CoV-2 began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK–B.1.1.7, South Africa–B.1.351 and Brazil–P.1. These variants have multiple changes in the immunodominant spike protein whic...
Article
Full-text available
Macrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that the distribution and prevalence of resident macrophages in the s...
Preprint
Full-text available
Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified recombinant viral components and inactivated viruses. However, structural and ultrastructural evidence on how the SARS-CoV-2 infection progresses in the frozen-hydrated native cellular context is scarce, and there is a lack of comprehensive knowled...
Article
Full-text available
Human induced Pluripotent Stem Cell (hiPSC) models are a valuable new tool for research into neurodegenerative diseases. Neuroinflammation is now recognized as a key process in neurodegenerative disease and aging, and microglia are central players in this. A plethora of hiPSC-derived microglial models have been published recently to explore neuroin...
Article
TREM2 is a microglia‐specific gene, with mutations linked to Alzheimer’s disease, including R47H (1). In AD mouse models, knockout (KO) of TREM2 impairs microglial clustering around amyloid and prevents microglia from being activated into a “disease‐associated” transcriptional state (2). The R47H mutation has been proposed to reduce ligand binding...