Center for Global Health

MSC10-5550
1 University of New Mexico
Albuquerque, NM 87131

Phone: (505) 272-8207
Fax: (505) 272-8441

Paratransgenesis Laboratory Research Projects

Grants

Lab work

National Institutes of Health: 1 R01 AI066045-01
“Molecular Targeting of T. cruzi for Paratransgenic Vectors”
Ravi Durvasula, MD (PI); 4 year project period
February 15, 2007- February 14, 2011


United States Dept. of Agriculture, Biotechnology Risk Assessment Grant CREES 04-2945
“A Paratransgenic Approach to Control of Pierce’s Disease”
Thomas Miller:PI
Role: Subcontractor; 2 year project period
Feb. 2005- Feb. 2007


University of New Mexico RAC Grant
“Paratransgenic Approaches to Human Clostridium difficle Infections”
Role: PI
Feb. 2007- Feb. 2008


National Institutes of Health RO1 AI073912-01
“A Paratransgenic Strategy for Southern Cone Vectors of Chagas disease”
Ravi Durvasula, MD (PI); 5 year project period
Pending


National Institutes of Health RO1, AI 48649-01
“A strategy for spreading foreign genes in Chagas disease vectors”
PI: Ravi Durvasula, MD 4 year award,
April 2001- May 2005; completed

Paratransgenic Approaches to Control of Chagas Disease

Chagas disease, or American Trypanosomiasis, remains a leading cause of heart disease south of the US border, with close to 12 million afflicted individuals, 40 million at-risk individuals and 50,000 deaths per year throughout Central and South America. It is caused by the parasite, Trypanosoma cruzi, and is transmitted to humans by triatomine or kissing bugs.

Projects related to Chagas disease are aimed at development of:

  • molecular strategies to target Trypanosoma cruzi
  • techniques to deliver engineered bacteria to field populations of triatomine bugs
  • mathematical models related to optimized gene delivery
  • risk assessment tools to evaluate environmental impact of paratransgenic interventions
  • detailed analysis of triatomine bugs in terms of microbiology and effects of foreign gene expression on vector physiology

Key collaborating institutions:

  • University of Westminster, London, UK
  • Universitad Del Valle, Guatemala City, Guatemala
  • Centers for Disease Control and Prevention, Atlanta, GA, USA
  • IPM Development Corporation, Portland, OR,USA
  • University of Buenos Aires, Buenos Aires, Argentina
  • FIOCRUZ, Belo Horizonte, Brazil
  • Sandia National Labs, Albuquerque, NM, USA

Paratransgenic Approaches to Clostridium Difficile Infections

Nosocomial infection with Clostridium difficile is rapidly emerging as a serious threat throughout the U.S. Cases of C. difficile infection have doubled in the Veterans Administration Hospital System since 1994, to an estimated number of 10/1000 discharges in 2004; for persons over 65 years of age, the rate has increased to 20/1000 discharges. Additional treatment cost due to C. difficile infection is estimated at $3600 per case. Incidence and complexity of C. difficile infection is likely to increase. An aging population, increasing levels of co-morbidity, and widespread use of broad-spectrum antibiotics will fuel the epidemic of nosocomial C. difficile.

The most worrisome aspects of the current C. difficile epidemic are (1) emergence of bacterial resistance to the front-line antibiotic metronidizole and (2) the appearance of a more virulent strain of C. difficile with enhanced toxigenic potential and floroquinolone resistance. Increasingly, oral vancomycin has become the treatment of choice for nosocomial C. difficile, though cost and emergence of vancomycin resistance limit this approach and result in frequent relapses.

The need for novel therapeutic and prophylactic approaches to C. difficile is urgent. We propose to develop a line of genetically modified Bifidobacteria –common human probiotic bacteria- that elaborate single chain antibodies capable of binding and neutralizing C. difficile toxins A and B. We will engineer the sFv from hybridoma lines that elaborate anti-C. difficile toxin monoclonal antibodies, clone genes encoding these sFv’s, characterize expression and binding of sFv’s, and test the efficacy of this approach in a hamster model of C. difficile infection. For these studies, we will use a matched system with B. pseudolongum and the corresponding animal (hamster) model. We hypothesize that engineered lines of Bifidobacteria elaborating antitoxin sFv will prevent pathological changes due to administered C. difficile toxins in the hamster model. These studies are the laboratory proof-of-concept of a paratransgenic approach that may eventually be developed for human application using common, non-pathogenic, probiotic organisms.

Key collaborating institutions:

  • University of Westminster, London, UK

Paratransgenic Approaches to Control of Visceral Leishmaniasis

The spectrum of leishmaniasis has tremendous global impact with over 300 million cases per year and incidence in over 80 countries. Parasites of the genus Leishmania are transmitted to humans via sandfly vectors. Visceral leishmaniasis, termed kala azar, is endemic to regions of Eastern India, Nepal and Bangladesh and, in India, is caused by the parasite, L. donovani, and transmitted via the sandfly Phlebotomus argentipes.

Current projects in the Durvasula lab are aimed at:

  • identification of commensal bacteria of P. argentipes in endemic and non-endemic regions of Eastern India
  • development of paratransgenic lines of P. argentipes and
  • identification of molecular targets on the surface of L. donovani for paratransgenic interventions

See also Kala Azar Research In India.

Key collaborating institutions:

  • Walter Reed Army Institute of Research, Bethesda, MD, USA
  • Rajendra Memorial Research Institute, Patna, India

Paratransgenic Approaches to Diseases of Commercial Mariculture

World aquaculture production has increased to 51.4 million metric tons (MT) in 2002, with a value of $60 billion. Of this, global shrimp production is greater than 5 million MT and remains the most important trade commodity. Farmed shrimp account for 1.6 million MT, representing a value of nearly $9 billion.

Disease outbreaks cause significant losses in aquaculture production throughout the world and greatly reduce export trade for affected nations. The most striking examples are shrimp viral diseases particularly White Spot Syndrome Virus (WSSV), which has devastated many parts of the world, with grave economic consequences and reduction in available food supply. The global annual economic loss due to WSSV is estimated to be $3 billion.

Antibiotic use as a prophylactic measure is tightly regulated in almost all countries due to emergence of antibiotic resistant microbes and offers no benefit against this viral disease. Effective vaccination techniques or antiviral treatments for WSSV are currently unavailable. Given the tremendous global impact of WSSV on shrimp farming and the constraints of high-intensity cultivation, new strategies to combat WSSV are highly essential.

Current projects in the Durvasula lab are focused on:

  • development of genetically engineered algae and cyanobacteria which can be used as feed for the shrimp, P. monodon
  • expression of molecules with activity against viral and Vibrio pathogens in transformed lines of algae and cyanobacteria
  • development of paratransgenic Artemia which can be deployed as feed to nauplii of P. monodon to confer passive immunity
  • testing of engineered organisms at shrimp hatchery settings in Andhra Pradesh, India

Key collaborating institutions:

  • BMR Hatcheries, Visakhapatnam, India
  • Shree Vasudha Labs, Visakhapatnam, India
  • Bedford Institute of Oceanography, Dartmouth, Canada