Biology subjects

Edwards, M. R.

Publications and source records attributed to Edwards, M. R..

3 recordsLinked to original sources

bioRxiv2026

A rhinovirus vaccine evokes T cell mediated cross-reactive immunity in a preclinical model of rhinovirus infection

Rhinovirus (RV) infection is the most common cause of acute exacerbations of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Vaccines are available for two less common respiratory viruses (influenza and respiratory syncytial viruses), but development of a RV vaccine to protect patients with chronic respiratory disease has been hampered by the large number of serologically distinct RV strains ([~]180, grouped genetically into [~]80 A, [~]30 B and [~]70 C strains). We have explored the potential of the RV-A16 VP0 subunit vaccine in both CpG-adjuvanted protein subunit and mRNA formats. We demonstrate that both vaccine formats induce strong effector CD4 and CD8 T cell responses in the airways and lungs of immunized mice that rapidly expand following infection with a heterotypic RV strain and are associated with enhanced virus clearance. Adjuvanted VP0 protein subunit vaccination evoked strong germinal center reactions in the lymph nodes and markedly accelerated the production of neutralizing antibodies following heterotypic RV infection. In contrast, VP0 mRNA vaccination evoked limited germinal center responses and neutralizing antibody production. Th1 polarized immune responses were induced against a large panel of 20 heterologous RV strains representative of all RV-A, -B and -C strains. This study confirms the potential of RV VP0 vaccination as an approach to overcome the serological diversity of RV and describes the immune response evoked, including cross-strain cellular immunity and protection against heterotypic RV infection.

immunology↗

bioRxiv2019

Impact of Mengla virus proteins on human and bat innate immune pathways

M[e]ngla virus (MLAV), identified in Rousettus bats, is a phylogenetically distinct member of the family Filoviridae. Because filoviruses Ebola virus (EBOV) and Marburg virus (MARV) modulate host innate immune pathways, MLAV VP35, VP40 and VP24 proteins were compared with their EBOV and MARV homologs for innate immune pathway modulation. In human and Rousettus cells, MLAV VP35 behaved like EBOV and MARV VP35s, inhibiting virus-induced activation of the interferon (IFN)-{beta} promoter. MLAV VP35 inhibited IRF3 phosphorylation and interacted with PACT, a host protein engaged by EBOV VP35 to inhibit RIG-I signaling. MLAV VP35 also inhibited PKR activation. MLAV VP40 was demonstrated to inhibit type I IFN induced gene expression in human and bat cells. It blocked STAT1 tyrosine phosphorylation induced either by type I IFN or over-expressed Jak1, paralleling MARV VP40. MLAV VP40 also inhibited virus-induced IFN{beta} promoter activation, a property shared by MARV VP40 and EBOV VP24. The inhibition of IFN induction was preserved in the presence of a Jak kinase inhibitor, demonstrating that inhibition of Jak-STAT signaling is not sufficient to explain inhibition of IFN{beta} promoter activation. MLAV VP24 did not inhibit IFN-induced gene expression or bind karyopherin 5, properties of EBOV VP24. MLAV VP24 also differed from MARV VP24 in that it failed to interact with Keap1 or activate an antioxidant response element reporter gene, due to the absence of a Keap1-binding motif. These studies demonstrate similarities between MLAV and MARV in how they suppress IFN responses and differences in how MLAV VP24 interacts with host pathways.\n\nImportanceEBOV and MARV, members of the family Filoviridae, are highly pathogenic zoonotic viruses that cause severe disease in humans. Both viruses use several mechanisms to modulate the host innate immune response, and these likely contribute to severity of disease. Here, we demonstrate that MLAV, a filovirus newly discovered in a bat, suppresses antiviral type I interferon responses in both human and bat cells. Inhibitory activities are possessed by MLAV VP35 and VP40, which parallels how MARV blocks IFN responses. However, whereas MARV activates cellular antioxidant responses through an interaction between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1 binding motif and fails to activate this cytoprotective response. These data indicate that MLAV possesses immune suppressing functions that could facilitate human infection. They also demonstrate key differences in MLAV versus either EBOV or MARV engagement of host signaling pathways.

microbiology↗

bioRxiv2018

Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium.

Asthma is a chronic airway disease driven by complex genetic-environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood. We undertook genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma and healthy controls. We identified 49,903 regions exhibiting differential H3K27ac enrichment in asthma, clustered at genes associated with type-2-high asthma (CLCA1) and epithelial processes (EMT). Asthma dramatically influenced the BEC enhancer landscape and we identified asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (NOX4). We integrated published protein, epigenomic and transcriptomic datasets and identified epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and dynamic relationships between asthma-associated changes in H3K27ac, DNA methylation, genetic susceptibility and transcriptional profiles. Finally, we used a CRISPR-based approach to recapitulate the H3K27ac-asthma landscape in vitro and provide proof of principal that asthma-associated gene expression (SERPINB2) is driven in part by aberrant histone acetylation, validating the combination of genome-wide and epigenome-editing approaches in deciphering the molecular mechanisms underlying asthma pathogenesis.

genomics↗