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Genes on Alert
Genomics and the Fight Against Infection
Edward R. Winstead

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Scientists have used genomic tools to ask this question about the human immune system: Do cells on the front lines of infection—dendritic cells—distinguish between a bacterium and a virus, and stimulate other cells to mount a response tailored to the microbial invader? The answer is yes, according to a new study.

Stained dendritic cell from the human lymph node. View larger

Nir Hacohen, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and colleagues used DNA microarrays, or gene chips, to characterize differences in gene expression in dendritic cells during invasions by a bacterium, a virus, and a yeast. They found that dendritic cells generated a stereotypical response to all three pathogens, but were also capable of more specialized responses.

The same set of 165 genes responded to each pathogen. But hundreds of other genes responded uniquely to one of the three organisms. The E. coli bacterium elicited a response from 685 genes in all. The influenza virus activated 531 genes. And finally, the yeast, Candida albicans, triggered a response from 298 genes.

"Microarrays provide a way to rigorously test the differences in immune response among pathogens," says Hacohen, who collaborated with Eric S. Lander and Richard A. Young at the Whitehead Institute. "We were asking, 'How flexible can dendritic cells be in their immune response?' so we used pathogens that have almost nothing in common. Bacteria, viruses, and fungi are far apart on the evolutionary tree."

The idea that dendritic cells discriminate among invaders was first proposed a decade ago by Charles A. Janeway, Jr., of Yale University School of Medicine in New Haven, Connecticut. The Whitehead study is the first genomic-scale test of this hypothesis using a broad selection of pathogens.

Detail of microarray cluster diagram. View larger

Nearly 7,000 genes were represented on the microarray, and 1,330 were expressed in response to infection. The researchers have classified the genes by family according to their known or predicted functions, a first step in making sense of the information generated by the microarrays.

In recent years, microarrays have provided clinically relevant information about cancer that was unattainable through other means. Gene expression profiles of tumor tissues have led to new classifications of breast cancer, leukemias, and melanomas, and some profiles are associated with a particular type of disease. This allows physicians to make predictions about whether a cancer might spread and to select appropriate therapies.

But no one is suggesting that these new immune response data will have an immediate benefit in the clinic. "It isn't enough to know which genes are expressed," says Hacohen. "We don't know which of the responding genes hurt the person and which genes hurt the pathogen. This is really the beginning of a long-term project for the field."

The authors of a commentary accompanying the paper in today's issue of Science express similar views. Robert L. Modlin, of the UCLA School of Medicine, and Barry R. Bloom, of the Harvard School of Public Health in Boston, write that it is important to know which of the activated genes were crucial for protective immunity, which had little to do with immune response, and which were involved in tissue injury.

"It is one thing for the expression of 1,000 genes to be altered by infection and neatly classified into families, but quite another to know which of these genes are crucial for host defense and which promote microbial invasion, survival, and pathogenesis," Modlin and Bloom observe. They point out that while large-scale gene expression studies of immune response can help identify genes of interest, microarrays do not answer crucial questions about complex interactions between pathogens and the people or animals they infect.

"I was surprised by how few genes were involved in the cells' immune response to yeast and that no genes specific to the immune response to yeast were identified," Modlin told GNN. "The low number means that either the core set of genes was sufficient, or key genes were involved that are not on the microarray."

Septic injury: The fly thorax is pricked with needle dipped in bacteria.

Noting that most of the human genome was not tested, he adds, "We may learn the answer to that question when we have all the genes on a chip." The microarrays had about 6,800 human genes.

In contrast to the human genome, almost all of the fruit fly genome has been put on chips, and French researchers are using the 13,000-gene microarrays to study immune response. Bruno Lemaitre, of the Centre National de la Recherche Scientifique, in Gif-sur-Yvette, France, and colleagues profiled gene expression throughout the fly body following infection by a bacterium and a fungus. They classified 400 genes as immune responders, including genes of unknown function and others not previously associated with immune response.

"This study is the first to analyze the expression of virtually all of an organism's genes after microbial infection, and it seems to confirm the power of the microarray approach," says Lemaitre. "The next step is to analyze the function of the genes using genetic tools."

Lemaitre and a colleague, Ennio De Gregorio, collaborated on the microarray study with Gerald M. Rubin and Paul T. Spellman, of the Howard Hughes Medical Institute at the University of California, Berkeley. The findings were published this week in Proceedings of the National Academy of Sciences.

"That such a large number of fly genes is involved in immune response is quite striking," says Kathryn V. Anderson, of the Sloan-Kettering Institute, in New York, who uses Drosophila as a model organism for investigating immune response. "The array data point to the richness of the phenomenon."

Natural infection: Anesthetized flies are shaken in dish with fungal culture. View larger

Last month, Anderson and colleagues identified fourteen genes on one Drosophila chromosome that are necessary for a normal immune response. The researchers screened mutagenized flies for immune deficiencies and traced the cause of the deficiencies to individual genes. The findings appeared in Genetics.

Some but not all of the fourteen genes were picked up by the microarray analysis. This may have been due to the method of the microarray study, which surveys the entire body rather than individual tissues. "Several hundred genes may only be a modest fraction of the total number that are important in fighting infection," says Anderson.

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Huang, Q. et al. The plasticity of dendritic cell responses to pathogens and their components. Science 294, 870-875 (October 26, 2001).
Modlin, R.L. & Bloom, B.R. Chip shots—Will functional genomics get functional?
Science 294, 799-801 (October 26, 2001).
De Gregorio, E. et al. Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays. Proc Natl Acad Sci USA 98, 12590-12595 (October 23, 2001).
Wu, L.P. et al. Drosophila immunity: Genes on the third chromosome required for the response to bacterial infection. Genetics 159, 189-199 (September 2001).

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