Yersinia pestis
Yersinia pestis is a gram-negative, non-motile, coccobacillus bacterium without spores. It is related to pathogens Yersinia enterocolitica, and Yersinia pseudotuberculosis, from which it evolved. Yersinia pestis is responsible for the disease plague, which caused the Plague of Justinian and the Black Death, one of the deadliest pandemics in recorded history. Plague takes three main forms: pneumonic, septicemic, and bubonic. Y. pestis is a facultative anaerobic parasitic bacterium that can infect humans primarily via its host, the oriental rat flea, but also through aerosols and airborne droplets for its pneumonic form. As a parasite of its host, the rat flea, which is also a parasite of rats, Y. pestis is a hyperparasite.
Y. pestis was discovered in 1894 by Alexandre Yersin, a Swiss/French physician and bacteriologist from the Pasteur Institute, during an epidemic of the plague in Hong Kong. Yersin was a member of the Pasteur school of thought. Kitasato Shibasaburō, a Japanese bacteriologist who practised Koch's methodology, was also engaged at the time in finding the causative agent of the plague. However, Yersin actually linked plague with a bacillus, initially named Pasteurella pestis; it was renamed Yersinia pestis in 1944.
Between one thousand and two thousand cases of the plague are still reported to the World Health Organization every year. With proper antibiotic treatment, the prognosis for victims is much better than before antibiotics were developed. Cases in Asia increased five- to sixfold during the time of the Vietnam War, possibly due to the disruption of ecosystems and closer proximity between people and animals. The plague is now most commonly found in the Democratic Republic of the Congo, Madagascar, and Peru. The plague also has a detrimental effect on non-human mammals; in the United States, these include the black-tailed prairie dog and the endangered black-footed ferret.
General features
Y. pestis is a non-motile coccobacillus, a facultative anaerobic bacterium with bipolar staining that produces an antiphagocytic slime layer. Similar to other Yersinia species, it tests negative for urease, lactose fermentation, and indole. The species grows best in temperatures of 28–30 °C, and at a pH of 7.2–7.6, but can live in a large temperature and pH range. It dies very rapidly if exposed to UV light, dried out, or exposed to temperatures higher than 40°C. There are 11 species in the Yersinia genus, and three of them cause human diseases. The other two are Yersinia pseudotuberculosis and Yersinia enterocolitica, infections by either of these are usually acquired from ingesting contaminated food or water.Genome and proteome
Genome
Several complete genome sequences are available for various strains and subspecies of Y. pestis: strain KIM, and strain CO92. In 2006 the genome sequence of a strain of biovar Antiqua was completed. Some strains are non-pathogenic, such as that of strain 91001, whose sequence was published in 2004.| KIM | CO92 | 91001 | |
| length | 4,600,755 | 4,653,728 | 4,595,065 |
| proteins encoded | 4,198 | 4,012 | 4,037 |
| pseudogenes | 54 | 149 | 141 |
| tRNAs | 73 | 70 | 72 |
Plasmids
Like Y. pseudotuberculosis and Y. enterocolitica, Y. pestis is host to the plasmid pCD1. It also hosts two other plasmids, pPCP1 and pMT1, that are not carried by the other Yersinia species. pFra codes for a phospholipase D that is important for the ability of Y. pestis to be transmitted by fleas. pPla codes for a protease, Pla, that activates plasmin in human hosts and is a very important virulence factor for pneumonic plague. Together, these plasmids and a pathogenicity island called HPI encode several proteins that 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 in the host cell, and acquisition and binding of iron harvested from red blood cells. Y. pestis is thought to be descended from Y. pseudotuberculosis, DNA studies have found that the two are 83% similar, which is high enough to be considered the same species. In 1981 it was proposed that Y. pestis be reclassified as a subspecies of Y. pseudotuberculosis, but the Judicial Commission of the International Committee on Systematic Bacteriology declined to do this because the course of Y. pestis disease is so different than that of Y. pseudotuberculosis, which usually causes a mild diarrhea, that reclassification would generate confusion.Proteome
A comprehensive and comparative proteomics analysis of Y. pestis strain KIM was performed in 2006. The analysis focused on growth under four different sets of conditions that were designed to model flea and mammal hosts.Small noncoding RNA
Numerous bacterial small noncoding RNAs have been identified to play regulatory functions. Some can regulate the virulence genes. Some 63 novel putative sRNAs were identified through deep sequencing of the Y. pestis sRNA-ome. Among them was Yersinia-specific Ysr141. Ysr141 sRNA was shown to regulate the synthesis of the type III secretion system effector protein YopJ. The Yop-Ysc T3SS is a critical component of virulence for Yersinia species. Many novel sRNAs were identified from Y. pestis grown in vitro and in the infected lungs of mice suggesting they play role in bacterial physiology or pathogenesis. Among them, sR035 is predicted to pair with the SD region and transcription initiation site of a thermo-sensitive regulator ymoA, and sR084 is predicted to pair with fur, ferric uptake regulator.Pathogenesis and immunity
In the urban and sylvatic cycles of Y. pestis, most of the spreading occurs between rodents and fleas. In the sylvatic cycle, the rodent is wild, but in the urban cycle, the rodent is primarily the brown rat. In addition, Y. pestis can spread from the urban environment and back. Transmission to humans is usually through the bite of infected fleas. If the disease has progressed to the pneumonic form, humans can spread the bacterium to others through airborne respiratory droplets; others who catch plague this way will mostly contract the pneumonic form themselves.Mammals as hosts
Several species of rodents serve as the main reservoir for Y. pestis in the environment. In the steppes, the natural reservoir is believed to be principally the marmot. In the western United States, several species of rodents are thought to maintain Y. pestis. Over 200 species of rodents are reservoirs for Y. pestis, with the common reservoirs varying geographically. In North America the common reservoirs are ground and rock squirrels, chipmunks, and prairie dogs; in Asia the common reservoirs are susliks and gerbils; in Africa the common reservoirs are gerbils and Mastomys natalensis; and in South America the short-tailed field mouse is a reservoir of note. Several species of rodents are known to have a variable resistance, which could lead to an asymptomatic carrier status. Evidence indicates fleas from other mammals have a role in human plague outbreaks.The lack of knowledge of the dynamics of plague in mammal species is also true among susceptible rodents such as the black-tailed prairie dog, in which plague can cause colony collapse, resulting in a massive effect on prairie food webs. However, the transmission dynamics within prairie dogs do not follow the dynamics of blocked fleas; carcasses, unblocked fleas, or another vector could possibly be important, instead.
The CO92 strain was isolated from a patient who died from pneumonia and who contracted the infection from an infected cat.
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.
Fleas as vector
The transmission of Y. pestis by fleas is well characterized, with over 125 species of flea capable of transmitting Y. pestis. 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 system and Yersinia murine toxin. Although Ymt is highly toxic to rodents and was once thought to be produced to ensure reinfection of new hosts, it is essential for flea colonization and for the survival of Y. pestis in fleas.The hemin storage system plays an important role in the transmission of Y. pestis back to a mammalian host. While in the insect vector, proteins encoded by hemin storage system genetic loci induce biofilm formation in the proventriculus, a valve connecting the midgut to the esophagus. The presence of this biofilm seems likely to be required for stable infection of the flea. Aggregation in the biofilm inhibits feeding, as a mass of clotted blood and bacteria forms. 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 lodged in the proventriculus, which is regurgitated back into the host circulatory system.
In humans and other susceptible hosts
due to Y. pestis infection of mammalian hosts is due to several factors, including the ability of these bacteria to suppress and avoid normal immune system responses such as phagocytosis and antibody production. Flea bites allow for the bacteria to pass the skin barrier. Y. pestis expresses a plasmin activator that is an important virulence factor for pneumonic plague and that might degrade blood clots to facilitate systemic invasion. Many of the bacteria's virulence factors are antiphagocytic. Two important antiphagocytic antigens, named F1 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 white 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.In addition, the type-III secretion system allows Y. pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins, called Yersinia outer proteins, include Yop B/D, which form pores in the host cell membrane and have been linked to cytolysis. The YopO, YopH, YopM, YopT, YopJ, and YopE are injected into the cytoplasm of host cells by T3SS into the pore created in part by YopB and YopD. The injected Yops limit phagocytosis and cell signaling pathways important in the innate immune system, as discussed below. In addition, some Y. pestis strains are capable of interfering with immune signaling.
Y. pestis proliferates inside lymph nodes, where it can avoid destruction by cells of the immune system such as macrophages. The ability of Y. pestis to inhibit phagocytosis allows it to grow in lymph nodes and cause lymphadenopathy. YopH is a protein tyrosine phosphatase that contributes to the ability of Y. pestis to evade immune system cells. In macrophages, YopH has been shown to dephosphorylate p130Cas, Fyb SKAP-HOM and Pyk, a tyrosine kinase homologous to FAK. YopH also binds the p85 subunit of phosphoinositide 3-kinase, the Gab1, the Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor.
YopE functions as a GTPase-activating protein for members of the Rho family of GTPases such as RAC1. YopT is a cysteine protease that inhibits RhoA by removing the isoprenyl group, which is important for localizing the protein to the cell membrane. YopE and YopT have been proposed to function to limit YopB/D-induced cytolysis. This might limit the function of YopB/D to create the pores used for Yop insertion into host cells and prevent YopB/D-induced rupture of host cells and release of cell contents that would attract and stimulate immune system responses.
YopJ is an acetyltransferase that binds to a conserved α-helix of MAPK kinases. YopJ acetylates MAPK kinases at serines and threonines that are normally phosphorylated during activation of the MAP kinase cascade. YopJ is activated in eukaryotic cells by interaction with target cell phytic acid. This disruption of host cell protein kinase activity causes apoptosis of macrophages, and this is proposed to be important for the establishment of infection and for evasion of the host immune response. YopO is a protein kinase also known as Yersinia protein kinase A. YopO is a potent inducer of human macrophage apoptosis.
It has also been suggested that a bacteriophage – Ypφ – may have been responsible for increasing the virulence of this organism.
Depending on which form of the plague infects the individual, the plague develops a different illness; however, the plague overall affects the host cell's ability to communicate with the immune system, hindering the body's ability to bring phagocytic cells to the area of infection.
Y. pestis is a versatile killer. In addition to rodents and humans, it is known to have killed camels, chickens, and pigs. Domestic dogs and cats are susceptible to plague, as well, but cats are more likely to develop illness when infected. In either case, the symptoms are similar to those experienced by humans and can be deadly to the animal. People can be exposed by coming into contact with an infected animal, or inhaling infectious droplets that a sick dog or cat has coughed into the air.