A5072582978- interferon and immune responses
- Poxvirus research and outbreaks
- Herpesvirus Infections and Treatments
- Immunotherapy and Immune Responses
- Immune Response and Inflammation
- Virus-based gene therapy research
- Mosquito-borne diseases and control
- Viral Infections and Vectors
- RNA regulation and disease
- T-cell and B-cell Immunology
- Retinoids in leukemia and cellular processes
- Inflammasome and immune disorders
- Immune Cell Function and Interaction
- Cytokine Signaling Pathways and Interactions
- NF-κB Signaling Pathways
- Ubiquitin and proteasome pathways
- Legume Nitrogen Fixing Symbiosis
- Cell death mechanisms and regulation
- Endoplasmic Reticulum Stress and Disease
- Cytomegalovirus and herpesvirus research
- Plant Virus Research Studies
- Clostridium difficile and Clostridium perfringens research
- Toxoplasma gondii Research Studies
- Prenatal Screening and Diagnostics
- Soybean genetics and cultivation
University of Cambridge
2015-2024
Icahn School of Medicine at Mount Sinai
2021
Cardiff University
2015
Imperial College London
2010-2013
University of Glasgow
2007
University College London
2007
Scripps Research Institute
2007
Bruce Power (Canada)
2003
Innate immunity is the first immunological defence against pathogens. During virus infection detection of nucleic acids crucial for inflammatory response. Here we identify DNA-dependent protein kinase (DNA-PK) as a DNA sensor that activates innate immunity. We show DNA-PK acts pattern recognition receptor, binding cytoplasmic and triggering transcription type I interferon (IFN), cytokine chemokine genes in manner dependent on IFN regulatory factor 3 (IRF-3), TANK-binding 1 (TBK1) stimulator...
The transcription factor NF-κB is essential for immune responses against pathogens and its activation requires the phosphorylation, ubiquitination proteasomal degradation of IκBα. Here we describe an inhibitor from vaccinia virus that has a closely related counterpart in variola virus, cause smallpox, mechanistic similarity with HIV protein Vpu. Protein A49 blocks by molecular mimicry contains motif conserved IκBα which, IκBα, phosphorylated IKKβ causing degradation. Like binds E3 ligase...
The innate immune system is critical in the response to infection by pathogens and it activated pattern recognition receptors (PRRs) binding pathogen associated molecular patterns (PAMPs). During viral infection, direct of nucleic acids, such as genomes DNA viruses, very important for activation immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting Ku70/Ku80 heterodimer catalytic subunit DNA-PKcs was identified cytoplasmic PRR that intracellular virus...
The linear ubiquitin chain assembly complex (LUBAC), consisting of SHANK-associated RH-domain-interacting protein (SHARPIN), heme-oxidized IRP2 ligase-1 (HOIL-1), and HOIL-1-interacting (HOIP), is a critical regulator inflammation immunity. This highlighted by the fact that patients with perturbed ubiquitination caused mutations in Hoip or Hoil-1 genes, resulting knockouts these proteins, may simultaneously suffer from immunodeficiency autoinflammation. TLR3 plays crucial, albeit...
Vaccinia virus (VACV) expresses many proteins that are non-essential for replication but promote virulence by inhibiting components of the host immune response to infection. These immunomodulators include a family have, or predicted structure related B-cell lymphoma (Bcl)-2 protein. Five members VACV Bcl-2 (N1, B14, A52, F1 and K7) have had their crystal solved, others been characterized function assigned (C6, A46), be uncharacterized hitherto (N2, B22, C1). Data presented here show N2 is...
Viruses have evolved sophisticated strategies to exploit host cell function for their benefit. Here we show that under physiologically normal oxygen levels (normoxia) vaccinia virus (VACV) infection leads a rapid stabilization of hypoxia-inducible factor (HIF)-1α, its translocation into the nucleus and activation HIF-responsive genes, such as vascular endothelial growth (VEGF), glucose transporter-1, pyruvate dehydrogenase kinase-1. HIF-1α is mediated by VACV protein C16 binds human sensing...
Developing T cells encounter peripheral self-antigens in the thymus order to delete autoreactive clones. It is now known that autoimmune regulator protein (AIRE), which expressed thymic medullary epithelial cells, plays a key role regulating transcription of these tissue-specific antigens. Mutations AIRE gene are associated with severe multiorgan syndrome (APECED), and reactivities manifest AIRE-deficient mice. Functional as distinct nuclear puncta, although no structural basis existed...
Vaccinia virus (VACV) strain Western Reserve protein C4 has been characterized and its function contribution to virulence assessed. Bioinformatic analysis showed that is conserved in six orthopoxvirus species shares 43 % amino acid identity with VACV C16, a known factor. A recombinant expressing C-terminally tagged version of that, like this 37 kDa expressed early during infection localizes both the cytoplasm nucleus. Functional assays using firefly luciferase reporter plasmid under control...
Cytosolic long double-stranded RNA (dsRNA), among the most potent proinflammatory signals, is recognized by MDA5. MDA5 binds dsRNA cooperatively, forming helical filaments. ATP hydrolysis fulfills a proofreading function promoting dissociation of shorter endogenous dsRΝΑs from while allowing longer viral dsRNAs to remain bound leading activation interferon-β responses. Here, we show that adjacent subunits in MDA5-dsRNA filaments hydrolyze inducing cooperative filament disassembly....
The IκB kinase (IKK) complex regulates activation of NF-κB, a critical transcription factor in mediating inflammatory and immune responses. Not surprisingly, therefore, many viruses seek to inhibit NF-κB activation. vaccinia virus B14 protein contributes virulence by binding the IKKβ subunit IKK preventing response pro-inflammatory stimuli. Previous crystallographic studies showed that has Bcl-2-like fold forms homodimers crystal. However, multi-angle light scattering indicated is...
Abstract IFN-stimulated gene 15 (ISG15) deficiency in humans leads to severe IFNopathies and mycobacterial disease, the latter being previously attributed its extracellular cytokine-like activity. In this study, we demonstrate a novel role for secreted ISG15 as an IL-10 inducer, unique primary human monocytes. A balanced ISG15-induced monocyte/IL-10 versus lymphoid/IFN-γ expression, correlating with p38 MAPK PI3K signaling, was found using targeted vitro ex vivo systems analysis of...
Nuclear domains of promyelocytic leukemia protein (PML) are known to act as signaling nodes in many cellular processes. Although the impact PML expression driving cell fate decisions for injured cells is well established, function context tissue development less understood. Here, vivo role developmental processes murine mammary gland has been investigated. Data presented showing that tightly regulated by three members Stat family transcription factors orchestrate functional secretory...
Vaccinia virus (VACV) uses microtubules for export of virions to the cell surface and this process requires viral protein F12. Here we show that F12 has structural similarity kinesin light chain (KLC), a subunit kinesin-1 motor binds cargo. KLC share similar size, pI, hydropathy cargo-binding tetratricopeptide repeats (TPRs). Moreover, molecular modeling TPRs upon crystal structure KLC2 showed striking conservation structure. We also identified multiple in VACV proteins E2 A36. Data...
Abstract The gut microbiota exerts profound influence on poultry immunity and metabolism through mechanisms that yet need to be elucidated. Here we used conventional germ-free chickens explore the of transcriptomic metabolic signatures along gut-lung axis in poultry. Our results demonstrated a differential regulation certain metabolites genes associated with innate peripheral tissues birds. Furthermore, evidenced microbiota’s capacity regulate mucosal chicken lung during avian influenza...
One of the fundamental features that make viruses intracellular parasites is necessity to use cellular translational machinery. Hence, this a crucial checkpoint for controlling infections. Here, we show dengue and Zika viruses, responsible nearly 400 million infections every year worldwide, explore such control optimal replication. Using immunocompetent cells, demonstrate arrest protein translations happens after sensing dsRNA information required avoid blocking contained in viral 5'-UTR....
Factors influencing T-cell responses are important for vaccine development but incompletely understood. Here, vaccinia virus (VACV) protein N1 is shown to impair the of both effector and memory CD8(+) T cells this correlates with its inhibition nuclear factor-κB (NF-κB) activation. Infection VACVs that either have N1L gene deleted (vΔN1) or contain a I6E mutation (vN1.I6E) abrogates NF-κB resulted in increased central populations, cytotoxicity lower titres after challenge. Furthermore,...
Vaccinia virus (VACV)-derived vectors are popular candidates for vaccination against diseases such as HIV-1, malaria and tuberculosis. However, their genomes encode a multitude of proteins with immunomodulatory functions, several which reduce the immunogenicity these vectors. Hitherto only limited studies have investigated whether removal genes in combination can increase vaccine efficacy further. To this end we constructed viruses based on VACV strain Western Reserve (WR) lacking up to...
There is a paucity of information on dendritic cell (DC) responses to vaccinia virus (VACV), including the traffic DCs draining lymph node (dLN). In this study, using mouse model infection, we studied skin DC migration in response VACV and compared it with tuberculosis vaccine Mycobacterium bovis bacille Calmette-Guérin (BCG), another live attenuated administered via skin. stark contrast BCG, did not relocate dLN VACV. Infection UV-inactivated or modified Ankara promoted movement dLN,...
Abstract Promyelocytic leukaemia nuclear domains (PML‐NDs) comprise a shell of PML protein and many labile cargo proteins. The nature their cargo, juxtaposition to foci damaged DNA following ionizing radiation (IR), the altered damage responses in null cells all implicate PML‐NDs response. In this work, propensity increase number decrease size IR has been studied. Serial quantitative studies endogenous prove that PML‐ND response is not result asymmetry cell cycle distribution can follow IR,...