Browsing by Author "Gennaro, Maria L."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain
    (National Academy of Sciences, 2021) Staquicini, Daniela I.; Tang, Fenny H.F.; Markosian, Christopher; Yao, Virginia J.; Staquicini, Fernanda I.; Dodero-Rojas, Esteban; Contessoto, Vinícius G.; Davis, Deodate; O’Brien, Paul; Habib, Nazia; Smith, Tracey L.; Bruiners, Natalie; Sidman, Richard L.; Gennaro, Maria L.; Lattime, Edmund C.; Libutti, Steven K.; Whitford, Paul C.; Burley, Stephen K.; Onuchic, José Nelson; Arap, Wadih; Pasqualini, Renata; Center for Theoretical Biological Physics
    Development of effective vaccines against coronavirus disease 2019 (COVID-19) is a global imperative. Rapid immunization of the entire human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and different vaccine approaches are being pursued. Engineered filamentous bacteriophage (phage) particles have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the development and initial evaluation of two targeted phage-based vaccination approaches against SARS-CoV-2: dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. For peptide-targeted phage, we performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein. One of these epitopes displayed on the major capsid protein pVIII of phage induced a specific and sustained humoral response when injected in mice. These phage were further engineered to simultaneously display the peptide CAKSMGDIVC on the minor capsid protein pIII to enable their transport from the lung epithelium into the systemic circulation. Aerosolization of these “dual-display” phage into the lungs of mice generated a systemic and specific antibody response. In the second approach, targeted AAVP particles were engineered to deliver the entire S protein gene under the control of a constitutive CMV promoter. This induced tissue-specific transgene expression, stimulating a systemic S protein-specific antibody response in mice. With these proof-of-concept preclinical experiments, we show that both targeted phage- and AAVP-based particles serve as robust yet versatile platforms that can promptly yield COVID-19 vaccine prototypes for translational development.
  • Thumbnail Image
    Item
    Non-monotonic Response to Monotonic Stimulus: Regulation of Glyoxylate Shunt Gene-Expression Dynamics inﾠ Mycobacterium tuberculosis
    (Public Library of Science, 2016) Ascensao, Joao A.; Datta, Pratik; Hancioglu, Baris; Sontag, Eduardo; Gennaro, Maria L.; Igoshin, Oleg A.; Bioengineering; Center for Theoretical Biological Physics
    Understanding how dynamical responses of biological networks are constrained by underlying network topology is one of the fundamental goals of systems biology. Here we employ monotone systems theory to formulate a theorem stating necessary conditions for non-monotonic time-response of a biochemical network to a monotonic stimulus. We apply this theorem to analyze the non-monotonic dynamics of the σB-regulated glyoxylate shunt gene expression in Mycobacterium tuberculosis cells exposed to hypoxia. We first demonstrate that the known network structure is inconsistent with observed dynamics. To resolve this inconsistency we employ the formulated theorem, modeling simulations and optimization along with follow-up dynamic experimental measurements. We show a requirement for post-translational modulation of σB activity in order to reconcile the network dynamics with its topology. The results of this analysis make testable experimental predictions and demonstrate wider applicability of the developed methodology to a wide class of biological systems.