David W Pascual

David W Pascual

Professor Of Immunology

Department: VM-RESEARCH / GRADUATE
Business Phone: (352) 294-4104
Business Email: pascuald@ufl.edu

Research Profile

The focus of my laboratory is to understand the basic tenets of mucosal immunology and their application to improve targeted mucosal vaccine delivery. Attenuated Salmonella vectors, adept at delivering vaccines to the Peyer’s patches, elicit T helper (Th) 1 cell (IFN-γ-dependent) immune responses to resolve its infection. However, our studies show we can obtain elevated Th2 cell (IL-4- and IL-13-dependent) immune responses, followed by a delayed onset of Th1 cells to colonization factor antigen I (CFA/I), from human enterotoxigenic Escherichia coli (ETEC). Subsequent studies reveal that proinflammatory cytokine production are abated, suggesting this acts as an anti-inflammatory vaccine. Current studies are evaluating the efficacy of this vaccine against autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis. Our recent findings show this vaccine induces regulatory T (Treg) cells, but the type of regulatory cell induced is disease-dependent: CD25+ Treg (EAE) and CD39+ Tregcells (arthritis). We are currently investigating how Salmonella-CFA/I stimulates the production of these Treg cells, and we are determining the involved dendritic cells that sustain these responses. Recent studies are focused on using the recombinant CFA/I fimbriae, since these were found to be as effective as the live vaccine in reducing arthritis, and on determining the underlying mechanisms for conferring protection against autoimmune insult.

Effective treatments for multiple sclerosis (MS) are problematic due to its unknown etiology. Current work has adapted the rodent EAE model to test whether our tolerogen vaccine delivery platform, the reovirus adhesin, protein sigma 1 (pσ1), can improve mucosal auto-antigen uptake. We have shown a single low-dose of pσ1-based vaccines induces tolerance and prevents or treats autoimmunity when applied mucosally. Amazingly, this new therapeutic can abate MS-like disease within 24 hrs, stimulating an array of regulatory cells to intervene in the central nervous system (CNS). This pσ1-mediated tolerance is, in part, IL-10-dependent via Treg cells. In addition, regulatory elements with the IL-4- and IL-28-producing CD25- CD4+ T cells have also been found. Further work will determine the mechanisms used by pσ1 and will help us to understand the involved dendritic cell subset(s) that stimulates regulatory T cells. Ultimately, these studies will determine the feasibility of using a pσ1-based single-dose delivery system to prevent and/or treat autoimmune diseases.

Members of Category B agents, Brucella species, are highly infectious Gram-negative bacteria that are a global health threat to both humans and livestock. Brucellosis is naturally transmitted via ingestion of unpasteurized dairy products, causing mostly a systemic disease manifesting with flu-like systems, which, despite antibiotic treatment, can cause a recurring sequelae evident as undulant fever and arthritis. Brucellae survival within the host is linked to its ability to resist intracellular recognition, thus, allowing them to sequester in various tissues. Vaccines that can recapitulate aspects of Brucella infection should prove effective to resolve such infections. Yet, to date, there are no effective vaccines for humans and inadequate vaccines for livestock. It is known protection is cell-mediated immunity-dependent and particularly involves TNF-α and IFN-γ. In this regard, we have recently developed live vaccine prototypes that can confer complete protection in some animals with no detectable brucellae. When given orally, these vaccines confer >80% protection against nasal B. melitensis infection, and of these, no brucellae (>4-5 log reduction in tissue colonization) could be detected in host tissues. Given the potency of these vaccine formulations, we are uniquely poised to test the efficacy of these vaccines against parenteral, oral, and pulmonary Brucella challenges.

Publications

2016 Veterinary Immunology and Immunopathology
2014 Experimental and molecular medicine (Online)

Grants

Apr 2020 ACTIVE
Snodgrassella alvi as an attenuated live vaccine against Neisseria gonorrhoeae
NATL INST OF HLTH NIAID ·
Aug 2019 – Aug 2020
Evaluation of VTC-D87 with IL-2mutein to measure Treg durability in the NOD model
VIRTICI LLC · Principal Investigator
Jul 2019 ACTIVE
A Novel Probiotic for the Treatment of Sj?grens Syndrome
RISE THERAPEUTICS · Principal Investigator
Oct 2018 – Mar 2020
Evaluation of VTC-MS3 in the EAE model
VIRTICI LLC · Principal Investigator
Jan 2018 – Mar 2019
Brucellosis Vaccine Prize: Phase 1
GALVMED ·
Aug 2017 ACTIVE
Naso-oropharyngeal Brucella Infections and Mucosal Immune Protection
NATL INST OF HLTH NIAID · Principal Investigator
Apr 2017 ACTIVE
Regulatory Cell Therapy for Sj?grens Syndrome.
NATL INST OF HLTH NIDCR · Principal Investigator
Apr 2017 ACTIVE
OoR CTSI Institutional Matching Support
UF DIV OF SPONSORED RES MATCHING FUNDS · Project Manager
Jan 2017 – May 2017
Evaluation of VTC-MS3 in the EAE model
VIRTICI LLC · Principal Investigator
Aug 2016 – Jul 2018
A Novel Probiotic for the Treatment of Sjogren's Syndrome.
VIRTICI LLC · Principal Investigator
May 2016 – Apr 2017
Sony cell sorter SH800 system
NATL INST OF HLTH OD · Principal Investigator
Mar 2016 – Feb 2019
Fimbriae Countermeasures for Type 1 Diabetes
NATL INST OF HLTH NIAID · Principal Investigator
Jan 2016 ACTIVE
Mucosal Vaccines for Brucellosis
NATL INST OF HLTH NIAID · Principal Investigator
Jan 2015 – Nov 2016
TARGETED MUCOSAL VACCINES FOR BOTULINUM
UF FOU · Principal Investigator
Sep 2013 – Aug 2018
Brucellosis Vaccines for Livestock
US DEPT OF AG NATL INST OF FOOD AND AG · Principal Investigator
Nov 2012 – Apr 2017
Subunit Vaccines for Brucella Pathogens.
NATL INST OF HLTH NIAID · Principal Investigator
Jul 2012 – Jun 2017
Mucosal vaccination to protect against HIV-1 infection
DUKE UNIV · Principal Investigator

Education

Doctor of Philosophy
1987 · University of Mississippi
Master of Science
1985 · University of Mississippi

Contact Details

Phones:
Business:
(352) 294-4104
Emails:
Business:
pascuald@ufl.edu

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