The Power of Plagues. Irwin W. Sherman

genes that are activated by body temperature and millimolar concentrations of calcium, conditions found in the mammalian host. These genes code for the T3SS (type III secretion system), containing an “injectosome,” a hypodermic-like structure, and a translocon that forms a pore across the host cell membrane. The T3SS functions to inject multiple toxic proteins, named Yops (Yersinia outer proteins), directly into the host cell cytoplasm. Once inside the cell, the Yops trigger a preprogrammed chain reaction that results in cell death. Yops also inhibit phagocytosis by macrophages and block cytokine function (see p. 97). Together this prevents the bacterium from being ingested, thereby avoiding the immune mechanisms of the host; another protein is able to degrade fibrin, a material found in the blood clot, allowing the Yersinia to move throughout the body by allowing it to escape from the clot at the site of the flea bite.

      While the above description refers to the disease in humans, the disease in fleas also has a distinctive pattern. Small mammals such as urban and sylvatic (or wood) rats, as well as squirrels, prairie dogs, rabbits, voles, coyotes, and domestic cats, are the principal hosts for Y. pestis. More than 80 different species of fleas are involved as plague vectors. Fleas are blood-sucking insects (Fig. 4.7), and when a flea bites a plague-infected host (at the bacteremic/septicemic stage), it ingests the rod-shaped bacteria; these multiply in the blood clot in the proventriculus (foregut) of the flea. This bacteria-laden clot obstructs the flea’s bloodsucking apparatus, and as a consequence the flea is unable to pump blood into the midgut, where it would be digested. As a result, the flea becomes hungrier, and in this ravenous state the flea bites the host repeatedly; with each bite it regurgitates plague bacteria into the wound. In this way infection is initiated. Y. pestis can also be pathogenic for the flea, and fleas with their foregut blocked rapidly starve to death. If the mammalian host dies, its body cools down, and the fleas respond by moving off the host to seek another live warm-blooded host. If there is an extensive die-off of rodents, however, then the fleas move on to less preferred hosts such as humans, and so an epidemic may begin.

      The Plague-Causing Bacterium, Yersinia pestis

Y. pestis has been subdivided into three varieties—Antiqua, Medievalis, and Orientalis. Epidemiological and historical records support the hypothesis that Antiqua, presently resident in Africa, is descended from bacteria that caused the first pandemic, whereas Medievalis, resident in central Asia, is descended from bacilli that caused the second pandemic; those of the third pandemic, and currently widespread, are all Orientalis. It is believed that Y. pestis probably evolved during the last 1,500 to 20,000 years because of changes in social and economic factors that were themselves the result of a dramatic increase in the size of the human population, which was coincident with the development of agriculture. This triggered the evolution of virulent Y. pestis from the enteric, food-borne, avirulent pathogen Y. pseudotuberculosis. This required several genetic changes: a gene whose product is involved in the storage of hemin resulted in blockage of the flea proventriculus and enhanced flea-mediated transmission, and other gene products (phospholipase D and plasminogen activator) facilitated blood dissemination in the mammalian body and allowed for the infection of a variety of hosts by fleas.

      Plague Today

      The mortality and morbidity from plague has been significantly reduced in the 21st century. The disease, however, has not been eradicated. On November 2, 2007, Eric York, age 37, a wildlife biologist, was found dead in his home on the South Rim of the Grand Canyon. He died from plague after performing an autopsy on a dead cougar on October 27. This was the first case reported in Arizona since 2000. A year earlier a woman in Los Angeles was reported in the Los Angeles Times Online to have caught the Black Death. She had been taken to the hospital on April 13 suffering with characteristic swollen inguinal lymph nodes (buboes), fever, and other telltale symptoms of plague. It was suspected (but not proven) that the woman caught the disease after being bitten by infected fleas in her home.

      Time magazine reported on October 30, 2015, that a 16-year-old girl from Oregon who had been on a hiking trip was in intensive care after being hospitalized a week earlier with bubonic plague. It was the 16th reported case that year, and so far, according to the Centers for Disease Control and Prevention, there already had been 4 deaths. In 2015 most of the bubonic plague cases were from Arizona, California, Colorado, Georgia, New Mexico, Utah, as well as Oregon. Two cases were linked to exposure in or near Yosemite National Park.

      Between 1900 and 2012, 1,006 confirmed or probable human plague cases occurred in the United States. More than 80% of U.S. plague cases have been the bubonic form. In recent decades an average of 7 human plague cases have been reported each year (range, 1 to 17 cases per year). Plague has occurred in people of all ages (infants up to age 96), though 50% of cases occur in people ages 12 to 45. It occurs in both men and women, though historically is slightly more common among men, probably because of increased outdoor activities that put them at higher risk.

      Worldwide between 2010 and 2015 there were 3,248 cases of plague reported and 584 deaths. Following the reappearance of plague in the 1990s in India, the World Health Organization considered plague as a reemerging disease. Over the years there has been a major shift of cases from Asia to Africa, with >90% of all cases occurring in Madagascar, Tanzania, Mozambique, Malawi, Uganda, and the Democratic Republic of the Congo (DRC). Most cases are of the bubonic variety; cases of pneumonic plague, however, were reported from the DRC in 2006 and Uganda in 2007. Madagascar is the most seriously affected country, with an overall fatality rate of 23% associated with pneumonic plague. In the United States plague has been encountered when houses have encroached on rural areas that harbor plague-infected rodents (sylvatic plague), such as prairie dogs, ground squirrels, mice, and rats. Infection may also be acquired from domestic pets (cats and dogs) that have come in contact with prairie dogs and can transmit disease to humans via fleas or in the pneumonic form. In the United States there has been an increase in the number of human cases of pneumonic plague, especially among veterinarians who have been exposed to infected cats.

      Control of plague can be effected by surveying wild populations for infections, monitoring die-offs in the rodent population, making plague-infested areas known to the public, reducing the appeal of residential areas to rodents, and treating rodent burrows with cabaryl dust or bait stations to kill fleas. In some cases, rodenticides have been used.

      Because of sylvatic plague and enzootic infections (i.e., outbreaks of a disease in animals other than humans), total eradication cannot be achieved.

      Though human disease is rare, a feverish patient who has been exposed to rodents or flea bites in an area where plague is endemic should be considered a possible plague victim. The potential for the spread of pneumonic plague has been increased by air travel. Passengers who have fever, cough, or chills and come from areas where plague is endemic should be placed in isolation and, if necessary, treated. The diagnosis of plague has remained virtually unchanged since the days of Yersin: Gram staining and culture of bubo aspirates or sputum. The bacteria can also be grown in the laboratory on blood agar.

      Unless specific treatment is given, the condition of a plague-infected individual deteriorates rapidly, and death can follow in 3 to 5 days. Untreated plague has a mortality rate of >50%. Streptomycin, tetracyclines, and sulfonamides are the standard treatments, and gentamicin and fluoroquinolones are alternatives when these other antibiotics are unavailable. In May of 2015 the U.S. Food and Drug Administration approved moxifloxacin (Avelox) to treat patients with plague. Earlier treatment was effected by using a serum Yersin had prepared in horses after injecting them with the plague bacilli he had isolated in Hong Kong in 1894.

      Vaccines

      The first vaccine for plague was developed by Waldemar Haffkine (1860-1930). Haffkine, the son