Dr. David Pascual, (Ph.D. Philosophy, University of Mississippi) Wyoming Excellence Chair in Brucellosis.

 

Research Interests:

Brucella species are highly infectious Gram-negative bacteria that pose a global health threat to humans and livestock.  Brucellosis continues to be problematic for livestock producers in western US, where Brucella has infected elk and bison.  Brucellosis can also be transmitted to humans via ingestion of unpasteurized dairy products, causing mostly a systemic disease manifesting with flu-like systems. Despite antibiotic treatment, infected patient can experience 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. Given Brucella’s stealth qualities, vaccines are needed to overcome such properties and make brucellae immunogenic to effectively resolve infection.  Current livestock vaccines recapitulate some aspects of Brucella infections, and these have proven to be suboptimally efficacious. It is known that protection is cell-mediated immunity-dependent, and particularly involves TNF-α and IFN-γ.  In this regard, we have recently developed several live vaccine prototypes that can confer complete protection in some animals with no detectable brucellae. We have found that these experimental vaccines prove more effective when administered mucosally, e.g., oral prime, nasal boost.  Mucosal formulations are used considering that disease transmission in livestock and wildlife occurss mostly via a mucosal surface; hence, arming the mucosa with anti-Brucella defense seems like a logical approach to improve animal protection.  Given the potency of our vaccine candidates, we are uniquely poised to test the efficacy of these vaccines against parenteral and mucosal Brucella challenges.

 

A significant focus of my laboratory is to understand the basic tenets of mucosal immunology and their application to improve mucosal vaccine and therapeutic delivery. An interesting development occurred when we used attenuated Salmonella vectors to elicit protective immunity against colonization factor antigen I (CFA/I) fimbriae, from human enterotoxigenic Escherichia coli (ETEC). In contrast to conventional Salmonella-based vaccines that typically elicit T helper (Th) 1 cell (IFN-γ-dependent) immune responses, we found that our Salmonella-CFA/I strain stimulated elevated Th2 cell (IL-4- and IL-13-dependent) immune responses, followed by a delayed onset of Th1 cells. Such results implicated the suppression of proinflammatory cytokine production, suggesting that CFA/I fimbriae act as an anti-inflammatory vaccine. When tested against various autoimmune disease models, we learned that CFA/I fimbriae expressed either by attenuated Salmonella vectors or Lactococcus lactis or purified fimbriae administered orally, could suppress autoimmune disease development or limit further tissue destruction. Current studies are evaluating the efficacy of L. lactis delivered CFA/I protein to treat Sjögren’s syndrome (SjS), a disease that manifests as an autoimmune attack of salivary and lacrimal glands leading to symptoms of dry mouth and eyes.  Current work is also investigating the potential treatment of patients with multiple sclerosis, type 1 diabetes, or rheumatoid arthritis.  Results from our studies show this therapeutic stimulates regulatory T (Treg) cells, but the type of regulatory cell induced is disease-dependent: CD25+ Treg (SjS) and CD39+ Treg cells (arthritis).  Using these tools, we seek to diminish autoimmune disease symptom.