Anthrax Immunity Gene Found In Mice

Harvard Medical School researchers have identified a mouse gene that, in certain forms, renders mice resistant to anthrax-an often fatal disease that is caused by a bacterium thought to be a prime biological weapon in the terrorist arsenal. The genetic variants appear to work by enhancing immune cells’ response to the lethal toxin released by the anthrax-causing germ. Intense efforts are being made to find ways to defend humans against a possible anthrax attack in the wake of the World Trade Center and Pentagon assaults. The new findings, which appear in the October Current Biology, could aid that effort in two ways. They could shed light on what happens during the early stages of anthrax infection, and in particular how the lethal toxin released by the bug affects immune cells. This knowledge could be used to devise therapies for human anthrax, which is virtually untreatable once symptoms develop.

“This is one of very few times we have a concrete molecular handle on what is happening during lethal factor intoxication,” said William Dietrich, HMS assistant professor of genetics and senior author of the study. “We can begin to think what if I manipulate this process-how might that help resist anthrax intoxication?”

The findings could help counter the threat of biological terrorism in another way. “The gene exists and is known to vary in humans,” Dietrich said. If these human variants are found to confer immunity, they could provide a basis for screening people who have been exposed to the anthrax bacterium.

“If it can be established that there are susceptible and resistant human individuals that are caused by differences in Kif1C, then one could identify these individuals,” he said. “If you knew someone was resistant to anthrax you might not worry so much about them if they had been exposed. Or you might want to know who among the soldiers in your army might be able to tolerate anthrax better.”

Dietrich’s hunt for the genetic variants began several years ago, when he and HMS professor of microbiology and molecular genetics John Collier, identified several strains of inbred mice that were immune to anthrax. They mapped the immunity-conferring gene to a stretch of DNA on chromosome 11. To identify the actual gene, Dietrich, JamesWatters, a graduate student and lead author of the new study, and their colleagues compared genes found in that region in resistant and susceptible mice. Only one, Kif1C, displayed variation in its genetic sequence. In fact, the gene came in four varieties-two resistant and two susceptible.

At first glance, Kif1C appeared an unlikely protagonist. Anthrax launches its attack in the body by releasing a deadly toxin which has a remarkable mechanism for entering a special class of immune cells, macrophages. Once inside, the toxin is thought to work by destroying critical proteins. In their search, the researchers looked for proteins that might be likely targets. But the Kif1C protein belonged to a family of motor molecules, the kinesins, that ferry membrane proteins around the cell along a set of internal tracks. It was not clear what advantage the resistant Kif1 proteins might have during an invasion.

Thinking that the resistant variants might be thwarting anthrax through some defect-for example by failing to effectively transport a protein critical to lethal factor intoxication-Dietrich and his colleagues destroyed sections of the internal transport system in both the susceptible and resistant macrophages and exposed them to anthrax lethal toxin. All the cells died.

The results were unexpected. By sabotaging the transport system of susceptible cells, thereby disrupting Kif1C’s activities, the researchers thought they would make the cells more like their resistant cousins. “We assumed the susceptible allele was the more functional allele,” Dietrich said. “But this said the resistant allele was the more functional.”

How exactly a more functional Kif1C works to thwart anthrax is unclear. What is known is that once entered by anthrax toxin, macrophages launch a burst of inflammatory and oxidative activity in an effort to kill the invader. So powerful is the internal assault, many macrophages self-destruct, releasing not just bacteria but also damaging inflammatory and oxidative agents. It is the release of such agents into the blood stream that induces the body-wide state of shock that eventually kills the infected host.

One possibility, said Dietrich, is that Kif1C may be involved in protecting macrophages from the potentially self-destructive effects of that assault-for example by helping to move toxin to a particular region of the cell where it can be attacked. By sequestering the toxin, the area of self-inflicted damage may be limited. The resistant variants may play their role in this sequestering process slightly more efficiently.

“I think of the cells as being under very dire stress, and even things as mundane as making sure that all the membrane gets moved around to the right place become critical,” said Dietrich. “What if there was a shortage of this boring but critical cellular component? Would the cell fail to be able to perform its job and die? You can imagine that over the course of a few hours these kinetic defects can catch up with you.”

Although speculative, the scenario suggests that one approach to treating anthrax infection might be to bolster the activities of Kif1C. “This might represent a foothold into a molecular process that can be affected,” said Dietrich.

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