The National Foundation for Infectious Diseases (NFID) has awarded seven infectious disease researchers with its New Investigator Matching Grants (NIMG). The program assists investigators who are beginning their research career by matching funding from the awardee's host institution to underwrite pilot work leading to further research. The awardees and their area of research are as follows:

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is now thought to be the most important single cause of senile dementia. This disease appears in two relatively distinct manners: early-onset, a genetically based form, and late-onset or the sporadic form. The etiology of AD is associated directly with atrophy and death of nerve cells in affected brain regions resulting in the characteristic neuropathology seen in essentially all AD patients. Denah M. Appelt, PhD, will explore pathologic manifestations induced by Chlamydia pneumoniae infected glial cells in Alzheimer's disease. "Recently, we have established what appears to be a relationship between CNS infection with a bacterial pathogen, Chlamydia pneumonia, and AD pathology. Our initial studies indicate that microglia and astroglia, which mediate the inflammatory response in the brain were infected and co-localized to areas of AD neuropathology." explained Dr. Appelt. Since Chlamydia pneumoniae induces a strong inflammatory response at sites of infection, this pathogen may be a major component to the CNS inflammatory process, a well-documented characteristic of late-onset AD. The study is designed to determine whether Chlamydia pneumoniae infected host cells such as microglia and astroglia contribute to the production of neuritic senile plaques and neurofibrillary tangles in response to this infection.

Dr. Appelt is assistant professor, Department of Biomedical Sciences, Division of Neurosciences, Philadelphia College of Osteopathic Medicine. She received her doctoral degree in anatomy and neurobiology from Hahnemann School of Medicine in Philadephia.

Late-onset bacterial sepsis is a major cause of morbidity and mortality in neonatal intensive care unit (NICU) patients. Because the symptoms of sepsis are non-specific, NICU patients frequently undergo sepsis evaluations and receive courses of broad-spectrum antibiotics while awaiting culture results. Thus, patients receive prolonged courses of antibiotics for "presumed, culture-negative sepsis" with the attendant risks of fungal superinfection or emergence of antibiotic resistance. Karen D. Fairchild, MD will focus her research on the detection of bactermia in hospitalized neonates using PCR for 16s ribosomal RNA. According to Dr. Fairchild, the current standard for diagnosing bacteremia is the blood culture. Blood cultures have number of pitfalls including low sensitivity with small sample volumes, false negatives due to prior antibiotic therapy, and delay in identifying organisms. An alternative to blood culture in the diagnosis of bacteremia is PCR for 16s rRNA, a gene that is highly conserved in most species of bacteria. The goal of the study is to determine if PCR will be more sensitive and eventually more cost effective than blood culture, enabling clinicians to limit the duration and narrow the spectrum of antibiotic therapy.

Dr. Fairchild is an assistant professor of pediatrics in the Division of Neonatology at the University of Maryland School of Medicine. She received her medical degree from Duke University and completed her pediatric residency at Johns Hopkins University.

The herpes-simplex viruses (HSV) are widespread among humans. HSV establishes lifelong infection in its host, and can cause significant morbidity. The public health impact of HSV infections has grown tremendously over the past two decades with an enormous increase in genital herpes. Among persons infected with the disease, the clinical course varies widely; some are asymptomatic, while others may experience frequent and severe recurrences. During his research year, Keith R. Jerome, MD, PhD, will study HSV inhibition of apoptosis and its influence on the severity of clinical disease. Apoptosis, simply put, is where cells infected with a virus will shut down, or "commit suicide." It is significant in this study, explains Dr. Jerome, because HSV inhibits apoptosis of infected cells, thus forcing the cells to stay alive long enough to replicate itself and infect neighboring cells, leading to clinical symptoms and the possibility of transmission. "I have found that HSV strains obtained from different individuals vary in their ability to inhibit apoptosis. These findings raise the possibility that the ability of a given HSV strain to inhibit apoptosis might be one factor which influences the severity of disease," states Dr. Jerome.

Currently acting assistant professor, department of Laboratory Medicine at the University of Washington, Dr. Jerome received both his doctoral degree in microbiology and immunology and his medical degree from Duke University.

Salmonella is one of the most prevalent food-borne pathogen. Salmonella infection in humans is characterized by symptoms ranging from fever to severe gastroenteritis, however little is known about the fate of Salmonella as it colonizes the intestinal tract to establish infection.

Cheryl A. Nickerson, PhD will focus her research on identifying Salmonella genes necessary for the colonization of the gut-associated lymphoid tissue (GALT), specifically the lymphoid follicles in the small intestines known as Peyer's patches. This approach, which is a modification to a cDNA enrichment strategy, allows for the selective identification of differentially expressed genes between cells grown in different conditions. "Utilizing this technique, we hope to identify and isolate bacterial sequences uniquely expressed within Peyer's patch tissue during the normal course of Salmonella infection as compared to those expressed in vitro," states Dr. Nickerson. "We anticipate that this research will provide significant insights into the molecular basis of Salmonella virulence, in particular the early stages of systemic infection."

Dr. Nickerson is an assistant professor of microbiology and immunology at the Tulane University Medical Center, New Orleans.

Lori Panther, MD will investigate the natural history of HPV infection in the anal canal and risk factors for development of anal dysplasia and invasive squamous cell anal cancer in HIV-positive men. Research to date supports many similarities between HPV infection and the development of squamous cell cancer of the anal canal in HIV-infected men and of the cervix in HIV-infected women. Though the natural history of HPV infection and cervical cancer in HIV-positive women has been broadly studied, data on anal intra-epithelial neoplasia (AIN) in males is just beginning to emerge.

According to Dr. Panther, the benefits of early detection, type of intervention and timing of prospective follow-up are all aspects of AIN in HIV-positive males which merit investigation. The relationships between CD4 count, viral load, antiretroviral therapy and conventional risk factors for anal cancer will be evaluated with respect to the development and/or progression of AIN. "I hope that these preliminary investigations will lead to prospective interventional studies of immune based therapies to treat pre-cancerous lesions as well as invasive squamous cell cancer of the genital tract."

Dr. Panther is currently an instructor in medicine at Harvard Medical School, Beth Israel Deaconess Medical Center, Division of Infectious Disease. She received her medical degree from the University of Iowa.

The spotted fevers are a group of tick-borne zoonotic diseases caused by a closely related group of rickettsiae. The most severe of these diseases is Rocky Mountain Spotted fever, which has a fatality-to-case ratio of twenty to twenty-five percent without specific therapy. Suzana Radulovic, M.D, PhD, will examine the role of rickettsial rOmpA as a DNA vaccine in protective immunity against R. rickettsii. According to Dr. Radulovic, the available data support the hypothesis that the major outer membrane surface protein of spotted fever group (SFG) rickettsiae (190 kDa, rOmpA) contains antigens that stimulate protective immunity. The rOmpA was found in all the known SFG rickettsiae.

"DNA vaccine technology has been utilized to study influenza, HIV, rabies, hepatitis B, herpes virus and malaria. It has been proven to produce long lasting cellular and humoral immunity," said Dr. Radulovic. Historically, vaccines produced from inactivated rickettsiae failed to protect those infected with virulent R. rickettsii. The objective of this study is to determine the role of rOmpA gene product as a DNA vaccine against R. rickettsii.

Dr. Radulovic is an assistant professor in the Department of Microbiology and Immunology in the School of Medicine at the University of Maryland at Baltimore. She received both her medical and doctoral degrees from the University of Ljubljana, Slovenia.

Worldwide, malaria infections continue to increase due, in part, to an increase in antimalarial drug resistance in Plasmodium falciparum. Two major classes of currently used antimalarial drugs, the quinolines like chloroquine and the endoperoxides like artemisinin, are thought to interact with iron to kill the parasite via toxic free-radicals produced from either heme or iron.

David J. Sullivan, Jr., MD, will explore iron transport in Plasmodium falciparum with the natural resistance associated macrophage protein (NRAMP). According to Dr. Sullivan, the source of parasitic iron or how iron is transported to essential compartments is not known. Therefore, iron interference is an important and promising chemotheraputic target for Plasmodium. "A P. falciparum homologue of the iron transport family NRAMP has recently been cloned in our laboratory. The design of this work will be to exploit the molecular characterization and localization of PfRAMP in order to trace the metabolism of iron critical to the survival of the parasite," explained Dr. Sullivan.

Dr. Sullivan is an assistant professor of molecular microbiology and immunology at the School of Hygiene and Public Health, Johns Hopkins University. He received his medical degree from the University of Alabama at Birmingham.

The NIMG program is supported by an unrestricted educational grant from Schering-Plough.