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Infectious Diseases

Research Activities

Director: Dr. Saul Tzipori
Investigators: Investigators: Donna Akiyoshi, Naomi Balaban, Arthur Donohue-Rolfe, Hanping Feng, John Herrmann, Jean Mukherjee, Xiaochuan Feng, Jong-Beak Park, Abhineet Sheoran, Charles Shoemaker, Patrick Skelly, Sam Telford and Giovanni Widmer

Funded largely by NIH, the Division of Infectious Diseases conducts research on infections that primarily affect the digestive system. This includes infectious diseases of childhood and opportunistic infections associated with immunodeficiencies caused by HIV/AIDS, malnutrition, or other factors.

The Division has recently received two major funding awards. In 2003, Tufts was one of six institutions selected to form the Food and Waterborne Diseases Integrated Research Network (F&WD-IRN). Within this network, the Division of Infectious Diseases was selected to host The Microbiology and Botulism Research Unit (MBRU). In 2005, the Gates Foundation selected Tufts for a Grand Challenge Award to develop oral recombinant vaccines against childhood diseases for the third world countries.

Multi-project programs that are currently active in the Division of Infectious Diseases include:

Botulism (Tzipori, Shoemaker, Park, Mukherjee, Akiyoshi)
This disease is a flaccid paralysis caused by intoxication of peripheral neurons by Clostridia botulinum neurotoxins. These are the most potent toxins known and are a Category A bioterrorism threat. Our program includes collaborations with a number of prominent national and international research teams and is primarily focused on the development of novel therapies to prevent or reverse botulism.

Cryptosporidiosis (Tzipori, Widmer, Sheoran, Akiyoshi, Feng (Hanping)
This infection is one of the major primary causes of chronic diarrhea and malnutrition in poor countries. Collectively, diarrhea is responsible for over 3.5 million deaths worldwide each year-a third of all deaths in children under the age of 14 years from infectious diseases. Cryptosporidiosis is also one of the opportunistic infections which complicate HIV/AIDS and other immuno-compromised individuals, leading to the untimely death of such patients. There is no effective treatment against this infection, which can be contracted from other infected humans, from animals or from consuming contaminated food and water.

Cryptosporidiosis has emerged over the last decade as the single most important cause of waterborne infections in the U.S. The waking call was a major waterborne outbreak in Milwaukee in 1994 involving 400,000 people and over 100 deaths. Cryptosporidium is on top of the list of concern of the EPA, FDA and USDA; in fact, the EPA will shortly mandate regular monitoring by water utilities for this infection. Tufts' research group is currently the largest federally-funded group in the U.S. working on many diverse aspects of cryptosporidiosis. Projects include laboratory-based studies on the biology of the microorganism, discovery and evaluation of drugs against the disease, functional genomics, association with HIV/AIDS, the role in malnutrition and wasting in children with and without HIV/AIDS, the role in respiratory tract infections.

Diarrheagenic E. coli/HUS associated diseases (Donohue-Rolfe, Tzipori, Akiyoshi, Sheoran)
E. coli O157 and related bacteria are responsible for 100,000 infections in the U.S. annually. People contract the bacteria by eating undercooked meat or by drinking contaminated milk, other drinks and water. While it causes bloody diarrhea in adults, in children and the elderly it can lead to kidney disease and kidney failure, known as "hemolytic uremic syndrome" or HUS. This syndrome is the single most important cause of kidney failure in children in the U.S. and other developed countries. HUS leads to death unless kidney damage is addressed through dialysis or kidney transplantation. Tufts faculty have recently developed a therapy for HUS that will soon be tested for efficacy in human clinical trials.

Enteric Viruses (Herrmann)
The virus laboratory is concentrating on studies with group A rotaviruses, which are the major cause of severe gastroenteritis in infants and young children worldwide, and are also important veterinary pathogens. The immune mechanisms for controlling and preventing rotavirus infection and illness are not well understood, despite extensive investigations concerning immune responses to various rotavirus proteins, experience with live attenuated oral rotavirus vaccines, and seroepidemiological studies. Tufts researchers are using plasmid DNAs (DNA vaccines) and encoding specific viral proteins to study and characterize the immune responses involved in protection against rotavirus infection. Inoculation with plasmid DNAs allows for the expression of immunizing proteins by host cells that take up inoculated DNA. Expression of the immunizing proteins in host cells results in the presentation of normally processed proteins to the immune system, which permits studying immune responses against the native forms of proteins. These studies are designed to determine the major viral proteins involved in induction of protective immunity, and to characterize the relative roles of cell-mediated, humoral, and mucosal responses in the immune process.

Microsporidiosis (Tzipori, Sheoran, Feng (Xiaochuan), Zhang, Akiyoshi)
This disease became recognized in humans with the emergence of AIDS in the mid-1980s. It is responsible for chronic diarrhea and wasting in people with AIDS (responsible for premature death in 35 percent of HIV/AIDS patients in poor countries) and, we believe, in children with malnutrition. The infection is contracted by contact with infected animals and humans and by consumption of contaminated food and water. TCSVM is one of the few research groups studying this infection; investigations include laboratory studies and field work in Africa.

Molecular Helminthology Lab (Skelly, Shoemaker)
The Molecular Helminthology laboratory specializes in the use of molecular biology tools for investigations into host-parasite interactions between helminth (worm) parasites and their mammalian hosts. Globally, worm infections cause diseases in over a billion people and create serious problems for companion and farmed animals. Our lab currently puts some emphasis on the blood flukes that cause human schistosomiasis although we have projects involving cestode tapeworms and several nematode parasites. We are using molecular genetic techniques to characterize the biochemical nature of the surface and to identify vaccine candidates that are exposed to the host and may be protective against parasite infection. The group is particularly interested in molecules involved in the uptake of nutrients across the parasite's body surface. Our laboratory has cloned and characterized genes encoding a wide variety of glucose and amino acid transporters. We are exploring the utility of several new molecular tools such as RNA-mediated interference (RNAi), transgenesis and display technologies to improve our ability to investigate host/parasite interactions.

Monitoring of Water Safety (EPA)
During the last 6 years we developed, optimized, and validated at Tufts University a novel method for concentration of waterborne protozoa from large volumes of water using a specifically designed continuous flow centrifugation. This includes water with complex matrices such as sewage, source and potable water. The method recently approved by the USEPA under Method 1623. It utilizes a compact, specifically designed, portable continuous flow centrifugation (PCFC), modified from a blood cell separator instrument, and has just become commercially available under the name CFC200. A water sample is delivered by a peristaltic pump into a spinning disposable plastic bowl where pathogens are retained within a small volume. Subsequent work has shown that the same approach can be used to concentrate other microorganisms such as cysts of the enteric protozoa Giardia (8-12 µ), and spores of the fungi microsporidia (1-2 µ). Procedures to concentrate E. coli (1-2 µ), and with some modifications the bacteriophage MS2 (<0.01 µ), are currently being developed. We are collaborating with Dr. Walt's laboratory which has developed a multiplex miniaturized fiber optic bead microarrays coupled with a portable confocal-type imaging system to detect both waterborne enteric pathogens and BWA's from the same concentration process.

Shigellosis (Tzipori, Donohue-Rolfe, Zhang, Jeong)
Shigellosis is a major cause of diarrhea and dysentery with high morbidity and mortality in many parts of the world. There have been several attempts to develop vaccines against the disease in the past. Since Shigella species are primarily pathogens of humans and some primates, studies on pathogenesis, vaccine reactogenicity and immunogenicity are mostly determined directly in human volunteers. The lack of animal models has been a major obstacle in the development of effective therapy and prevention. The aim of this project is to develop and evaluate the gnotobiotic piglet as a model for Several drawbacks for using non-human primates as a model include expense and the high ID50 required to induce infection and disease which is some 6 logs higher than that required for humans. The objective of this work is to develop a well characterized reproducible animal model and identify disease parameters that are shared with shigellosis in humans, and those that are unique to the model.

Staphylococcal infections and enterotoxins (Balaban)
Staphylococcus aureus is a major human pathogen that is associated with several life-threatening diseases, particularly in hospitalized patients undergoing major procedures who often become colonized with antibiotic resistance S. aureus. The bacteria produce a protein, termed RNAIII activating protein, or RAP, which induces the bacteria to produce toxins. One approach for therapy is to block the activity of this molecule by either RAP antibodies or by a blocking peptide termed RIP. The peptide RIP indeed was shown to prevent all Staphylococcus-induced infections, including sepsis, cellulitis, keratitis, osteomyelitis, septic arthritis and mastitis. This investigator was instrumental in demonstrating that RAP and RIP regulated bacterial virulence by activating the phosphorylation of a novel signal transducer termed TRAP. TRAP may therefore represent a new class of signal transducers. For example, bacteria that adhere to implanted medical devices or damaged tissue can become the cause of persistent infections through biofilm formation.

Thermostable oral vaccines (Tzipori, Herrmann, Brown)
The goal of this project is to develop thermostable vaccines based on the natural thermostability of spore-forming bacteria. Protective antigens of rotavirus and TPD (tetanus/pertusses/diphtheria) will be expressed on spores and vegetative cell walls of the bacteria Bacillus subtilis. This portion of the work will be done at Dr. Sonenshein's laboratory. At the Division of Infectious Diseases at TCSVM, the safety, immunogenicity which includes humoral and cell-mediated immunity, and resistance to challenge, will be measured in mice, gnotobiotic piglets and non-primates.

Tickborne diseases and Tularemia (Telford)
This project lab focuses on the perpetuation of tick-transmitted infections such as Lyme disease, babesiosis, ehrlichiosis, deer tick virus, and tularemia. The researchers is interested in identifying phenomena occurring at the level of populations, and in particular, processes and factors that regulate how these infectious agents persist from generation to generation (ecological and evolutionary time). Such knowledge is needed for two reasons: (1) it may provide general concepts on the evolution of infectious agents; and (2) such processes or factors may serve as the basis for public health interventions.

A second complementary focus is to measure the public health burden and epidemiology of these environmental infections. The proposed work may provide new approaches to investigating outbreaks of tularemia, plague, and spotted fever that may develop due to unnatural releases in suburban sites, and ultimately, provide needed information on the cellular and molecular basis for limits to natural transmission of these zoonotic pathogens. The investigator's work on Babesia microti is focused on the cause of human babesiosis in eastern North America.

Faculty and Staff

Faculty:

Administrative Staff:

Laboratory Managers:

  • Donald Girouard, Lab Manager
  • Curtis Rich (deputy), Research Assistant

Technical Staff:

  • Hellen Amuguni, PhD student
  • Karen Baldwin, Animal Technician
  • Mike Beshiri, Research Assistant
  • Rita (Fnu) Bhardwaj, PhD student
  • Ruben Bonilla, Sr. Research Technician
  • Patricia Boucher, Assistant Lab. Animal Technician
  • James Brinker, Sr. Research Assistant
  • David Brown, Research Associate
  • Susan Chapman-Bonofiglio, Research Assistant
  • Michelle Debatis, Research Assistant
  • Zahra Faghiri, Research Associate
  • Xiaochuan Feng, Research Associate
  • Elliott Garber, DVM/MS student
  • Heidi Goethert, Research Associate
  • Xianqyun He, PhD, Postdoctoral Associate
  • Dorothy Henry, Sr. Research Assistant
  • Kwang IL Jeong, Research Associate
  • Greice Krautz-Peterson, Research Associate
  • Chueh-Ling Kuo, PhD student
  • Jong-O Lee, Research Associate
  • Sangun Lee, Research Associate
  • Eric London, Research Technician
  • Siobhan Mor, PhD student
  • Catherine McCann Lane, Asst. Animal Lab. Tech.
  • David Ndegwa, Research Assistant
  • Weijia Nie, Research Assistant
  • John Nunnari, Em/Histology Research Assistant
  • Kwasi Ofori, Research Technician
  • Gregory Raih, Sr. Research Technician
  • Curtis Rich, Research Assistant
  • Jingwei Sheng, Postdoctoral Associate
  • Jennifer Steele, PhD student
  • Xingman Sun, PhD, Postdoctoral Associate
  • Jacqueline Tremblay, Research Assistant
  • Anthony Wiffin, Sr. Research Technician
  • Yi-Lin Yang, PhD student
  • Linghui Zhang, Postdoctoral Associate
  • Quanshun Zhang, Research Associate
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