The National Foundation for Infectious Diseases (NFID) has awarded seven 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:

Chester R. Cooper, Jr., PhD, will investigate the pathogenic fungus Penicillium marneffei, an emerging disease-causing agent among AIDS patients in the tropical regions of Southeast Asia. Left untreated, P. Marneffei infections are nearly always fatal, and antifungal treatment options are limited and frequently unsuccessful in eliminating the fungus. More than 20 non-Asian HIV-positive individuals visiting this area of the world have acquired infections by P. Marneffei. Countless others, both Asian and non-Asian, are believed to harbor latent infections after traveling in parts of Southeast Asia. Debilitation of their immune systems may lead to systemic fungal disease. "Given the continuing explosion of the world-wide AIDS epidemic, particularly in Southeast Asia, P. Marneffei will remain a major pathogen," said Dr. Cooper.

In nature, P. Marneffei grows as a multicellular filament. Upon invasin of the host, however, it undergoes a change in cell shape growing instead as a single-celled, yeast-like form.

"Because the change in cell shape is crucial to the disease process, we wish to understand those genes that function in the production of the yeast-like form. We propose to use a recently developed and unique technique, differential display reverse transscription, to identify these genes," Dr. Cooper said.

Identification of such genes will aid in the understanding of this emerging tropical infectious disease, and may also uncover potential targets that could be exploited to develop newer and more effective antifungal therapies, he added.

Dr. Cooper is currently an assistant professor of pathology at The University of Texas Medical Branch at Galveston. He received his doctoral degree in microbiology from the University of Texas at Austin.

An estimated 3.5 million people in the US have chronic hepatitis C (HCV). Each year nearly 80,000 people die of complications stemming from this infection, and 1,000 undergo liver transplants. Vaccines to treat HCV have been largely unsuccessful and antiviral drugs have a limited response rate.

Liver-directed gene therapy is a potentially novel method for treating viral disorders. Kenneth E. Drazan, MD, will examine a novel yeast messenger RNA which has the capacity to sequester critical translation proteins important to RNA virus replication. "I plan to examine the role of this yeast mRNA, referred to as I-RNA, in preventing hepatitis C virus replication," states Dr. Drazan. Dr. Drazan believes that this study will help to determine the capacity of this unique RNA virus inhibitor to evolve into a potential therapy for hepatitis C in pre- and post-transplant patients.

Dr. Drazan is currently in the Department of Surgery, Division of Liver Transplantation at the UCLA School of Medicine in Los Angeles. He received his medical degree from the State University of New York--Brooklyn.

Viruses replicate within a host cell, and during replication they actively alter various host cell components to facilitate their growth. Many viruses, including HIV, measles, and human coronaviruses, also cause the host cells to fuse with one another to form multinucleated giant cells called syncytia. It is speculated that cell-cell fusion is important in the growth or dissemination of the virus.

Cells possess a cytoskeleton consisting of a complex, internal network of filaments that gives structural integrity to the cell, provides for cell motility, and allows for organelle transport within the cell. Since the cytoskeleton would be expected to interfere with the fusion of adjacent cells during infection, it is likely that the disassembly and possible reorganization of some or all of the components of the cytoskeleton is necessary for cell-cell fusion to occur.

James L. Gombold, PhD, will examine the changes that occur in the organization of the cellular cytoskeleton during the course of virus replication using a murine coronavirus as a model system of virus-induced cell fusion. "Examination of the interactions between viral proteins and the cell cytoskeleton is expected to lead to a better understanding of the processes active during the initial stages of virus infection, the mechanisms involved in cell cytotoxicity and death, and may aid in the rational design of antiviral drugs," said Dr. Gombold.

Dr. Gombold is an assistant professor of microbiology and immunology at Louisiana State University Medical Center in Shreveport. He received his doctorate from Baylor College of Medicine in Houston, and did postdoctoral work at the University of Pennsylvania School of Medicine.

Rotavirus, a member of the Reoviridae virus family, is a major agent of acute gastroenteritis in children. Group A rotaviruses are the leading cause of severe dehydrating diarrhea in those under five years old. As a consequence of the rotavirus infection, there are millions of severe cases in the developing world with nearly one million deaths annually. In the United States, over 50,000 cases each year result in hospitalization and over 100 deaths.

To explain rotaviruses' incompletely defined processes of viral assembly, replication, and genetic variation, Paul Gottlieb, PhD, will focus upon a simple model of Reoviridae, the ø viruses. Both of these virus families contain multiple segments of double-stranded RNA as their genome. Previous experiments with one member of the ø group, ø6, established an in vitro RNA replication, transcription, and assembly system. "This replication model suggested answers to existing rotavirus assembly questions such as how do these types of viruses incorporate, or package, all these genome segments into their assembled structure," stated Dr. Gottlieb. "If, as we anticipate, newly discovered viruses employ a similar method for genome replication, packaging, and assembly, we will have traversed a major barrier in our understanding of Reoviridae replication."

Dr. Gottlieb is an assistant professor of medicine at the City University of New York Sophie Davis School of Biomedical Sciences. He received his doctorate from the City University of New York and completed his postdoctoral work at the Public Health Research Institute of New York City.

Strongyloidiasis is a parasitic disease caused by a small roundworm, Strongyloides stercoralis, afflicting more than 30 million people in over 70 countries worldwide. This parasite is also endemic in the Southeastern United States. Infection of humans with S. stercoralis usually results in asymptomatic chronic infection of the gastrointestinal tract that remains undetected for up to 50 years.

However, in immunocompromised patients, widespread dissemination of larvae to extra-intestinal organs may occur, often resulting in high mortality rates. The potential for severe disease is enormous in certain persons at high risk for acquiring strongyloides. High risk groups include persons with chronic lung disease who are inhabitants of or emigrants from endemic areas; children; the elderly; and those with altered cellular immunity, including patients on chronic steroid therapy, lymphoma patients, and kidney allograft recipients.

The lack of a suitable diagnostic test for detection of latent S. stercoralis infection prior to the start of chemotherapy or immunosuppression in patients at risk is behind the project of Afzal A. Siddiqui, PhD. "Using sera from patients infected with S. stercoralis, we have identified two immunodominant antigens," said Dr. Siddiqui. "The cDNAs of these two novel S. stercoralis antigens have also been identified. The recombinant proteins from these cDNAs will be used to develop a sensitive, specific, reliable, efficient, rapid, and economical immunodiagnostic test for strongyloides." It is hoped that this test can also be used in multiple parasitic infections.

Dr. Siddiqui is an assistant professor of internal medicine at the James H. Quillen College of Medicine, East Tennessee State University in Johnson City. He received his doctorate in parasitology at the University of Western Ontario, London, Canada.

Michael B. Smith, MD, will focus his research on Cryptococcus neoformans, a yeast that produces systemic infections in both immunocompetent and immunocompromised patients alike. The organism possesses a number of virulence factors which make it particularly devastating in AIDS patients, including the ability to make a polysaccharide capsule that protects it from ingestion by inflammatory cells. Strains which are incapable of capsule production are less virulent than those which can produce capsules.

"Interestingly, the capsule is either nonexistent or rudimentary when the yeast in present in the environment," states Dr. Smith. "However, when it invades a suitable host, it produces the thick protective capsule. What stimulates the production of this capsule and how the capsule is produced are two fundamental questions that need to be answered before the pathogenesis of Cryptococcus neoformans infections can be understood."

Utilizing differential display, a process by which pools of messenger RNA obtained from disrupted yeasts can be separated and screened for manifestation of gene expression under different conditions, Dr. Smith plans to investigate the genetic basis for capsule production. "We hope to identify genes which are involved in the regulation of capsule production," he explains.

Dr. Smith hopes that a better understanding of the regulation of this crucial virulence factor may lead to the development of a new therapy based on disruption of capsule production.

Dr. Smith serves as assistant professor of pathology at the University of Texas Medical Branch, Galveston, where he also received his medical degree.

Malaria results frominfections with parasites of the genus Plasmodium, and it places an untold burden on the global population. Today, over 40 percent of the worldís population is at risk for malaria. The disease is endemic in 91 countries, and infects 300 to 500 million people worldwide. Malaria results in the death of over two million children under five years of age annually. The economic strain placed on developing countries reached $2 billion annually in 1995, and is predicted to climb.

Due to increased parasite resistance to antimalarials and increased resistance of the mosquito vector to insecticides, malaria is once again resurgent. Consequently, the development of new drugs to combat drug-resistant strains of Plasmodium is critical. "We will develop a new class of antimalarial agents based on metalloporphyrins which targets a critical heme detoxification process within the parasite," states David W. Wright, PhD. "We believe that this detoxification process is mediated by the histidine-rich proteins within the digestive vacuole of the parasite which are critical to the formation of the crystalline detoxification heme polymer (hemozoin)."

Dr. Wright is an assistant professor of chemistry and biochemistry at Duquesne University, Pittsburgh. His doctorate in inorganic chemistry was earned at the Massachusetts Institute of Technology, and he was a postdoctoral fellow at Boston College.