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The National Foundation for Infectious Diseases (NFID) awarded six infectious disease researchers with its Young Investigator Matching Grants (YIMG). The YIMG program, which is intended for young investigators who are beginning their research career, is supported by an educational grant from Schering-Plough.
The YIMG program matches funding from the awardee's host institution to underwrite pilot work leading to further research. A peer review system comprised of members from the Infectious Diseases Society of America and the American Society for Microbiology evaluated the proposals. The awardees and their area of research are as follows:
Glenn J. Fennelly, MD, aims to develop a novel strategy in which to immunize against the measles virus in the presence of maternal neutralizing antibody. He plans to accomplish this by using naked DNA or "nucleic acid vaccine" plasmids, which is a small piece of circular DNA that can reproduce itself in bacteria, but not in other cells, delivered to mucosal surfaces by a highly attenuated strain of Shigella flexneri.
The purpose of Dr. Fennelly's research is to develop a more effective measles vaccine for small children. Measles kills an estimated one million children worldwide each year, with many of its victims in developing nations. Existing live attenuated or weakened measles virus vaccines are not always effective in infants under 12 months because they are neutralized by maternal antibodies. When live vaccines are given at a higher concentration to overcome these antibodies, they are associated with increased mortality.
"Naked DNA vaccines have been shown to induce protective immune responses in animal models," Dr. Fennelly said. His goal is to deliver these naked DNA plasmids orally, circumventing the need to immunize with the existing live attenuated viruses. This will prevent the need for an injection and may allow for the induction of measles immunity at the respiratory mucosa.
Dr. Fennelly is currently an assistant professor of pediatrics at the Montefiore Medical Center and the Albert Einstein College of Medicine in New York. He received his medical degree from the University of Medicine and Dentistry of New Jersey.
Pathogens such as Haemophilus influenzae are responsible for a wide range of local respiratory and systemic disease. They may play a significant role in the pathophysiology of ongoing lung destruction in patients persistently colonized, such as those with cystic fibrosis and chronic bronchitis, by stimulating the release of inflammatory mediators.
Disease due to H. influenzae begins with the colonization of the respiratory tract mucosa and is facilitated by hair-like adhesive appendages called pili. Graham P. Krasan, MD, believes that these pili can trigger exaggerated immunological responses in phagocytes, also known as scavenger cells.
Dr. Krasan's hypothesis is that this phenomenon also occurs during infection of the epithelial cells which line the air passages of the respiratory tract. According to Dr. Krasan, this interaction may immunologically wound the mucosa. It then becomes more vulnerable to persistent bacterial colonization through expressing a greater number of H. influenzae pilus receptors on the damaged and reparative epithelial cells. This then leads to cycles of injury and repair resulting in further lung injury, he explained.
Dr. Krasan is hopeful that these studies "may provide generalizable insights into the initiation of the complex cross-talk which occurs between respiratory pathogens and the host, and ultimately lead to novel therapeutics and new antimicrobial regimens based on exploiting an understanding of these bacterial adherence factors."
Dr. Krasan is currently in the Department of Pediatric Infectious Disease at the Washington University School of Medicine in St. Louis, MO. He received his medical degree from McGill University School of Medicine in Montreal, Quebec, Canada.
J. Conrad Schwab, MD, is hopeful that his study of Toxoplasma gondii, a parasite which causes life-threatening disease in immunocompromised individuals, including infants in utero and persons with AIDS, will lead to new avenues of drug therapy.
Dr. Schwab believes that his study "will lead to a better understanding of molecular communication occurring between this obligate intracellular parasite and its host cell." Furthermore, pharmacological disruption of such signaling could represent a new approach to drug therapy.
To achieve his goals, Dr. Schwab will study a calcium signaling system activated late in the intracellular life cycle of T. gondii which triggers the parasite to leave the dying host cell. He will test his hypothesis that a receptor in the parasite plasma membrane transduces this signal by attempting to isolate the receptor from T. gondii and express it exogenously. Dr. Schwab plans to use the technique of exogenous protein expression in Xenopus oocytes to identify and characterize this proposed T. gondii calcium-sensing receptor.
Dr. Schwab is an assistant professor of medicine at the State University of New York Health Science Center at Syracuse. He received his medical degree from Baylor College of Medicine and did research training in infectious diseases at the University of Virginia and Yale University.
Cholera is a disease that has caused periodic devastating epidemics for centuries and continues to pose a worldwide health problem. Vibrio cholerae, the bacterium that causes the disease, produces a repertoire of virulence factors involved in intestinal colonization, toxin production, and bacterial survival within the host which are regulated at the genetic level by specific environmental stimuli including temperature, pH, and osmolarity.
To investigate the molecular basis for this regulation and to gain insights into how bacterial pathogens cause disease, Karen A. Skorupski, PhD, developed a genetic screen in V. cholerae which identified the global regulator in enteric bacteria--cAMP-CRP--as a system influencing the expression of virulence genes under certain environmental conditions. Her research will focus on explaining how this regulator turns virulence genes on and off in response to particular stimuli with the hope that this knowledge will one day lead to improved methods for treating and preventing bacterial infections.
"The goals of my research are to ultimately understand the mechanisms by which stimuli from the environment regulate virulence in V. cholerae so as to facilitate the development of new strategies to control and prevent cholera as well as other bacterial diseases," Dr. Skorupski said.
Dr. Skorupski is a research assistant professor of microbiology at Dartmouth Medical School. She received her doctorate from the Waksman Institute of Microbiology at Rutgers and completed postdoctoral work at the DuPont Merck Pharmaceutical Company in Wilmington, DE.
Despite the development of an effective vaccine for the hepatitis A virus (HAV), its cost has precluded worldwide vaccination. In economic terms, the cost of this infection to the United States alone has been estimated at over $200 million annually due to lost time at work and health care costs. Worldwide, it is estimated that there are approximately 1.4 million cases each year.
The research goal of Phoebe L. Stewart, PhD, is to determine the structure of the human pathogen HAV by using the novel imaging technique of cryo-electron microscopy (cryo-EM) and three-dimensional (3-D) computer image reconstruction. "The structural information obtained from these studies will potentially aid in the design of a more cost-effective subunit-based vaccine and lead to a better understanding of HAV's unusual stability and resistance to known antiviral agents," she said.
Cryo-EM combined with 3-D imagery construction has yielded high resolution structures of other icosahedral or 60-fold symmetric viruses, including the hepatitis B core antigen. Dr. Stewart will rapidly freeze the virus in a cryogen and then collect digital electron micrographs of unstained, frozen-hydrated material. She will then use computer imagery construction methods, which will enable averaging of multiple particle images to generate a 3-D structure that will be analyzed with computer graphics. Dr. Stewart gives cryo-EM high marks because it offers the ability to study biological structures without having to obtain diffraction quality crystals.
"In summary, visualizing the structure of HAV with cryo-EM will provide a foundation for future structural and pharmacological studies of this infectious human pathogen," Dr. Stewart stated.
Dr. Stewart is an assistant professor of molecular and medical pharmacology at the University of California at Los Angeles School of Medicine. She received her doctorate in chemistry at the University of Pennsylvania and did her postdoctoral work at the Wistar Institute in Philadelphia, PA.
Stephanie N. Taylor, MD, will focus her research on the development of rapid, non-culture based diagnostic methods for the detection of Haemophilus ducreyi infection. H. ducreyi is the agent that causes chancroid, a sexually transmitted genital ulcer disease--the incidence of which has exceeded that of syphilis as the cause of genital ulceration in some areas of Africa, Asia, and South America. It has also been associated with the heterosexual transmission of HIV.
Dr. Taylor's research is important since H. ducreyi "requires isolation and bacteriological procedures that are time-consuming and laborious. Thus, the development of rapid, non-culture based diagnostic methods is of prime importance," she said.
To accomplish these goals, Dr. Taylor will draw upon her previous studies in which she successfully generated a recombinant antibody library to surface components of H. ducreyi using variable heavy and light chain genes of murine B-cells expressing specific antibody. Recent technological advances have made it possible for her to mimic the immune system through display of antibody fragments on the surface of a bacteriophage and expression of soluble recombinant antibodies fragments.
She will reengineer the genes coding for these antibodies to allow expression of antibody fragments as fusion proteins with alkaline phosphatase (AP) or green fluorescent protein. These reagents will then be used in non-culture based assays that will allow direct detection of the organism in clinical samples without the use of secondary antibodies. By using recombinant antibody-AP in a solid phase colorimetric assay, she will eliminate the need for specialized equipment.
"This is of particular importance in resource poor settings where the disease is prevalent, but such equipment is unavailable and economically unfeasible," Dr. Taylor explained.
Dr. Taylor currently serves as assistant professor of medicine and microbiology at the Louisiana State University (LSU) School of Medicine in New Orleans. She received her medical degree and completed an infectious diseases research fellowship at the LSU School of Medicine.