Ebola virus or TB bacterium: Which one would you bet on as themore successful pathogen?
Ebola kills its human victims in days, and by the hundred. Except insmall children and AIDS victims, Mycobacterium tuberculosislingers for decades before felling its sufferers, usually in old age. YetTB wins out over Ebola hands down as the microorganism mostlikely to succeed in the evolutionary scheme of things.
"A third of the world's population is probably infected with TB,"observed molecular biologist C. Kendall Stover of PathoGenesisCorp. in Seattle. "That's the current estimate," he told BioWorldToday. "In most cases, it doesn't cause disease; it's just a verysuccessful pathogen, because it doesn't often kill its human host.That's why TB is so common and widespread.
"A pathogen like Ebola," Stover continued, "that just kills its hostvery rapidly, isn't necessarily successful. And that's probably whyyou don't see more of it."
M. tuberculosis is a microbe of many paradoxes. Once inhaled by ahuman victim, the bug, which measures 3 microns long by 0.47 thick,goes to earth in its new victim's macrophages. These specializedphagocytic cells are tasked by the immune system with engulfing,taking up, killing and expelling foreign bodies, especially infectiousones.
Paradoxically, TB settles inside a macrophage for the long haul,which may last decades. How does it evade or overwhelmtermination with extreme prejudice?
"Macrophages generate oxygen free radicals," Stover explained."That oxidative stress tends to oxidize and destroy enzymes andlipids. That's a mechanism for killing these TB."
But TB has a few counter-mechanisms. Its first line of defense is alipid-rich cell wall, which contains mycolic acids. "These tend toabsorb the oxidative damage," Stover said, "and insulate the TB cell.But if anything gets through the cell wall, the bacterium has a fewenzymes that deal with oxidative stress and anti-microbial attack."
Once infection sets in, and the lungs come under attack, thetubercular patient needs out-of-the-body help. For half a century, thefront-line therapy has been isoniazid, an anti-microbial drug thatcures TB but no other disease. "Isoniazid was first used commerciallyin 1953," said PathoGenesis microbiologist David Sherman. Headded: "The first bacterial resistance to isoniazid was reported in1954."
Sherman and Stover are, respectively, first author and senior authorof a paper in the current Science, dated June 14, titled:"Compensatory ahpC gene expression in isoniazid-resistantMycobacterium tuberculosis."
Whereby hangs the second paradox.
Isoniazid is a prodrug, which means it can't go into action until it'sbeen activated. Strange as it seems, its bacterial target performs thatservice for its molecular adversary. M. tuberculosis harbors anenzyme, KatG, which obligingly strips isoniazid down to fightingtrim by oxidizing its precursor moieties.
The enzyme's gene then promptly mutates, and the TB cell ought byright to lose its resistance to the drug.
Until the research reported in this week's Science, Sherman said,"everyone believed that the KatG catalase peroxidase was crucial forisoniazid activity. It was well known that most isoniazid-resistantstrains of TB had lost that enzyme, which was assumed to be the onlycatalase peroxidase in the cell.
"So the question then was, `How was it possible for the bacterium tosurvive without any catalase at all?'"
While investigating TB's defense against macrophages, Sherman andhis co-authors discovered the gene for a second enzyme, ahpC, in thebacterial cell.
"While we were scratching our heads," he recalled, "trying to figureout what the role of ahpC might be, a collaborator of ours, CliftonBarry at the NIH's Rocky Mountain Laboratory [in Hamilton,Mont.,] was looking for isoniazid's target. They found some strainsof TB that were supposedly resistant, but did not have KatG activity.
"Barry looked at those gels," Sherman continued, "and said, `Doesn'tthat look like the ahpC that they discovered at PathoGenesis?' Welooked at them, and it was. Serendipity of the best kind."
Sherman continued: "That led us to ask how it was possible that thebacterium has two mutations that appear simultaneously. BecauseahpC had apparently taken over KatG's oxidative stress-resistancechores.
"Each bug would be expected to appear at the rate of one mutation ina million. We think that the odds against two of those simultaneouslyshould be astronomical. Yet both appear at the one-in-a-millionfrequency."
In 20 animal strains and more than a score of human clinical isolates,the team has verified ahpC up-regulation.
Now they are trying to determine where within the process of TBinfection the second mutation occurs. "Is it within macrophages?Does it happen in caseous [infected tissue] lesions? At this point wedon't know. But we're trying to set up experiments to determinethat."
Sherman went on: "And of course, because we're a drug company,we're interested in exploiting this information to develop new drugs.But that's a long way down the road from where we are today."
Stover added: "In fact, one can learn many lessons from the old drug,isoniazid, which is thought to be archaic. It's still a very good TBdrug. It actually targets some virulence mechanisms. They seem to gotogether with resistance.
"That's the new wave in antimicrobials _ drugs that target virulence.We're going to continue to look at these mechanisms, and developassays that might help us find new compounds," he concluded. "Ican't get much more specific than that, obviously." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.