Bubonic plague pathophysiology

# Overview
Yersinia pestis is the bacteria that causes the bubonic plague, or black death. Typically during the incubation period of the disease, buboes form under the armpits and in the groin area. These buboes are located where the lymph nodes are because that is the location that the bacteria congregates during infection. If untreated, the plague will spread rapidly and cause infection of many other organs.

# Pathophysiology
Yersinia was formerly classified in the family Pasteurellaceae, but based on DNA- DNA hybridization similarities to Escherichia coli, the Yersinia group has been reclassified as members of the Enterobacteriaceae family by Farmer in 1995. Differentiation of the Enterobacteriaceae family members is based on biochemical and antigenic profiles. More recently, nucleic acid techniques have been applied to assist the definition of genera and species within this family; hence, as more techniques are applied, newly defined genetic relationships sometimes lead to changes in classification.  Though there are 11 named species in the genus Yersinia, only 3 are considered important human pathogens: Y. pestis, the etiologic agent of plague, and the enteropathogenic strains, Y. pseudotuberculosis and Y. enterocolitica. Y. pseudotuberculosis is the closest genetic relative to Y. pestis but can be distinguished from the plague bacteria by its clinical manifestations and by laboratory test results. Both Y. pestis and Y. pseudotuberculosis do not frequently infect humans in contrast to Y. enterocolitica, which may be more commonly found in clinical specimens.
A very small number of the Yersinia Pestis organisms are needed to infect a mammal. As little as 1 to 10 organisms would be enough to infect a small mammal, such as a rodent or primate, with the plague via subcutaneous, oral, intravenous, and intradermal routes. On the other hand, the respiratory route will take approximately 100 to 200,000 organisms for nonhuman primates. When the bacteria enters the host, there are a multitude of environmental signals that are believed to induce the synthesis and many other factors the contribute to the virulence of the bacteria. These environmental signals include things such as:
- Elevated temperature
- Location within cells at low pH
- Contact with eukaryotic cells
During the incubation phase, the common symptom of bubonic plague, the bubo, is because the bacilli most commonly spreads to regional lymph nodes. The infection will rapidly progress if it is left untreated and then septicemia will develop and the infection will spread to other organs. Cyanosis and necrosis are commonly seen in septicemic plague, which may be caused by coagulase activity of the plasminogen activator. There are a few tissues that are most commonly infected. They include:
- Liver
- Lungs
- Skin
- Mucous membranes
- Spleen
- Also, late infection of meninges possible
Yersinia pestis is a Gram-negative facultative anaerobic bipolar-staining (giving it a safety pin appearance) bacillus bacterium belonging to the family Enterobacteriaceae. The infectious agent of bubonic plague, Y. pestis infection can also cause pneumonic and septicemic plague. All three forms have been responsible for high mortality rates in epidemics throughout human history, including the  Black Death that accounted for the death of approximately one-third of the European population in 1347 to 1353.
The genus Yersinia is Gram-negative, bipolar staining coccobacilli, and, similarly to other Enterobacteriaceae, it has a fermentative metabolism. Y. pestis produces an antiphagocytic slime. The organism is motile when isolated, but becomes nonmotile in the mammalian host.

# Pathophysiology
- Pathogenicity of Y. pestis is in part due to two anti-phagocytic antigens, named F1 (Fraction 1) and V, both important for virulence. These antigens are produced by the bacterium at 37C.
- Furthermore, Y. pestis survives and produces F1 and V antigens within blood cells such as monocytes, but not in polymorphonuclear 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.
- 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.

## Genetics
- 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 not yet been completed.
- 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 pathogenicity 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 recent comprehensive and comparative proteomics analysis of Y. pestis: strain KIM was recently performed  , this analysis focused on the transition to a growth condition mimicking growth in host cells.

## Susceptibility
- 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.
- It should be noted that strains resistant to one or two agents specified above have been isolated: treatment should be guided by antibiotic sensitivities where available.