On the Front Lines in the Labs: (left to right) Tony Fauci, José Ribeiro, Kanta Subbarao, and Bruce Chesebro

"The war against infectious diseases has been won."

—Surgeon General William H. Stewart
testifying before the U.S. Congress in 1967S

Quoting the former surgeon general, NIAID Director Tony Fauci set the stage for the Research Festival symposium on 21st-century challenges in infectious disease research.

He did not have to belabor the folly of Stewart’s declaration—the fact that infectious diseases were the second leading cause of death worldwide in 2002 was enough.

In his introductory overview of emerging and re-emerging infectious diseases, Fauci said that:

n Prevention of HIV infection—about 3 million people globally were newly infected in 2003—remains the most difficult challenge in the HIV arena today, particularly with regard to the development of an HIV vaccine.

n The sequencing of the genomes of the most lethal malarial parasite and its mosquito vector offers fresh approaches for overcoming malaria, currently the cause of 1.5–2.5 million deaths annually.

n The threat of an influenza pandemic is "significant." Infections of humans with lethal H5N1 avian influenza have been detected in Asia since 1997 and, together with a pervasive lack of immunity to the H5N1 strain in the population and shifts in influenza antigenicity, add to the complexity of this public health issue.

n West Nile virus, a classic re-emerging microbe, is currently endemic in the United States but likely to spread to the Caribbean and South America in coming years. On the positive side is the development by the NIAID Laboratory of Infectious Diseases of a chimeric West Nile virus vaccine with a dengue virus backbone.

n The anthrax attacks of 2001, which generated fear and disruption of routine activities, also led to a large increase in NIH biodefense spending—from $291.1 million in 2002 to an estimated $1.6 billion in 2004—and the expansion of NIH research facilities, including the construction on campus of a biosafety level 3 building, that will accelerate the development of countermeasures to an array of infectious agents.

Fauci ended with a cautionary thought taken from the book The Restless Tide by former NIAID director Richard Krause: Microbes will continue to bombard the shores of mankind and, try as they may, neither of the adversaries—humans or pathogens—will fully eliminate the other.

Insect Vectors:
Transgenic Solutions?

It has long been clear that the eradication of infectious diseases transmitted by insect vectors requires intervention at the level of the vector itself.

Not only are there more than 15,000 species of insect vectors on the globe, said José Ribeiro, head of the Vector Biology Section, NIAID, but they are "r-selected" species whose large numbers of offspring give rise to enormous genetic diversity in the population and hence adaptability to a rapidly changing environment.

International commerce has abetted the spread of insect vectors. One example, he said, was the importation into the United States in the 1980s of rubber tires from Malaysia that harbored the eggs of the West Nile–associated mosquito species Ochlerotatus japonicus and Aedes albopictus.

On a more local level, changing habitats through the movement of people into suburbs has broken the fragile balance of the environment and imposed a greater risk of zoonotic diseases such as Lyme disease.

Recent achievements, however, rival these challenges, Ribeiro said. He cited the sequencing of a mosquito genome, the expanded knowledge of insect population genetics, and the unprecedented ability to compile large amounts of geographical and biological data through the use of geographical information systems.

The most significant advance, he said, is probably the characterization of the vector genes that affect host selection, habitat choice, blood feeding, and parasite susceptibility.

He projected that although several ethical dilemmas remain regarding the creation of transgenic mosquitoes, this type of research over perhaps the next 20 years could lead to novel approaches in the control of vector-borne illnesses.

Animal Models of SARS

In 2003, the World Health Organization identified 8,000 cases of severe acute respiratory syndrome (SARS) across the globe; 774 people died before the outbreak ended in July 2004.

Kanta Subbarao, a senior investigator in the Laboratory of Infectious Diseases, NIAID, has worked extensively on the development of animal models of SARS. She aims to clarify the pathogenesis of the disease and evaluate vaccine candidates.

"We wanted to explore a range of animal species, as their susceptibilities may vary," she said. She described results in intranasally inoculated mice and golden Syrian hamsters and intratracheally inoculated African green monkeys, rhesus monkeys, and cynomolgus monkeys.

None of the animals tested developed clinical signs of disease, but virus was detected in the respiratory tract of mice, hamsters, and African green monkeys, and serology showed that they were indeed infected. The animals were protected from replication of virus after subsequent viral challenge by antibody production.

Hyperimmune serum from infected animals could be used to protect naïve animals, clearly defining the role of antibodies in preventing virus replication, Subbarao noted.

The African green monkey was found to be the most permissive model among the three species of nonhuman primates tested, she reported, but because the course of infection in these monkeys is significantly different from that in humans, she urged caution in their use for the evaluation of vaccine efficacies.

Several SARS vaccines are currently being evaluated in this animal model, including inactivated subunit DNA and live attenuated forms, and the prospects look promising, Subbarao said.

Another aspect of SARS infection requiring targeted research is that old age (over 60) appears to be a significant risk factor in disease progression. To better understand the pathogenesis of SARS in the elderly, Subbarao’s group has created an older mouse model, which shows a dramatically different response to SARS infection and progression.

"We are very interested in investigating this model further," Subbarao said, implying there is reason for optimism.

Prion Diseases:
Are Prions Infectious?

Prions have been described as the agent of transmissible spongiform encephalopathies (TSE), but not all investigators are convinced, said Bruce Chesebro, chief of the Laboratory of Persistent Viral Diseases at NIAID’s Rocky Mountain Laboratories in Hamilton, Mont. He placed himself in this group of skeptics.

Prion protein diseases belong to a class of protein-folding diseases, which also include Alzheimer’s, type 2 diabetes, and cystic fibrosis, in which the accumulation of misfolded proteins disrupts the function of various organs. However, prion diseases differ in that they are transmissible.

Creutzfeldt-Jakob disease (CJD), a prion disease that has a familial, sporadic, and infectious form (vCJD), has gained much notoriety in recent years due to the link between vCJD and mad cow disease and the suggestion of a possible trans-species spread.

Chesebro agrees with the delineation of the prion protein, PrPc, as the protein that misfolds in these diseases to a form known as PrPsc. But he disagrees that the evidence unequivocally defines this protein as the infectious agent itself.

Several animal models designed to mimic the familial form of CJD with a mutation in the gene encoding PrPc show evidence of brain diseases but no infectivity. The infectious agent—a virus—may remain to be identified, Chesebro said.

The misfolding of PrPc in that case would serve as the necessary susceptibility factor.

Better vCJD screening strategies are also needed, Chesebro added, noting that current tests are only sensitive enough to detect infection at the late preclinical stages—at about 30 months of age in cattle—whereas the majority of cattle are slaughtered between 14 and 16 months of age.

Chesebro’s group has created a mouse infected with a hamster variant of prion disease protein that has shown no clinical signs of disease for two years. There is evidence, however, that the agent is becoming better able to infect mice. This carrier of infectivity may serve as a great model for understanding the adaptability of the prion disease agent and its cross-species spread to humans, Chesebro suggested. n

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