Researchers Identify Pathogen-specific Gene Response in Human Immune Cells

CAMBRIDGE, Mass. — Using DNA microarray technology, researchers at the Whitehead Institute for Biomedical Research have discovered that a type of human immune cell, known as a dendritic cell, initiates an immune response that is tailor-made for specific infectious organisms. The researchers found that dendritic cells turn on different sets of genes, or a signature pattern of gene response, depending on whether the organism is a bacteria, virus, or fungus. This study shows that even at the earliest stages of infection, the human body knows the nature of the infectious organism, or pathogen, and responds with a specific type of immune response to eliminate the pathogen.

Although researchers have suspected that dendritic cells can mount tailored responses in addition to a set of common responses, they haven’t had much concrete evidence to support this view. This DNA array study provides the first comprehensive evidence for such specific responses and offers snapshots of what such pathogen-specific responses look like at the genetic level.

“The knowledge that dendritic cells are able to sense and respond specifically to each pathogen could ultimately help clinical scientists detect the presence of particular pathogens and measure the nature of the immune response by looking for the signatures of pathogen-specific genes described in this study,” says Whitehead Fellow Nir Hacohen, who led the study.

DNA array technology has already proved useful in diagnosing different types of cancers by detecting signatures of gene expression and may thus play a similar role for infectious diseases in the future.

By measuring the activity of many genes in these immune cells as they respond to pathogens, researchers hope to gain information about the strengths and vulnerabilities of the microbes and our own immune system during an immune response to infection. Such information coupled with more detailed studies of pathogen-specific genes will eventually enable the development of customized therapeutics for the optimal elimination of each type of human pathogen, says Hacohen.

This study, published in the October 26 issue of Science, was conducted in Hacohen’s lab, with lead authors Qian Huang and Dongyu Liu, in collaboration with Whitehead Members Eric Lander and Richard Young.

Initiators of Immune Response

Dendritic cells—among the first cells in the body to encounter infectious organisms—are key players in initiating an immune response. These cells arise in the bone marrow but migrate to and seed tissues throughout the body. Before dendritic cells encounter an infectious agent, they are “immature,” and act as roving sentinels of the immune system. Upon an encounter with an infectious agent, the dendritic cell reaches maturity—capturing the infectious agent and processing it for presentation to the T-cell, thus initiating a cascade of immune events that fight infection.

“What we’ve discovered is that dendritic cell maturation—as a result of its recognition of a pathogen—is highly specialized,” says Hacohen. “The dendritic cell fine tunes its response based upon the nature of the pathogen–for every pathogen, there is a specific set of genetic programs that are activated or not activated, which then impacts how the immune system as a whole reacts to the infectious agent. In this way, pathogens have taught us an important and useful lesson: it is possible to program particular immune responses through the activation of dendritic cells.”

The Hacohen lab used Affymetrix DNA microarray technology to investigate at a genetic level how dendritic cells discriminate between pathogens. Also called DNA chips, DNA arrays consist of rows and rows of DNA probes mounted on a silicon wafer or glass slide. These “labs-on-a-chip” allow scientists to study the activity, or expression, of thousands of genes simultaneously.

These arrays were used to identify genes involved in the dendritic cell’s response to three common pathogens: a virus (influenza), a bacterium (Escherichia coli), and a fungus (Candida albicans). They looked for genes that were turned on or off in a dendritic cell after it encountered a pathogen, thus generating a snapshot of which genes were active during a dendritic cell’s response to a specific pathogen.

Several clear results emerged from these studies. First, dendritic cells were able to activate genes that regulate several phases of the immune response — from the early and rapid defenses (neutrophils and macrophages) to the later, long-lived, and potent responses (T and B cells). Second, pathogens were able to guide activation of these dendritic cell genes, so that only particular arms of the immune response were induced by a pathogen. For example, E. coli was able to rapidly induce a set of genes that attracts neutrophils; however influenza virus was not able to activate these genes. These kind of results allowed the authors to conclude that the dendritic cell plays an important role as a messenger in the body–it senses infections in the body’s tissues and carries instructions to the immune system to activate its different arms.

Hacohen says that only a small fraction of the identified genes may become targets for therapy, but that the larger set of genes does provide clues to finding the key players, or group of genes, involved in the tussle between the microbe and the immune cell. The most important task right now is to determine whether the responding genes are most beneficial to the life of the host or the pathogen.

“In this study, we have identified a large set of genes that are activated in the presence of pathogens. The next step is to determine what specific function those genes have in dendritic cells,” says Hacohen. “In addition, we can now ask more meaningful questions about how these genetic programs get turned on and off, and use those insights to design better therapies.”

Supported by grants from the Whitehead Institute Fellows Program, Affymetirx, Bristol Meyers Squibb, Millennium Pharmaceuticals, Rippel Foundation, and Hascoe Foundation.