Yersinia pestis

Yersinia pestis (formerly Pasteurella pestis) is a Gram-negative rod-shaped bacterium belonging to the family Enterobacteriaceae. It is a facultative anaerobe that can infect humans and other animals.

Human Y. pestis infection takes three main forms: pneumonic, septicemic, and the notorious bubonic plagues. All three forms have been responsible for high mortality rates in epidemics throughout human history, including the Black Death (a bubonic plague) that accounted for the death of approximately one-third of the European population in 1347 to 1353.

Recently Y. pestis has gained attention as a possible biological warfare agent and the CDC has classified it as category A pathogen requiring preparation for a possible terrorist attack.


Y. pestis was discovered in 1894 by Alexandre Yersin, a Swiss/French physician and bacteriologist from the Pasteur Institute, during an epidemic of plague in Hong Kong. Yersin was a member of the Pasteur school of thought. Shibasaburo Kitasato, a German-trained Japanese bacteriologist who practiced Koch's methodology was also engaged at the time in finding the causative agent of plague. However, it was Yersin who actually linked plague with Yersinia pestis. Originally named Pasteurella pestis, the organism was renamed in 1967.

Three biovars of Y. pestis are known, each thought to correspond to one of the historical pandemics of bubonic plague. Biovar Antiqua is thought to correspond to the Plague of Justinian; it is not known whether this biovar also corresponds to earlier, smaller epidemics of bubonic plague, or whether these were even truly bubonic plague. Biovar Medievalis is thought to correspond to the Black Death. Biovar Orientalis is thought to correspond to the Third Pandemic and the majority of modern outbreaks of plague. Y. pestis was transmitted by fleas infesting rats.


The role of Y. pestis in the Black Death is debated among historians; some have suggested that the Black Death spread far too rapidly to be caused by Y. pestis. DNA from Y. pestis is alleged to have been found in the teeth of an individual who supposedly died from the Black Death, however, and medieval corpses who died from other causes did test positive for Y. pestis. This suggests that Y. pestis was, at the very least, a contributing factor in some (though possibly not all) of the European plagues. It is possible that the selective pressures induced by the plague might have changed how the pathogen manifests in humans, selecting against the individuals or populations which were the most susceptible.

General characteristics

Y. pestis is a rod-shaped facultative anaerobe with bipolar staining (giving it a safety pin appearance). Similar to other Yersinia members, it tests negative for urease, lactose fermentation, and indole. The closest relative is the gastrointestinal pathogen Yersinia pseudotuberculosis, and more distantly Yersinia enterocolitica.


The complete genomic sequence is available for two of the three sub-species of Y. pestis: strain KIM (of biovar Medievalis), and strain CO92 (of biovar Orientalis, obtained from a clinical isolate in the United States). As of 2006, the genomic sequence of a strain of biovar Antiqua has been recently completed. Similar to the other pathogenic strains, there are signs of loss of function. The chromosome of strain KIM is 4,600,755 base pairs long; the chromosome of strain CO92 is 4,653,728 base pairs long. Like its cousins Y. pseudotuberculosis and Y. enterocolitica, Y. pestis is host to the plasmid pCD1. In addition, it also hosts two other plasmids, pPCP1 and pMT1 which are not carried by the other Yersinia species. Together, these plasmids, and a pathogenicity island called HPI, encode several proteins which cause the pathogenesis for which Y. pestis is famous. Among other things, these virulence factors are required for bacterial adhesion and injection of proteins into the host cell, invasion of bacteria into the host cell, and acquisition and binding of iron harvested from red blood cells. Y. pestis is thought to be descendant from Y. pseudotuberculosis, differing only in the presence of specific virulence plasmids.

A comprehensive and comparative proteomics analysis of Y. pestis: strain KIM was performed in 2006; this analysis focused on the transition to a growth condition mimicking growth in host cells.

Pathogenics and immunity

In reservoir host

The reservoir commonly associated with Y. pestis are several species of rodents. In the steppes, the reservoir species is principally believed to be the marmot. In the United States, several species of rodents are thought to maintain Y. pestis. However, the case is not very clear because the expected disease dynamics have not been found in any rodent species. It is known that some individuals in a rodent population will have a different resistance, which could lead to a carrier status. There is some evidence that fleas from other mammals have a role in human plague outbreaks.

This lack of knowledge of the dynamics of plague in mammal species is also true among susceptible rodents such as the black-tailed prairie dog (Cynomys ludovicianus), in which plague can cause colony collapse resulting in a massive effect on prairie food webs. However, the transmission dynamics within prairie dogs does not follow the dynamics of blocked fleas; carcasses, unblocked fleas, or another vector could possibly be important instead.

In other regions of the world the reservoir of the infection is not clearly identified, which complicates prevention and early warning programs. One such example was seen in a 2003 outbreak in Algeria.

In vector

The transmission of Y. pestis by fleas is well characterized. Initial acquisition of Y. pestis by the vector occurs during feeding on an infected animal. Several proteins then contribute to the maintenance of the bacteria in the flea digestive tract, among them the hemin storage (Hms) system and Yersinia murine toxin (Ymt).

Although Ymt is highly toxic to rodents and was once thought to be produced to insure reinfection of new hosts, it has been demonstrated that murine toxin is important for the survival of Y. pestis in fleas.

The Hms system plays an important role in the transmission of Y. pestis back to a mammalian host. The proteins encoded by Hms genetic loci aggregate in the esophagus and proventriculus of the flea, which is a structure that ruptures blood cells. Aggregation of Hms proteins inhibits feeding and causes the flea to feel hungry. Transmission of Y. pestis occurs during the futile attempts of the flea to feed. Ingested blood is pumped into the esophagus, where it dislodges bacteria growing there and is regurgitated back into the host circulatory system.

In humans and other susceptible hosts

Pathogenesis of Y. pestis in mammalian hosts is due to several factors, which predominately focus on the initial immune response. Flea bites allow for the bacteria to enter through the skin. Y. pestis expresses the yadBC gene, which is similar to Invasin in other Yersinia species, allowing for adherence and invasion of epithelium. There are reports that isolates from the pneumatic plague patients have a plasminogen activator, which can remove clots in order to facilitate systematic invasion. The majority of the bacteria's virulence factors are anti-phagocytic in nature. Two important anti-phagocytic antigens, named F1 (Fraction 1) and V or LcrV, are both important for virulence. These antigens are produced by the bacterium at normal human body temperature. Furthermore, Y. pestis survives and produces F1 and V antigens while it is residing within blood cells such as monocytes, but not in neutrophils. Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils.

Additionally, the Type III secretion system allows y. pestis to inject six different substances into macrophages and other immune cells. These are collectively call YOPs (Yersinia Outercoat Proteins) and include Yop B/D for cytolysis , YpkA for serine/threonine kinase activity, YopO, YopH, YopM for platelet aggregation, YopT, YopJ for apoptosis, and YopE for actin microfilament disruption. These proteins are injected via a long syringe into a pore created in part by YopB and YopD. These proteins limit phagocytosis by targeting actin and other cell signaling pathways important in the innate immune system.


A formalin-inactivated vaccine once was available for adults at high risk of contracting the plague until removal from the market by the FDA. It was of limited effectiveness and may cause severe inflammation. Experiments with genetic engineering of a vaccine based on F1 and V antigens are underway and show promise; however, bacteria lacking antigen F1 are still virulent, and the V antigens are sufficiently variable, that vaccines composed of these antigens may not be fully protective. A report found that Europeans were less likely to catch the plague, because they are the descendants of the survivors of the plagues that affected Europe in the medieval times.

Clinical aspects

Symptoms and disease progression

  • Bubonic plague
    • Incubation period of 2-6 days, when the bacteria is actively replicating in lymph nodes
    • Universally a general lack of energy
    • Fever
    • Headache and chills occur suddenly at the end of the incubation period. From this point the infection is resolved or lethal.
    • Swelling of lymph nodes resulting of buboes, this is the classic sign of bubonic plague
  • Septicemic plague
  • Pneumonic plague
    • Fever
    • Chills
    • Cough
    • Chest pain
    • Dyspnea
    • Hemoptysis
    • Lethargy
    • Hypotension
    • Shock
    • Symptoms of bubonic or septicemic plague, not always present

If this occurs with the classic buboes, this is considered primary, while secondary occurs after symptoms of bubonic or pneumonic infection. Since the bacteria are blood-bourne, several organs can be affected including the spleen and brain. The diffuse infection can cause an immunologic cascade to occur, leading to DIC, which in turn results in bleeding and necrotic skin and tissue. Such a disseminated infection increases mortality to 22%.

Pneumonic plague can be spread from one human to another directly by aerosol. Rarely bubonic and even more rarely septicemic plague can gain pneumonic characteristics. As with the other forms of plague, after the incubation period there is a sudden onset of coughing, high temperature, and lack of energy. From this point the infection increases in severity. Due to its high replication rates, plague proves fatal in roughly 50% of cases even with medical treatment, and is almost universally fatal without treatment.

With the exception of the buboes, the initial symptoms of plague are very similar to many other disease, making diagnosis difficult.

ICD-9 codes for the diseases caused by Y. pestis:

  • 020.0 Bubonic plague
  • 020.2 Septicemic plague
  • 020.5 Unspecified pneumonic plague
  • 020.3 Primary pneumonic plague
  • 020.4 Secondary pneumonic plague

Clinical determination

Grams stains can confirm the presence of gram negative rods, and in some cases the identification of the double curved shape. More definitive test is a Anti-F1 serology test, which can differentiate between different species of Yersinia.


The traditional first line treatment for Y. pestis has been streptomycin, chloramphenicol, tetracycline, and fluoroquinolones. There is also good evidence to support the use of doxycycline or gentamicin. Resistant strains have been isolated; treatment should be guided by antibiotic sensitivities where available. Antibiotic treatment alone is insufficient for some patients, who may also require circulatory, ventilator, or renal support.

In an emergency department setting, Harrison's principles of internal medicine outlines the following treatment course. Antibiotics within the first 24 hours is very beneficial, with intravenous being preferred in pulmonary or advance cases. Streptomycin or gentamicin are the first-line drugs, with chloramphenicol for critically ill patients, or rarely for suspected neuro-involvement.

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