Infectious Diseases

The goal of the doctoral graduate training program in the Infectious Diseases specialty is to prepare scientists to become future research and academic leaders in the field of infectious diseases. A key emphasis is placed on the many and diverse aspects of the interactions of pathogenic and opportunistic microogranisms with the normal and immunodeficient host. This specialty provides a multidisciplinary perspective in the investigation of microbial infections covering the entire spectrum from the molecular level to that of the whole organism. Graduates of this program are able to apply their scientific knowledge and technical skills to address significant health problems that relate to infectious diseases of both human and nonhuman animals.

Research Areas
This program supports research initiatives in the following areas:

• Cryptosporidiosis (Tzipori, Widmer, Sheoran, Singh, Akiyoshi)
  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 and sequencing of the genome.

• Microsporidiosis (Tzipori, Singh, Sheoran, Feng)
  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.

• E. coli disease (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.

• Molecular Helminthology Lab (Skelly, Shoemaker)
  Our 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.

  Molecular Helminthology Lab Web Site

• 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.

• 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.

• 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.

• The Microbiology Research Unit (MRU)
  Foodborne illness is an ongoing major problem in the United States, which annually experiences approximately 76 million illnesses and 5,000 deaths due to foodborne pathogens. In 2003, the NIH selected six institutions to form the Food and Waterborne Diseases Integrated Research Network (FWD-IRN). The MRU at Tufts University is part of this network, which, together with other units, was established to evaluate vaccines, therapeutics, rapid detection methods, body defenses, and microbiology and ecology of diseases transmitted between human and animals. The network's goal is to establish coordinated groups to enhance the United State's capacity to prevent, treat and control food and waterborne diseases that pose significant health risks to humans and are bioterrorist agents. Scientists at the MRU at Tufts are charged with the task to identify and characterize multiple human pathogens that can cause human diseases in food or water suspected of either accidental or deliberate contamination.

• The National Center for Botulinum Therapies Research and Development
  The Centers for Disease Control rates botulinum - a virulent and often deadly form of food poisoning affecting humans and animals - as a biologic agent of highest concern because of its ease of produce and dissemination, difficulties to treat, and potential to damage public health extensively. Researchers working in the MRU at Tufts are collaborating with other U.S. public and private institutions to establish the nation's first Center for Botulinum Therapies Research and Development to develop and evaluate antitoxin therapies against each of seven botulinum neurotoxins.