Yersinia pestis is the causative agent of the systemic invasive infectious disease often referred to as the plague. The Y. pestis is an extremely virulent pathogen that is likely to cause severe illness and death upon infection unless antibiotics are administered. In the past, Y. pestis has caused devastating epidemics during three periods of modern history; the Justinian Plague spread from the Middle East to the Mediterranean during the 6th-8th centuries AD and killed approximately 25% of the population below the Alps region. Perhaps the most famous incidence of any disease was the devastating Black Plague of 8th-14th century Europe that eradicated 25 million people (nearly 25% of the population) and marked the end of the Dark Ages. The third endemic began in 1855 in China and was responsible for millions of deaths.
Yersinia pestis is a Gram-negative, bipolar-staining coccobacillus member of the Enterobacteriaceae family, and is an obligate intracellular pathogen that must be contained within the blood to survive. It is also a fermentative, motile organism that produces a thick anti-phagocytic slime layer in its path.
Y. pestis has the ability to cause disease in rodents, insects and humans. The primary carriers of the pathogen are the Oriental rat flea, Xenopsylla cheopis, and infected rodents. The path of transmission to humans usually involves a flea feeding on an infected rodent and becoming a carrier of infection. Once internalized, the bacteria will continue to reproduce until a large blockage is formed in the midgut of the flea, causing digestion and other gastrointestinal functions to cease. When the flea attempts to feed on humans, the blockage inhibits any blood from entering the stomach cavity; instead, portions of the blockage, often containing 11,000-24,000 bacilli, are regurgitated into the mammalian host.
Yersinia pestis encodes two antigenic molecules: Fraction 1 (F1) capsular antigen, and VW antigen. Both of these molecules are needed for pathogenicity, and are not expressed at temperatures lower than 37°C. This requirement is the main reason why Yersinia is not virulent in fleas, since their body temperature normally levels around 25°C. Yersinia is a model for studying Type III Secretion Systems (TTSS) that inject bacterial proteins into a host cell. In Y. pestis, it is the translocation of Yersinia outer proteins (Yop’s) that blocks the host cell’s ability to communicate with immune system cells and down-regulates the response of phagocytic host cells to infection. Through the TTSS, YopH and Yersinia protein kinase A (YpkA) are delivered by YopB and YopD into the host cell, where they subvert signal transduction and inhibit oxidative bursts. Also, the rough/short lipopolysaccharide (LPS) chains on the outer membrane of Yersinia mediate antibody resistance by causing abnormal attachment of membrane attack complexes (MACs).
There are three forms of the plague that commonly occur worldwide: bubonic, septicemic, and pneumonic. Bubonic plague is easily diagnosed by the presence of extremely swollen and tender lymph glands called “buboes” that can grow to the size of an egg, and typically arise in the groin, neck and armpits. Disease becomes evident 2-6 days after infection, and carries symptoms such as high fevers, chills, headache, and extreme exhaustion. One nasty side effect is the development of gangrene in the extremities, lending it the name “Black Death”. Bacteremia and death from Gram-negative induced shock occurs in 40-60% of untreated cases, while only 1-10% of treated cases are lethal. Septicemic plague often develops secondarily to bubonic plague, and is a result of direct invasion of the bloodstream without involvement of the lymph nodes. Due to the lack of buboes, symptoms generally resemble the flu and make diagnosis difficult. In severe cases, seizure and shock can take place. Death rates for this form are 40% for treated cases and 100% for untreated cases. The most serious form of infection is the pneumonic plague, which is 100% lethal if not treated within the first 24 hours. This mode of infection is the result of inhaled droplets of infectious material that proceed to directly colonize the lung tissue. Symptoms, on top of those found in the other two forms, include a severe cough, bloody sputum, chest pains, confusion, cyanosis, shock and eventual death.
Diagnosis and Treatment
Yersinia pestis expresses an envelope glycoprotein called Fraction 1 (F1) antigen only at temperatures >33°C. Serum antibodies to F1 are measured using passive hemagglutination assays (PHA). High titers of antibody along with correlating symptoms, such as buboes, generally indicate a positive diagnosis. Further testing may include X-rays of the lung to check for presence of pneumonic plague, examination of sputum, and lymph node biopsies. A short-term inactivated vaccine against Y. pestis has existed since the mid-19th century. Though its efficacy has never been precisely measured, field data does show that it lessens incidence and severity of disease resulting from animal transmission. The vaccine is recommended only for laboratory or field workers working with the pathogen, or persons (e.g. Peace Corps volunteers) residing temporarily in rural areas containing the enzootic plague in both human and animal carriers. Though death rates for untreated cases usually approach 100%, antibiotics can be a very effective treatment against the plague. In some instances, the vaccine will only ameliorate illness, in which case a rigorous treatment of antibiotics is administered. Yersinia pestis is very susceptible to streptomycin and chloramphenicol; however, concomitant therapy is highly recommended to avoid shock resulting from the lysis of high numbers of Gram-negative cells and the induction of a severe inflammatory response.
The plague can currently be found in every continent in the world with the exception of Australia, though it is particularly endemic in third world countries such as India, Brazil, Peru, Madagascar, Vietnam and China. In the United States, the loci of infection are in New Mexico, Arizona, Colorado, California, Oregon and Nevada. There are approximately 10-15 cases a year in the rural U.S. and 1-3,000 worldwide. The last urban epidemic in the United States was from 1924-1925 in Los Angeles; worldwide, a 1994 endemic in India killed almost 10 million.
The plague cycles naturally with quiescent periods that can last several years; however, it will always be found in areas of poor sanitation, overcrowding and a high rodent population. Due to these factors, it is extremely unlikely that the plague will ever be eradicated like the smallpox or polioviruses. Current research on Yersinia pestis is focused on the identification of genes responsible for transferring infection from fleas to humans, as well as the disease-causing proteins genes that allow bacterial colonization and infection in the lungs. Work is also being done to develop a fully effective vaccine against pneumonic plague and more powerful antibiotic treatments to treat infectious cases.
Parkhill, J., Wren, B.W., Thomson, N.R. et al. Genome sequence of Yersinia pestis, the causative agent of plague. Nature 413, 523 - 527 (04 October 2001); doi:10.1038/35097083
Perry, R. D. & Fetherston, J. D. Yersinia pestis--etiologic agent of plague. Clin. Microbiol. Rev. 10, 35-66 (1997)