Links to Other ASM Pages:



• Table of Contents
• ASM News Issues

Next Big Microbial Genome Step amid Many Other Smaller Ones

Even while officials at the National Institute of Allergy and Infectious Diseases (NIAID) were announcing "the next genome step" late last year, microbiologists in scattered venues seemed intent on taking their own next steps along microbial genomes—probing microbial genomic information and uncovering some unsuspected toxins within viral and bacterial pathogens. Consider these exercises mere practice for greater, Olympic-scale steps to follow.

Chlamydia trachomatis can cause chronic infections at several different sites, including the eyelids, where it can scar the eyes and lead to blindness, and the genito-urinary tract, where it can lead to pelvic inflammatory disease, tubal pregnancies, and infertility in women. Since the late 1940s, researchers suspected that a toxin might cause this inflammation, but no candidate toxin was forthcoming—until late last year.

NIAID researchers Harlan Caldwell, Robert Belland, and their collaborators learned that some particularly invasive forms of this intracellular pathogen carry a gene encoding a toxin resembling the potent toxin B of Clostridium difficile (R. J. Belland, M. A. Scidmore, D. D. Crane, D. M. Hogan, W. Whitmire, G. McClarty, and H. D. Caldwell, Proc. Natl. Acad. Sci. USA 98:13984-13989, 2001). The putative toxin gene showed up when the researchers compared the genomes of two C. trachomatis strains, one invasive and the other restricted to mucosal surfaces. One segment along those two genomes differed markedly from the other, with the segment from the invasive strain encoding a sequence that matches closely with the toxin B gene found in C. difficile. The toxin B protein can disrupt intracellular structures, leading affected cells to collapse and intercellular structures to break apart.

"Finding that toxin would have been nearly impossible without genome information," Belland says. It immediately became a prime target for new diagnostic tests, vaccines, and drugs, adds Caldwell. Several experiments indicate that cells infected with C. trachomatis are producing this toxin, but details are lacking—but will be sought—to explain its possible role in such cells or in affecting immune system responses, the researchers say.

In much the same spirit, and thanks to another type of genomic (or quasigenomic) analysis, NIAID viral immunologist Jonathan Yewdell and his colleagues recently uncovered an influenza virus toxin protein that may kill host immune system cells and thereby contribute to the potency of this virus. (W. Chen et al., Nature Med. 7:1306-1312, 2001). He and his collaborators found this protein while sifting through bits and pieces of "junk" peptides that the flu virus creates once it infects a cell and begins replicating.

When the scientists examined the gene encoding one particular junk peptide that can trigger immune responses in mice, they noticed that it is "suspiciously long" to be mere junk, according to Yewdell. In subsequent experiments, he adds, "We saw large amounts of this molecule in the mitochondria of flu-infected cells, and we knew it was a real protein. It was one of those ‘eureka’ moments of discovery you live for in science. The junk turned out to be a jewel."

Factors behind Virulence of 1918 Influenza Remain Mysterious

Seeking the 1918 Spanish Influenza Virus

The previously unrecognized influenza-specified protein is produced when ribosomes of infected host cells "misread" the influenza PB-1 gene, according to Yewdell. "This alternate translation may have started out as a mistake, but the protein it produced was useful, so through evolution the gene was maintained and improved." Tests show the protein is toxic to human cells, especially immune system cells, making it a candidate to explain the long-elusive virulence of past influenza outbreaks, especially the Spanish flu of 1918, which killed 20 million people worldwide (ASM News, May 2001, p. 243, and July 1999, p. 473).

With such discoveries as a backdrop, NIAID Director Anthony Fauci late last year announced a genome-based initiative to identify molecules that pathogens use to infect and cause illness and death. Its centerpiece is a six-year, $25-million contract to establish a functional genomics resource center at the Institute for Genomic Research (TIGR) in Rockville, Md. "The new functional genomics center will help us use [genomic sequence] information [from microbial pathogens] to better understand the roles of individual genes and proteins, and to develop new drugs and vaccines that specifically target each organism," he says. "This is an unprecedented period in infectious diseases research because we now know the genetic information that helps dictate the biology of many microbes."

Pathogen Functional Genomics Resource Center

The new Pathogen Functional Genomics Resource Center will be a centralized training and resource facility that will support research on 3 to 10 important pathogens over the next three years. Plans call for the center to develop new technologies that enable scientists to more rapidly analyze gene function by studying the whole genome rather than small regions or individual genes. The center will also train researchers on the latest techniques in functional genomics and will be a repository for required reagents. As the genomes of more pathogens are sequenced and technologies are developed to analyze the growing number of known genes, the center's repository function will become increasingly important.

Jeffrey L. Fox
Jeffrey L. Fox is the ASM News Current Topics and Features Editor.