Scott, A. E. | Search bioRxiv

bioRxiv2020

Assessments of hepatitis B virus-like particles and Crm197 as carrier proteins in melioidosis glycoconjugate vaccines

The Tier 1 select agent Burkholderia pseudomallei is the causative agent of melioidosis, a global pathogen and a major cause of pneumonia and sepsis for which no licensed vaccines currently exist. Previous work has shown the potential for Burkholderia capsular polysaccharide (CPS) to be used as a vaccine antigen but the T-cell independent nature of the immune response to this molecule requires the use of this polysaccharide as a glycoconjugate for vaccination. Recent studies have focussed on the use of Crm197 (a non-toxic mutant protein derived from diphtheria toxin) as the carrier but there are concerns regarding its potential to cause interference with other vaccines containing Crm197. Therefore research with alternative carrier proteins would be beneficial. In this study, CPS was isolated from the non-pathogenic B. thailandensis strain E555. This was chemically conjugated to Crm197, or Tandem Core virus-like particles (TCVLP) consisting of hepatitis B core protein, which is the first documented use of VLPs in melioidosis vaccine development. Analysis of CPS-specific IgG antibody titres showed that mice vaccinated with the Crm197 conjugate generated significantly higher titres than the mice that received TCVLP-CPS but both conjugate vaccines were able to protect mice against intraperitoneal B. pseudomallei strain K96243 challenges of multiple median lethal doses.

immunology↗

bioRxiv2017

Integrated Human-Virus Metabolic Modelling Predicts Host-Based Antiviral Targets Against Chikungunya, Dengue and Zika Viruses

Current and reoccurring viral epidemic outbreaks such as those caused by Zika virus illustrate the need for rapid development of antivirals. Such development would be immensely facilitated by computational approaches that can provide experimentally testable predictions for possible antiviral strategies. A key factor that has not been considered fully to date in the study of antiviral targets is the high dependence of viruses to their host metabolism for reproduction. Here, we focus on this dependence and develop a stoichiometric, genome-scale metabolic model that integrates human macrophage cell metabolism with the biochemical demands arising from virus production. Focusing this approach to currently epidemic viruses Chikungunya, Dengue and Zika, we find that each virus causes specific alterations in the host metabolic flux towards fulfilling their individual biochemical demands as predicted by their genome and capsid structure. Subsequent analysis of this integrated model allows us to predict a set of host reactions, which when constrained can inhibit virus production. We show that this prediction recovers most of the known targets of existing antiviral drugs, while highlighting a set of hitherto unexplored reactions with either broad or virus specific antiviral potential. Thus, this computational approach allows rapid generation of experimentally testable hypotheses for novel antiviral targets within a host.\n\nSIGNIFICANCE STATEMENTA key challenge in combatting any new and emerging virus outbreaks is rapid drug development. In particular, generation of experimentally testable hypotheses through computational approaches is mostly lacking. Here, we address this gap by developing host-virus metabolic models for three viruses that cause current (or previously) epidemic viral outbreaks. We develop viral biomass functions using information from their genomes and physical structure, and incorporate these within a genome-scale metabolic model of human macrophage cells. The resulting integrated model allows us to predict host reactions, which when blocked, stop the system from attaining optimal viral production. These predictions recover currently known antiviral targets within human cells, and highlight a set of new reactions that are hitherto not explored for antiviral capacity.

systems biology↗