Thursday, June 17, 2010

microcosmic mafia wars

The Scientist | When searching for an appropriate description of the mammalian immune system, the vast majority of scientists settle on the metaphor of a war. It’s a battle scene, with the foot soldiers of the immune system (e.g., killer T cells) battling the bacterial or viral particles in an open field (the host’s body). Painting a picture in such strong terms is a good way to attract attention (and funding), and in many ways, it is a good fit—one paper I stumbled on as a graduate student that elegantly modeled the conflict generated nearly identical equations to those used in traditional models of warfare, which predict that military losses are proportional to the size of enemy forces.

Over the last several years, however, scientists have begun to realize that the molecular interactions between a pathogen and its host are quite a bit more complex than simple open field battle, where the power of one’s army is measured by bodies alone. The immune system is a multifaceted defense system, and pathogens have evolved numerous molecular strategies to evade its wrath, including methods that resemble more the devious tactics of organized crime than those of traditional warfare, such as setting up fronts to conduct covert operations, going undercover to infiltrate the opposing gang, and terrifying the enemy into admitting defeat (or committing Seppuku).

In the late 1990s, the discovery of pathogenicity islands—large regions of bacterial and viral genomes unique to pathogenic species—led researchers to recognize that many pathogens were involved in some complex racketeering, says immunologist and microbiologist Igor Brodsky of Yale University. Encoding specialized systems to inject virulence proteins into cells, pathogens are able to manipulate cellular processes in the host for their own benefit, such as initiating immune cell death and blocking a continued immune response.

This prompted the field to start identifying specific virulence factors important for a particular pathogen—either by mining databases for genes that might be behind those factors, knocking them out, and observing the effects on the pathogen’s ability to infect its host, or doing random mutagenesis. Once scientists identified some factors important for virulence, “then the question was what were these genes or proteins doing,” Brodsky says.