Biology subjects

Ravenhill, B. J.

Publications and source records attributed to Ravenhill, B. J..

4 recordsLinked to original sources

bioRxiv2025

Viral Diversity Influences T Cell Responses to Enteric Human Adenoviruses F40 and F41

BackgroundHuman enteric species F adenoviruses are a leading cause of diarrhoea-associated paediatric morbidity and mortality worldwide. The cellular immune response (antigen-specific cytotoxic T cells and secreted cytokines) to human adenovirus (HAdV) infection is known to ameliorate symptoms and is critical for viral clearance. We hypothesised that the capsid proteins (hexon and penton) of HAdV-F40 and 41 (F40, F41) are evolving to escape cellular immune responses. Major histocompatibility complex (MHC) binding of viral peptides is a key step in the presentation of peptide-MHC complexes which activate the T cell receptor and the cytotoxic T cell response. MethodsUsing global HAdV genomic data, we predicted MHC-peptide binding within the hexon and penton proteins of F40 and F41. We focused on MHC class I alleles common in the UK and Kenya and identifying predicted CD8+ T cell epitopes. Eight predicted epitope pairs from the F41 hexon were synthesised as 15mer peptides, comparing the wildtype (1970 F41 reference) to the variant (2019-2022) sequences. Cellular IFN{gamma} responses to these epitopes were measured in healthy donors using FluoroSpot assays. ResultsWe identified multiple predicted CD8+ T cell epitopes shared between HAdV-species C and F, but also unique to species F, and epitopes unique to each genotype. We show that IFN{gamma} and IL2 peripheral blood mononuclear cell (PBMC) responses to HAdV-F are ubiquitous among healthy adult donors from Cambridge, UK. Among predicted CD8+ epitopes within the F41 hexon, 11/16 peptides elicited donor positive IFN{gamma} responses from healthy donor PBMC (at least one epitope from seven out of eight peptide pairs). ConclusionsThe hexon and penton proteins of HAdV-F-40 and F41 are predicted to contain a number of genotype-specific, but conserved, CD8+ T cell epitopes which could be used to inform future vaccine design. Using the hexon of F41 as a case study, we show that predicted T cell epitopes in emergent strains are able to elicit an inflammatory cytokine response from healthy donor PBMC. The role of T cell recognition in driving enteric adenovirus evolution deserves further consideration.

microbiology↗

bioRxiv2024

Spatial proteomics identifies a novel CRTC-dependent viral sensing pathway that stimulates production of Interleukin-11

Appropriate cellular recognition of viruses is essential for the generation of effective innate and adaptive antiviral immunity. Viral sensors and their signalling components thus provide a crucial first line of host defence. Many exhibit subcellular relocalisation upon activation, triggering expression of interferon and antiviral genes. To identify novel signalling factors we analysed protein relocalisation on a global scale during viral infection. CREB Regulated Transcription Coactivators-2 and 3 (CRTC2/3) exhibited early cytoplasmic-to-nuclear translocation upon a diversity of viral stimuli, in diverse cell types. This movement was depended on Mitochondrial Antiviral Signalling Protein (MAVS), cyclo-oxygenase proteins and protein kinase A. We identify a key effect of transcription stimulated by CRTC2/3 translocation as production of the pro-fibrogenic cytokine interleukin-11. This may be important clinically in viral infections associated with fibrosis, including SARS-CoV-2.

immunology↗

bioRxiv2020

Comprehensive cell surface proteomics defines markers of classical, intermediate and non-classical monocytes

Monocytes are a critical component of the cellular innate immune system, and can be subdivided into classical, intermediate and non-classical subsets on the basis of surface CD14 and CD16 expression. Classical monocytes play the canonical role of phagocytosis, and account for the majority of circulating cells. Intermediate and non-classical cells are known to exhibit varying levels of phagocytosis and cytokine secretion, and are differentially expanded in certain pathological states. Characterisation of cell surface proteins expressed by each subset is informative not only to improve understanding of phenotype, but may also provide biological insights into function. Here we use highly multiplexed Tandem-Mass-Tag (TMT)-based mass spectrometry with selective cell surface biotinylation to characterise the classical monocyte surface proteome, then interrogate the phenotypic differences between each monocyte subset to identify novel protein markers.

immunology↗

bioRxiv2018

Red blood cell tension controls Plasmodium falciparum invasion and protects against severe malaria in the Dantu blood group

Malaria has had a major effect on the human genome, with many protective polymorphisms such as sickle cell trait having been selected to high frequencies in malaria endemic regions1, 2. Recently, we showed that a novel blood group variant, Dantu, provides 74% protection against all forms of severe malaria in homozygous individuals3-5. This is a similar degree of protection to sickle cell trait and considerably greater than the most advanced malaria vaccine, but until now the mechanism of protection has been unknown. In the current study, we demonstrate a significant impact of Dantu on the ability of Plasmodium falciparum merozoites to invade RBCs. The Dantu variant was associated with extensive changes to the RBC surface protein repertoire, but unexpectedly the malaria protective effect did not correlate with specific RBC-parasite receptor-ligand interactions. By following invasion using video microscopy, we found a strong link between RBC tension and parasite invasion and, even in non-Dantu RBCs, identified a tension threshold above which RBC invasion did not occur. Dantu RBCs had higher average tension, meaning that a higher proportion of Dantu RBCs could not be invaded. These findings not only provide an explanation for the protective effect of Dantu against severe malaria, but also provide fresh insights into the essential process of P. falciparum parasite invasion, and how invasion efficiency varies across the heterogenous populations of RBCs that are present both within and between individuals.

genetics↗