By David N. Leff
From anthrax to the common cold, many pathogenic infections are described as having ¿flu-like symptoms.¿ This broadside rap bestowed its sinister name on the influenza virus itself, for which the annual vaccination season has just begun.
In the aftermath of World War I, beginning in September 1918, influenza killed some 50 million people worldwide ¿ 548,000 in the U.S. How did everyone else on the planet escape that viral pandemic? The same question could apply to TB: Of every 10 individuals infected with the Mycobacterium tuberculosis bacterium, only one ¿ 10 percent ¿ will develop the disease. Likewise, of every 100 people who acquire the malaria parasite, Plasmodium falciparum, in their blood, a mere 0.5 percent will die. And when a toxic strain of Escherichia coli taints raw meat, not everyone who consumes it comes down with enteritis.
By a similar statistical token, millions of people, primarily women, are afflicted with the ruthless fungal infection wreaked by Candida albicans. In 30 percent or so of its victims, C. albicans maintains a benign standoff with the body¿s immune system. But death threatens patients on immunity-wrecking chemotherapy or with AIDS. Antifungal remedies are so drastic as themselves to be life threatening.
How do all of these infected human targets evade or avoid their lethal outcome?
¿It¿s certainly possible that a subset of people susceptible to contracting these diseases are able to come up with different types of immune responses,¿ conjectured research immunologist Nir Hacohen, at the MIT-affiliated Whitehead Institute for Biomedical Research in Cambridge, Mass. ¿And that may be due to their ability to recognize the pathogens ¿ how they sense them and how they respond.
¿However,¿ Hacohen added, ¿the ability to eliminate a pathogen is dependent on every part of the immune system working correctly. Dendritic cells [DCs] are only one of its many components. If they or your T cells or B cells don¿t work well, you¿re more likely to contract the disease.
¿However,¿ he went on, ¿if a person has a very pathogen-specific defect, it is more likely that the sensing of that pathogen by the immune system is problematic. In case they don¿t have a systemic problem that affects every pathogen, infection may be due to recognition of the pathogen, which could be accomplished by dendritic cells or other cell types.¿
How To Tell Foe From Foe
Hacohen is senior author of a paper in today¿s Science, dated Oct. 26, 2001, which bears the title: ¿The plasticity of dendritic cell responses to pathogens and their components.¿ (The pathogens they probed covered three fronts ¿ viral, bacterial and fungal ¿ namely, influenza, E. coli and C. albicans.)
¿The most novel part of our finding in this paper,¿ Hacohen told BioWorld Today, ¿is that dendritic cells are able to distinguish between different types of pathogens, and turn on specific types of immune-response genes against them. What we really learned,¿ he continued, ¿is that this single cell type has the capability of making this discrimination by the immune system, and then becomes a messenger that tells the rest of the immune system what types of immune reactions to stimulate. So the novelty of our report is in saying that there exists such a sensor in the mammalian body, and that sensor is embodied in the dendritic cell. And that DC, as the result of its ability to discriminate among viral, bacterial and fungal pathogens, can be a regulator of the immune system.¿
To demonstrate this finding, Hacohen and his co-authors went straight to the Human Genome Sequence map, and tested 6,800 genes with known functions on DNA microchips. ¿We did not synthesize the chip,¿ Hacohen pointed out, ¿but Affymetrix Inc. did. It chose the genes from the genome and then synthesized oligonucleotides corresponding to the known genes, which it arrayed directly onto the chips. Oligos are short strands of DNA that have been synthesized, and are identical in sequence to the genes we¿re interested in.
¿Of the 6,800 genes represented on the microarray,¿ Hacohen recounted, ¿1,330 changed their expression significantly upon encountering one of the three pathogens or their molecular components. Gene expression was most rapidly induced by E. coli, less rapidly by C. albicans and most slowly by influenza. These three responses revealed a common set of 166 highly regulated genes, constituting part of DC¿s core response.¿
Then the co-authors refined their focus. To further dissect DC¿s ability to call each pathogen in the corner pocket, as it were, they zeroed in on a single molecular subunit of each, serving as an antigenic flag or badge to identify it to the immune system. Thus E. coli¿s cell wall, lipopolysaccharide, was able to mimic and account for almost the entire bacterial response.
¿The fungal component of C. albicans, mannan, which is also a fungus-derived cell-wall product,¿ he related, ¿proved unexpectedly more stimulatory than the entire fungus itself. It mimicked the magnitude and biological character of the bacterial response more closely than it did the fungal or viral response profiles. We don¿t know what the reason is, but we do know that mannan was more potent than the entire fungal organism. In the case of the virus,¿ Hacohen continued, ¿the component that we took was double-stranded RNA, which is inside the RNA virus. That turned out not to be an ideal model for viral interaction with DCs.¿
Species Discrimination Hints At Diagnostics
He and his team have tested DNA chip gene response to Staphylococcus aureus, a Gram-positive bacterium, against the Gram-negative E. coli. They ¿saw a very small number of differences, but enough to distinguish between the two species¿ ¿ suggesting some diagnostic application in the distant future.
¿The knowledge that dendritic cells are able to sense and respond specifically to each pathogen,¿ Hacohen observed, ¿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. In this study, we have identified a large set of genes that are activated in the presence of pathogens.
¿Our next step is to determine what specific functions those genes have in DCs. In addition, we can now ask more meaningful questions about how these genetic programs get turned on and off,¿ he concluded, ¿and use these insights to design better therapies.¿