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Whitehead Researchers Use Microarrays to Probe Immune Response to Pathogens

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Researchers from the Whitehead Institute recently used microarrays to study gene expression patterns that bacteria set off in certain immune cells as part of the immune response, opening the door to diagnostic tests for bacterial infection and increasing scientists’ understanding of vaccine and therapeutic mechanisms of action.

In the study, published in this week’s Proceedings of the National Academy of Sciences, Gerard Nau, Eric Lander, Rick Young, and others used Affymetrix Hu6800 chips to examine gene expression patterns in human macrophages exposed to eight different types of bacteria or to bacterial components.

“We wanted to identify similarities and differences in the responses of host cells to the pathogens that they see,” said Nau.

The researchers found that the bacteria and some of their components set off a common transcriptional response, a “macrophage activation program,” which involved 132 induced and 59 repressed genes. Other genes differed in expression level between different bacterial species; for example, Mycobacterium tuberculosis inhibited the expression of interleukin-12 and interleukin-15.

“The fact that we could identify the differences in expression profiles argues that this is a sensitive, potentially quite useful measure to try and diagnose, for instance, kinds of infections,” Nau said. He is currently reevaluating the data to see if the expression profiles can distinguish between bacteria. If distinct expression profiles can be found, the genes or the proteins they encode could be used in a diagnostic test for infection. “The goal is to identify genus and species of any kind of bacterium infecting a human,” Nau said.

However, Nau is not sure if the 6,800 genes on the chips are sufficient to reach this goal. “We just don’t know because we don’t have the whole genome represented on our arrays,” he said. But the Young lab, which Nau says has used microarrays since 1998, is about to upgrade to U95 arrays, which have about 12,000 genes represented. He is also eager to use the new two-chip U133 set with 33,000 genes that Affymetrix has just launched. “I look forward to the day when we can do those studies in a more comprehensive genome-wide fashion with human cells,” he said.

Apart from offering potential new diagnostic tools, the results of this study help to clarify how certain heat-shock proteins bolster the effect of vaccines — they activate the macrophages. Also, the results deliver a rational basis for the use of immunomodulators like interleukin-12 to treat tu-berculosis.

Nau, who was initially interested in tuberculosis, said microarrays have affected his research profoundly. “It took me personally into very unexpected directions, because I would not have predicted that I would have been working on potentially very clinically applicable diagnostics,” he said.

— JK

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