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November/December 2000
Vol. 3, No. 9, pp. 96,

Clinical trials track

A plague on all our houses

As pointed out in this issue’s “Time Line” (p 75) the plague caused by the bacillus Yersinia pestis not only has a long and deadly history, but remains a current threat.

Plague is endemic in the United States, with 10–15 cases of rodent–flea–human (sylvatic cycle) transmission in the rural West and Southwest yearly. The facultative anaerobic, Gram-negative rods are transmitted in flea regurgitant during bites. This is the classic “bubonic plague” characterized by acute regional lymph adenopathy (buboes). Septicemic plague occurs when the bloodstream is invaded. The true fear of a plague epidemic is the possibility of a human–human pneumonic (urban cycle) version (not reported in the United States since 1925), in which the transmission vehicle is airborne droplets of human sputum. For untreated bubonic plague, mortality is usually 60%; for pneumonic plague, it is nearly 100%. Because an untreated bubonic plague epidemic almost inevitably transforms into septicemic and then pneumonic plague, all plague outbreaks are considered serious public health risks. Plague is treated as a Class I notifiable disease subject to International Health Regulations by the World Health Organization and, in the United States, by the Centers for Diseas
Figure 1. Schematic representation of Caco-2 permeablility assay.
The common image of the Dance of Death grew out of the nightmare of plague in the Middle Ages.
e Control and Prevention.

Although plague is treatable in its early stages with several antibiotics—streptomycin is the most common—a strain of plague was detected in Madagascar in the late 1990s that was resistant to five antibiotics. The bacillus apparently incorporated a resistance plasmid from another species of bacteria, further fueling fears of plague as a disease that could reemerge catastrophically in the future, especially as antibiotic resistance increases worldwide.

Preventing plague, as with preventing endemic rabies, requires monitoring the vectors and maintaining sanitary conditions rather than using vaccination. Generally available plague vaccines are effective against only the bubonic form of plague and are somewhat unreliable. They require multiple inoculations over several months, so vaccination is not routinely recommended except for laboratory personnel or certain field workers (mammalogists, ecologists, etc.) who have regular contact with rodents in infested areas. Prophylactic antibiotics are suggested more often. More convenient and effective vaccines are being investigated, including a nasally delivered vaccine to prevent the pneumonic form of plague. Genetically engineered vaccines that use bacterial subcomponents rather than whole, formaldehyde-inactivated bacilli are also being tested.

Biowarfare bacillus
Much of this vaccine work is sponsored by the military. Why? In part because it is extremely lethal in untreated cases, and in part because of the atavistic fear raised by the very thought of the Black Death, plague has been touted as a biological warfare agent. Numerous agencies throughout the developed world, including the United States, have action plans for dealing with a terrorist-initiated outbreak. Countermeasures in such an event include containment and antibiotic treatment.

What makes the plague effective as a killer is the bacilli’s own form of covert biological warfare within an infected host (rat or human). Kim Orth and co-workers at the University of Michigan have demonstrated that Yersinia pestis produces six proteins that attack immune system macrophages. One protein, YopJ, binds to the superfamily of mitogen-activated protein kinases (MAPK) and blocks phosphorylation, thereby inhibiting kinase activation of signaling pathways common to mammalian cells. These pathways, which control cell growth, regulate the immune inflammatory response, and inhibit apoptosis, are critical to fighting off infections. This protein’s behavior may help to explain the extreme virulence of the pathogen and the fact that untreated victims develop vast numbers of bacteria in their lymph nodes, bloodstreams, and/or lungs.

Suggested reading

Orth, K., et al. Science 1999, 285, 1920–1923.

Sanger Center Web site. www.sanger.ac.uk/Projects/Y_pestis (Yersinia genome project).

WHO Plague Manual. www.vaccines.ch/emc-documents/plague/whocdsc sredc992c.html.

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