Jeffrey L. Fox is the ASM News Current Topics and Features editor.
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Perspectives on Pathogens at ASM Centennial Symposium
Malaria, TB, and the upstart AIDS present immense challenges but are also stimulating dazzling new approaches to study them
Jeffrey L. Fox
Among three of the most prominent infectious disease challenges facing microbiologists at the outset of the 21st century--malaria, tuberculosis (TB), and AIDS--only the third would be seen as a genuine newcomer by the founders of ASM. In the century since ASM began, they would likely be more amazed at the diseases that dropped off that list, the dazzling approaches now available to investigate those remaining on it, and the drugs that come onto and--because of resistance, or for other reasons--drop off an accompanying list of medications used for combatting those diseases.
However, one message seems just as indisputable now as it did a century ago. Meeting infectious disease challenges typically requires a special appreciation of the microorganisms involved. This concept served as a leitmotif during the symposium ``Confronting Emergent Microbes: Forging New Paradigms,'' that was convened last November by officials of the National Institute for Allergy and Infectious Diseases (NIAID) to honor the ASM Centennial.
Malaria: an Episodic Chronicle of Successes and Setbacks
The devastating disease of malaria often proved frustrating to health officials and researchers throughout the past two centuries and more. Long before modern scientists entered the fray, native peoples of the Western world began to share some of their lore with explorers and other newcomers from Europe, who proved vulnerable to this mosquito-borne pestilence.
That wisdom held that extracts from the bark of the Chinchona tree, including the drug we know more familiarly as quinine, were of benefit for treating fevers. In the early 1600s, Jesuit missionaries brought back some of that bark to Europe, where malaria was widely prevalent. The bark proved a highly useful addition to the pharmacopoeia. Francesco Torti, an Italian physician (1658-1741) delineated the differential responses of various fevers, including those of malaria, to this bark. However, it was not until the 1820s that French chemists succeeded in purifying quinine, one of the active ingredients against malarial fevers, from such barks.
More than a century passed before serious improvements came--specifically, the synthesis of chloroquine in 1934 by German chemists. However, the upheavals surrounding World War II kept the drug more or less under wraps for another decade until U.S. malaria experts identified it near the end of the war as the antimalarial ``drug of choice,'' according to NIAID researcher and symposium participant Thomas Wellems. For nearly two decades following the war, it almost seemed that this and other antimalaria drugs, together with heroic mosquito control efforts, might vanquish that disease once and for all.
However, the first reports of drug resistance were circulated during the late 1950s and mid-1960s, about the same time that World Health Organization (WHO) officials were administering this drug in mass quantities as part of their global campaign against this disease. At first those reports of resistance were confined to South America and Southeast Asia.
Since then, however, resistance to chloroquine has proved a ``disaster,'' spreading from those few isolated geographic pockets to nearly everywhere that malaria is endemic, according to Wellems. Yet, this drug would otherwise remain a first-line choice for treating this disease because it is inexpensive and relatively free of side effects. Hence, in 1986, he and his collaborators began studying how malaria parasites develop resistance to chloroquine, hoping to understand and perhaps somehow overcome that process.
Key to chloroquine action against the parasite is that the drug interferes with how the parasite manages by-products of hemoglobin metabolism, Wellems says. Specifically, chloroquine blocks polymerization of heme--a complex ring substituent of this oxygen-binding protein that is found in host red blood cells--part of a process for detoxifying this substituent when its levels increase within the parasite's cells.
After a number of sophisticated genetic manipulations, Wellems and his colleagues learned that this resistance trait is embodied in a single gene locus on chromosome 7 of the parasite. En route to identifying that gene locus, this research team also developed a comprehensive map describing gene markers on all 14 chromosomes carried by the malaria parasite, Plasmodium falciparum. The map should prove useful for ongoing efforts to determine the sequence of the parasite genome.
Meanwhile, the chloroquine-resistance gene, designated pfcrt and containing many exons, encodes a protein with several membrane-spanning segments and an overall structure that ``is not related to any other proteins in available data bases,'' Wellems says. Although ongoing experiments suggest that this protein acts as a transport molecule, ``lots of questions'' remain to be addressed about its role in parasite cells and whether its resistance-conferring actions can be overcome.
Tuberculosis: a Comprehensive Counterattack To Develop New Drugs
TB is another globally devastating infectious disease in which drug resistance--indeed, multidrug resistance (MDR)--plays a prominent role, points out NIAID investigator and symposium participant Clifton Barry III. Mycobacterium tuberculosis is an infectious agent of monstrous global reach. It infects about one-third the world population, or about 1.9 billion people, leading to 8 million cases of TB and some 3 million deaths worldwide each year. Perhaps as many as 50 million individuals are infected with MDR forms of M. tuberculosis. In no uncertain terms, this disease is a major global public health threat, he says.
MDR develops in part because patients typically must take one or more drugs for many months, even after symptoms disappear, a situation that is conducive to poor adherence to that regimen and consequent multidrug failure. Until a few years ago, however, waning public health interest in and frustrations with studying this slow-growing pathogen led to little research activity or progress in understanding how this pathogen works. But, as the scope of this public health threat has come to be more widely recognized, scientists are again stepping up to the research challenges that M. tuberculosis presents.
Indeed, that one-time latency has given way to intensified activity, particularly after a recently completed genome-based sequencing analysis provided a sudden wealth of new clues about the inner workings of M. tuberculosis as well as abundant potential targets at which to aim new drug candidates, according to Barry. Those sequencing efforts indicate that the 4.4-megabase genome encodes nearly 3,300 proteins, with about 250 apparently involved in lipid metabolism.
Barry and his collaborators at NIAID and at several companies in the private sector are using that information to evaluate literally millions of newly synthesized compounds as part of an ambitious search for new anti-TB drugs. Part of their strategy is to use genetic information about the presumed targets of current anti-TB drugs to find new compounds that aim at some of those same molecular targets. With information about the genomic sequence and new methods to synthesize and test huge numbers of compounds, including close chemical analogs of anti-TB drugs, ``we can very quickly work through large series of compounds,'' he says. Already some promising inhibitory compounds are undergoing systematic further evaluation.
Of the six now-standard drugs available for treating this disease, four affect biosynthesis of the M. tuberculosis cell wall, Barry says (see figure). Although the undergirding of the wall is a gigantic but relatively simple single-polymeric peptidoglycan, the overall structure consists of a waxy and all-but-impenetrable mycolic acid coating--which serves as a major target of, but also a frequent obstacle to, many otherwise promising, would-be anti-TB drugs.
Another part of the drug discovery strategy is to examine successful anti-TB drugs in light of the wealth of new information now available and the broad range of new molecular tools for probing this pathogen. For instance, the widely used anti-TB drug isoniazid exerts minor effects on a large number of proteins within M. tuberculosis, but causes major changes in bacterial proteins associated with fatty acid biosynthesis, Barry and his colleagues find. To follow up on this clue, they and some of their private-sector collaborators made 1.6 million chemical compounds that target the same fatty acid biosynthetic genes that isoniazid seems to affect and subsequently identified three ``structurally unique'' compounds with particularly promising mycolic acid-inhibiting properties, he says.
Yet another part of the new drug-development strategy is to examine which M. tuberculosis genes certain of the currently available anti-TB drugs may activate or suppress. For example, Barry recently learned that the anti-TB drug ethambutol strongly induces several specific genes of M. tuberculosis, perhaps thereby activating a previously unrecognized and presumably lethal prophage that appears at other times to be nestled harmlessly within this pathogen's genome.
Delaying AIDS Antiviral Treatments May Help Prime Immunity
Meanwhile, the nearly two-decade-old AIDS epidemic is responsible for an estimated 16.3 million deaths--2.6 million in 1999--and the human immunodeficiency virus (HIV) infects more than 33 million adults and children, according to the World Health Organization and the United Nations Programme on HIV/AIDS. At current rates, another 5.6 million individuals become infected each year with the virus.
This epidemic also continues to furnish researchers with challenges, puzzles, and controversies. Among the most perplexing of those puzzles has to do with the small group of HIV-infected individuals who do not develop full-blown AIDS, even after extended periods lasting about as long as the epidemic itself has been recognized, says symposium participant Bruce Walker, who directs the AIDS Research Center at Massachusetts General Hospital in Boston, Mass. Such individuals usually are referred to as ``long-term nonprogressors.''
The immediate explanation for HIV-infected individuals who are nonprogressors is that they ``maintain a vigorous cytotoxic T lymphocyte (CTL) response after many years,'' meaning that this component of the immune system continues to recognize and withstand HIV that in typical cases steadily undermines immune system responses, according to Walker. Further evidence pointing to the importance of this CTL response among nonprogressors includes ``idealized'' lab tests indicating that CTLs from such individuals are ``highly efficient'' at killing HIV in vitro, he says.
This status of CTLs, in turn, seems to be managed by a set of T helper cells. The orchestration of these cells is complex and, apparently, utterly critical during the development of AIDS in HIV-infected individuals. ``The most blatant defect'' within this disparate set of T cells among HIV-infected individuals who progress to full-blown AIDS is in ``virus-specific helper cells,'' Walker says. With that loss of helper cells comes a loss of the vital CTL response. He and his collaborators are now testing whether this disastrous disruption of specific T cell sets, which they say leads to the generalized immune system collapse that characterizes AIDS, can be avoided by intervening during the very early, acute stage of an HIV infection.
However, their approach to achieving this end bucks the current widely accepted strategy for treating AIDS patients--a strategy that is characterized by intensive and simultaneous treatment with several antiviral drugs. However, this strategy, known as HAART, may actually be detrimental to AIDS patients because it ``may put CTL and helper cells to sleep . . . and may eliminate the CTL response,'' Walker says.
Thus, he advocates testing an alternative approach in which antiviral therapy begins on a more tempered note, permitting the immune system of an HIV-infected individual to mount a better response to the virus. This alternative strategy, which is geared to ``generating an augmented immune [response] to go along with antiviral therapy,'' aims at ``converting the infection to something that can be controlled,'' he says. The strategy of enabling the immune system to provide ``more durable suppression of viremia . . . has great potential to have a tremendous impact on this infection . . . by harnessing immunity in a more effective way.''
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