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Yersinia pestis

Yersinia pestis

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Yersinia pestis is a Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

 rod-shaped
Bacillus
Bacillus is a genus of Gram-positive, rod-shaped bacteria and a member of the division Firmicutes. Bacillus species can be obligate aerobes or facultative anaerobes, and test positive for the enzyme catalase. Ubiquitous in nature, Bacillus includes both free-living and pathogenic species...

 bacterium. It is a facultative anaerobe that can infect humans and other animals.

Human Y. pestis infection takes three main forms: pneumonic
Pneumonic plague
Pneumonic plague, a severe type of lung infection, is one of three main forms of plague, all of which are caused by the bacterium Yersinia pestis. It is more virulent and rare than bubonic plague...

, septicemic
Septicemic plague
Septicemic plague is a deadly blood infection, one of the three main forms of plague. It is caused by Yersinia pestis, a gram-negative bacterium....

, and the notorious bubonic
Bubonic plague
Plague is a deadly infectious disease that is caused by the enterobacteria Yersinia pestis, named after the French-Swiss bacteriologist Alexandre Yersin. Primarily carried by rodents and spread to humans via fleas, the disease is notorious throughout history, due to the unrivaled scale of death...

 plagues. All three forms are widely believed to have been responsible for a number of high-mortality epidemic
Epidemic
In epidemiology, an epidemic , occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience...

s throughout human history, including the Plague of Justinian
Plague of Justinian
The Plague of Justinian was a pandemic that afflicted the Eastern Roman Empire , including its capital Constantinople, in 541–542 AD. It was one of the greatest plagues in history. The most commonly accepted cause of the pandemic is bubonic plague, which later became infamous for either causing or...

 in 542
542
Year 542 was a common year starting on Wednesday of the Julian calendar. From this year forward, the appointment of particular Roman consuls was abandoned and the office was merged with that of Byzantine emperor...

 and the Black Death
Black Death
The Black Death was one of the most devastating pandemics in human history, peaking in Europe between 1348 and 1350. Of several competing theories, the dominant explanation for the Black Death is the plague theory, which attributes the outbreak to the bacterium Yersinia pestis. Thought to have...

 that accounted for the death of at least one-third of the Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...

an population between 1347 and 1353. It has now been shown conclusively that these plagues originated in rodent populations in China. More recently, Y. pestis has gained attention as a possible biological warfare agent and the CDC has classified it as a category A pathogen requiring preparation for a possible terrorist attack.

Y. pestis was discovered in 1894 by Alexandre Yersin
Alexandre Yersin
Alexandre Emile Jean Yersin was a Swiss and French physician and bacteriologist. He is remembered as the co-discoverer of the bacillus responsible for the bubonic plague or pest, which was later re-named in his honour .Yersin was born in 1863 in Aubonne, Canton of Vaud, Switzerland, to a family...

, a Swiss
Switzerland
Switzerland name of one of the Swiss cantons. ; ; ; or ), in its full name the Swiss Confederation , is a federal republic consisting of 26 cantons, with Bern as the seat of the federal authorities. The country is situated in Western Europe,Or Central Europe depending on the definition....

/French
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...

 physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...

 and bacteriologist from the Pasteur Institute
Pasteur Institute
The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax...

, during an epidemic of plague in Hong Kong
Hong Kong
Hong Kong is one of two Special Administrative Regions of the People's Republic of China , the other being Macau. A city-state situated on China's south coast and enclosed by the Pearl River Delta and South China Sea, it is renowned for its expansive skyline and deep natural harbour...

. Yersin was a member of the Pasteur
Louis Pasteur
Louis Pasteur was a French chemist and microbiologist born in Dole. He is remembered for his remarkable breakthroughs in the causes and preventions of diseases. His discoveries reduced mortality from puerperal fever, and he created the first vaccine for rabies and anthrax. His experiments...

 school of thought. Kitasato Shibasaburō
Kitasato Shibasaburō
Baron was a Japanese physician and bacteriologist. He is remembered as the co-discoverer of the infectious agent of bubonic plague in Hong Kong in 1894, almost simultaneously with Alexandre Yersin.-Biography:...

, a German
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...

-trained Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...

ese bacteriologist who practiced Koch's methodology
Robert Koch
Heinrich Hermann Robert Koch was a German physician. He became famous for isolating Bacillus anthracis , the Tuberculosis bacillus and the Vibrio cholerae and for his development of Koch's postulates....

, 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.

Every year, thousands of cases of plague are still reported to the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

, although, with proper treatment, the prognosis
Prognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...

 for victims is now much better. A five- to six-fold increase in cases occurred in Asia during the time of the Vietnam war
Vietnam War
The Vietnam War was a Cold War-era military conflict that occurred in Vietnam, Laos, and Cambodia from 1 November 1955 to the fall of Saigon on 30 April 1975. This war followed the First Indochina War and was fought between North Vietnam, supported by its communist allies, and the government of...

, possibly due to the disruption of ecosystems and closer proximity between people and animals. Plague also has a detrimental effect on non-human mammals. In the United States of America, animals such as the black-tailed prairie dog
Black-tailed Prairie Dog
The black-tailed prairie dog , is a rodent of the family Sciuridae found in the Great Plains of North America from about the USA-Canada border to the USA-Mexico border. Unlike some other prairie dogs, these animals do not truly hibernate. The black-tailed prairie dog can be seen aboveground in...

 and the endangered black-footed ferret
Black-footed Ferret
The Black-footed Ferret , also known as the American polecat or Prairie Dog Hunter, is a species of Mustelid native to central North America. It is listed as endangered by the IUCN, because of its very small and restricted populations...

 are under threat from the disease.

Role in Black Death



Confirmed presence of Y. pestis would suggest that it was a contributing factor in some of (though possibly not all) the European plagues.

In 2000, Didier Raoult and others reported finding
Y. pestis DNA by performing a "suicide PCR
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....

" on tooth pulp
Pulp (tooth)
The dental pulp is the part in the center of a tooth made up of living connective tissue and cells called odontoblasts.- Anatomy :Each person can have a total of up to 52 pulp organs, 32 in the permanent and 20 in the primary teeth....

 tissue from a fourteenth-century plague cemetery in Montpellier
Montpellier
-Neighbourhoods:Since 2001, Montpellier has been divided into seven official neighbourhoods, themselves divided into sub-neighbourhoods. Each of them possesses a neighbourhood council....

.

A study by an international team of researchers published in October 2010 confirmed that
Y. pestis was the cause of the Black Death and later epidemics on the entire European continent over a period of 400 years. The team used ancient DNA and proteins recovered from the bodies of plague victims buried in Hereford
Hereford
Hereford is a cathedral city, civil parish and county town of Herefordshire, England. It lies on the River Wye, approximately east of the border with Wales, southwest of Worcester, and northwest of Gloucester...

 in England, in Saint-Laurent-de-la-Cabrerisse
Saint-Laurent-de-la-Cabrerisse
Saint-Laurent-de-la-Cabrerisse is a commune in the Aude department in southern France.-Population:- External links :*...

 in France, and Bergen op Zoom
Bergen op Zoom
Bergen op Zoom is a municipality and a city located in the south of the Netherlands.-History:Bergen op Zoom was granted city status probably in 1266. In 1287 the city and its surroundings became a lordship as it was separated from the lordship of Breda. The lordship was elevated to a margraviate...

 in the Netherlands
Netherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...

 to identify the pathogen. They found two previously unknown, older strains of Y. pestis that had spread from China by two different routes, rather than the modern Orientalis and Medievalis.

Three biovar
Biovar
A biovar is a variant prokaryotic strain that differs physiologically and/or biochemically from other strains in a particular species. Morphovars are those strains that differ morphologically. Serovars are those strains that have antigenic properties that differ from other strains....

s of
Y. pestis were originally thought to correspond to one of the historical pandemics of bubonic plague. Biovar Antiqua is thought to correspond to the Plague of Justinian
Plague of Justinian
The Plague of Justinian was a pandemic that afflicted the Eastern Roman Empire , including its capital Constantinople, in 541–542 AD. It was one of the greatest plagues in history. The most commonly accepted cause of the pandemic is bubonic plague, which later became infamous for either causing or...

; it is not known whether this biovar also corresponds to earlier or smaller epidemics of bubonic plague, or whether these were even truly bubonic plague. Biovar
Mediaevalis was formerly thought to correspond to the Black Death
Black Death
The Black Death was one of the most devastating pandemics in human history, peaking in Europe between 1348 and 1350. Of several competing theories, the dominant explanation for the Black Death is the plague theory, which attributes the outbreak to the bacterium Yersinia pestis. Thought to have...

, while Biovar
Orientalis was thought to correspond to the Third Pandemic
Third Pandemic
Third Pandemic is the designation of a major Bubonic plague pandemic that began in the Yunnan province in China in 1855. This episode of bubonic plague spread to all inhabited continents, and ultimately killed more than 12 million people in India and China alone...

 and the majority of modern outbreaks of plague. However, calculations of
Y pestiss evolutionary age, found using the number of synonymous
Synonymous substitution
A synonymous substitution is the evolutionary substitution of one base for another in an exon of a gene coding for a protein, such that the produced amino acid sequence is not modified. Synonymous substitutions and mutations affecting noncoding DNA are collectively known as silent mutations...

 single nucleotide polymorphisms (SNPs) in conjunction with molecular clock
Molecular clock
The molecular clock is a technique in molecular evolution that uses fossil constraints and rates of molecular change to deduce the time in geologic history when two species or other taxa diverged. It is used to estimate the time of occurrence of events called speciation or radiation...

 rates, date the emergence of the biovars prior to any of the historical epidemics due to the length of time needed to accumulate such mutations. Additional evidence against this hypothesis includes the fact that Mediaevalis is likely too young to have produced the Black Death
Black Death
The Black Death was one of the most devastating pandemics in human history, peaking in Europe between 1348 and 1350. Of several competing theories, the dominant explanation for the Black Death is the plague theory, which attributes the outbreak to the bacterium Yersinia pestis. Thought to have...

 due to its recent divergence from Orientalis.

Use in biological warfare


Y. pestis has been used as a biological weapon in World War II
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...

, when on October 4, 1940 a Japanese airplane flying over Chushien, Chekiang Province, China
China
Chinese civilization may refer to:* China for more general discussion of the country.* Chinese culture* Greater China, the transnational community of ethnic Chinese.* History of China* Sinosphere, the area historically affected by Chinese culture...

 released rice and wheat plus rat flea
Rat flea
The Oriental rat flea , also known as the tropical rat flea, is a parasite of rodents, primarily of the genus Rattus, and is a primary vector for bubonic plague and murine typhus. This occurs when the flea has fed on an infected rodent, and then bites a human...

s carrying Y. pestis. A second plane load was released 3 weeks later. These actions led to a local plague that killed 121 people. Leon A. Fox from the U.S. Army Medical Corps had suggested a similar approach in 1933 proposing to drop infested rats from planes.

General characteristics


Y. pestis is a rod-shaped facultative anaerobe with bipolar staining (giving it a safety pin
Safety pin
A safety pin is a simple fastening device, a variation of the regular pin which includes a simple spring mechanism and a clasp. The clasp serves two purposes: to form a closed loop thereby properly fastening the pin to whatever it is applied to, and to cover the end of the pin to protect the user...

 appearance). Similar to other Yersinia
Yersinia
Yersinia is a genus of bacteria in the family Enterobacteriaceae. Yersinia are Gram-negative rod shaped bacteria, a few micrometers long and fractions of a micrometer in diameter, and are facultative anaerobes. Some members of Yersinia are pathogenic in humans; in particular, Y. pestis is the...

members, it tests negative for urease, lactose fermentation, and indole
Indole test
The indole test is a biochemical test performed on bacterial species to determine the ability of the organism to split indole from the amino acid tryptophan...

. The closest relative is the gastrointestinal pathogen Yersinia pseudotuberculosis
Yersinia pseudotuberculosis
Yersinia pseudotuberculosis is a Gram-negative bacterium that causes Pseudotuberculosis disease in animals; humans occasionally get infected zoonotically, most often through the food-borne route.-Pathogenesis:In animals, Y...

, and more distantly Yersinia enterocolitica
Yersinia enterocolitica
Yersinia enterocolitica is a species of gram-negative coccobacillus-shaped bacterium, belonging to the family Enterobacteriaceae. Yersinia enterocolitica infection causes the disease yersiniosis, which is a zoonotic disease occurring in humans as well as a wide array of animals such as cattle,...

.

Genome


The complete genomic
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

 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 mutations. The chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

 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
Yersinia pseudotuberculosis
Yersinia pseudotuberculosis is a Gram-negative bacterium that causes Pseudotuberculosis disease in animals; humans occasionally get infected zoonotically, most often through the food-borne route.-Pathogenesis:In animals, Y...

and Y. enterocolitica
Yersinia enterocolitica
Yersinia enterocolitica is a species of gram-negative coccobacillus-shaped bacterium, belonging to the family Enterobacteriaceae. Yersinia enterocolitica infection causes the disease yersiniosis, which is a zoonotic disease occurring in humans as well as a wide array of animals such as cattle,...

, Y. pestis is host to the plasmid
Plasmid
In microbiology and genetics, a plasmid is a DNA molecule that is separate from, and can replicate independently of, the chromosomal DNA. They are double-stranded and, in many cases, circular...

 pCD1. In addition, it also hosts two other plasmids, pPCP1 (also called pPla or pPst) and pMT1 (also called pFra) that are not carried by the other Yersinia species. pFra codes for a phospholipase D
Phospholipase D
Phospholipase D is an enzyme which is located in the plasma membrane and catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid , releasing the soluble choline headgroup into the cytosol...

 that is important for the ability of Y. pestis to be transmitted by fleas. pPla codes for a protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

, Pla, that activates plasminogen in human hosts and is a very important virulence factor
Virulence factor
Virulence factors are molecules expressed and secreted by pathogens that enable them to achieve the following:* colonization of a niche in the host...

 for pneumonic plague. Together, these plasmids, and a pathogenicity island
Pathogenicity island
Pathogenicity islands are a distinct class of genomic islands acquired by microorganisms through horizontal gene transfer. They are incorporated in the genome of pathogenic organisms but are usually absent from those non-pathogenic organisms of the same or closely related species...

 called HPI, encode several proteins that cause the pathogenesis, for which Y. pestis is famous. Among other things, these virulence
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...

 factors are required for bacterial adhesion and injection of proteins into the host cell, invasion of bacteria in the host cell (via a Type III secretion system), and acquisition and binding of iron that is harvested from red blood cells (via siderophores). Y. pestis is thought to be descendant from Y. pseudotuberculosis, differing only in the presence of specific virulence plasmids.

A comprehensive and comparative proteomics
Proteomics
Proteomics is the large-scale study of proteins, particularly their structures and functions. Proteins are vital parts of living organisms, as they are the main components of the physiological metabolic pathways of cells. The term "proteomics" was first coined in 1997 to make an analogy with...

 analysis of Y. pestis strain KIM was performed in 2006. The analysis focused on the transition to a growth condition mimicking growth in host cells.

Pathogenics and immunity


In the urban and sylvatic (forest) 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 domestic. In addition, Y. pestis can spread from the urban environment and back. Every infected animal can transmit the infection to humans through contact with skin tissue. Humans can also spread the bacteria to other humans through sneezing, coughing, or direct contact with infected tissue.

In reservoir hosts


The reservoir commonly associated with Y. pestis is several species of rodents. In the steppe
Steppe
In physical geography, steppe is an ecoregion, in the montane grasslands and shrublands and temperate grasslands, savannas, and shrublands biomes, characterized by grassland plains without trees apart from those near rivers and lakes...

s, the reservoir species
Natural reservoir
Natural reservoir or nidus, refers to the long-term host of the pathogen of an infectious disease. It is often the case that hosts do not get the disease carried by the pathogen or it is carried as a subclinical infection and so asymptomatic and non-lethal...

 is believed to be principally the marmot. In the United States, several species of rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....

s are thought to maintain Y. pestis. However, the expected disease dynamics have not been found in any rodent species. It is known that rodent populations will have a variable resistance, which could lead to a carrier
Asymptomatic carrier
An asymptomatic carrier is a person or other organism that has contracted an infectious disease, but who displays no symptoms. Although unaffected by the disease themselves, carriers can transmit it to others...

 status in some individuals. There is 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
Algeria
Algeria , officially the People's Democratic Republic of Algeria , also formally referred to as the Democratic and Popular Republic of Algeria, is a country in the Maghreb region of Northwest Africa with Algiers as its capital.In terms of land area, it is the largest country in Africa and the Arab...

.

Infector


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 Yersinia murine toxin is highly toxic to rodents and was once thought to be produced to ensure reinfection of new hosts, it has been demonstrated that Ymt 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. While in the insect vector, proteins encoded by Hms genetic loci induce biofilm
Biofilm
A biofilm is an aggregate of microorganisms in which cells adhere to each other on a surface. These adherent cells are frequently embedded within a self-produced matrix of extracellular polymeric substance...

 formation in the proventriculus
Proventriculus
The proventriculus is part of the digestive system of birds, invertebrates and insects.-Birds:The proventriculus is a standard part of avian anatomy...

, a valve connecting the midgut
Midgut
The midgut is the portion of the embryo from which most of the intestines develop. After it bends around the superior mesenteric artery, it is called the "midgut loop"...

 to the esophagus
Esophagus
The esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...

. Aggregation in the biofilm inhibits feeding and causes the flea to regurgitate blood. 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
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...

 due to Y. pestis infection of mammalian hosts is due to several factors including an ability of these bacteria to suppress and avoid normal immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 responses such as phagocytosis and antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 production. Flea bites allow for the bacteria to pass the skin barrier. Y. pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...

 cells. Y. pestis expresses a plasminogen activator that is an important virulence factor for pneumonic plague and that might degrade on blood clots in order to facilitate systematic invasion. Many of the bacteria's virulence factor
Virulence factor
Virulence factors are molecules expressed and secreted by pathogens that enable them to achieve the following:* colonization of a niche in the host...

s are anti-phagocytic in nature. Two important anti-phagocytic antigens, named F1 (Fraction 1) and V or LcrV
LcrV
LcrV is a somewhat unstudied part of the Yersinia pestis virulence protein factors that also includes all Yop's, which used to stand for Yersinia outer protein, but now has kept the name out of convention. LcrV's main function is not actually known, but it is essential for the production of other...

, are both important for virulence
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...

. 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 monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s, but not in neutrophils. Natural or induced immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

 is achieved by the production of specific opsonic
Opsonin
An opsonin is any molecule that targets an antigen for an immune response. However, the term is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane. Molecules that...

 antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...

 against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils.

In addition, the Type III secretion system (T3SS) allows Y. pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins are called Yops (Yersinia Outer Proteins) and include Yop B/D, which form pores in the host cell membrane and have been linked to cytolysis
Cytolysis
Cytolysis, or osmotic lysis, occurs when a cell bursts due to an osmotic imbalance that has caused excess water to move into the cell. It occurs in a hypotonic environment, where water diffuses into the cell and causes its volume to increase. If the volume of water exceeds the cell membrane's...

. The YopO, YopH, YopM, YopT, YopJ, and YopE are injected into the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

 of host cells via T3SS into the pore created in part by YopB and YopD. The injected Yop proteins limit phagocytosis and cell signaling pathways important in the innate immune system
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...

, as discussed below. In addition, some Y. pestis strains are capable of interfering with immune signaling (e.g., by preventing the release of some cytokines).

Yersinia pestis proliferates
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...

 inside lymph nodes where it is able to avoid destruction by cells of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

 such as macrophages. The ability of Yersinia pestis to inhibit phagocytosis allows it to grow in lymph nodes and cause lymphadenopathy
Lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....

. YopH is a protein tyrosine phosphatase
Protein tyrosine phosphatase
Protein tyrosine phosphatases are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. Protein tyrosine phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular...

 that contributes to the ability of Yersinia pestis to evade immune system cells. In macrophages, YopH has been shown to dephosphorylate
Dephosphorylation
Dephosphorylation is the essential process of removing phosphate groups from an organic compound by hydrolysis. Its opposite is phosphorylation...

 p130Cas
BCAR1
Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the BCAR1 gene.-External links:* Info with links in the...

, Fyb
FYB
FYN binding protein , also known as FYB, ADAP , and SLAP-130 is a protein that in humans is encoded by the FYB gene....

 (Fyn
FYN
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...

 binding protein) SKAP-HOM
SKAP2
Src kinase-associated phosphoprotein 2 is an enzyme that in humans is encoded by the SKAP2 gene.-Further reading:...

 and Pyk
PTK2B
Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.-Protein:-Interactions:PTK2B has been shown to interact with PTPN11, PTPN6, PITPNM1, Gelsolin, Src, GRIN2A, Ewing sarcoma breakpoint region 1, RB1CC1, TGFB1I1, NPHP1, BCAR1, FYN, DLG4, DLG3, DDEF2, Cbl gene, RAS...

, a tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....

 homologous to FAK
PTK2
PTK2 protein tyrosine kinase 2 , also known as Focal Adhesion Kinase , is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes...

. YopH also binds the p85 subunit of phosphoinositide 3-kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...

, the Gab1
GAB1
GRB2-associated-binding protein 1 is a protein that in humans is encoded by the GAB1 gene.-Interactions:GAB1 has been shown to interact with Grb2, PIK3R1, PTPN11, CRKL, PLCG1 and MAP3K3.-Further reading:...

, the Gab2
GAB1
GRB2-associated-binding protein 1 is a protein that in humans is encoded by the GAB1 gene.-Interactions:GAB1 has been shown to interact with Grb2, PIK3R1, PTPN11, CRKL, PLCG1 and MAP3K3.-Further reading:...

 adapter proteins, and the Vav
VAV1
Proto-oncogene vav is a protein that in humans is encoded by the VAV1 gene.-Interactions:VAV1 has been shown to interact with Ku70, PLCG1, Lymphocyte cytosolic protein 2, Janus kinase 2, SIAH2, S100B, Abl gene, ARHGDIB, SHB, PIK3R1, PRKCQ, Grb2, MAPK1, Syk, Linker of activated T cells, Cbl gene and...

 guanine nucleotide exchange factor
Guanine nucleotide exchange factor
Guanine nucleotide exchange factors activate monomeric GTPases by stimulating the release of guanosine diphosphate to allow binding of guanosine triphosphate . A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity...

.

YopE functions as a GTPase activating protein
GTPase activating protein
GTPase-Activating Proteins, or GAPs, or GTPase-Accelerating Proteins are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event...

 for members of the Rho family of GTPases
Rho family of GTPases
The Rho family of GTPases is a family of small signaling G protein , and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic organisms including yeasts and some plants...

 such as RAC1
RAC1
Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...

. YopT is a cysteine protease
Cysteine protease
Proteases are enzymes that degrade polypeptides. Cysteine proteases have a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic dyad. The first step is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a...

 that inhibits RhoA
RHOA
Ras homolog gene family, member A is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. In humans, it is encoded by the gene RHOA....

 by removing the isoprenyl group
Prenylation
Prenylation, or isoprenylation, or lipidation is the addition of hydrophobic molecules to a protein. It is usually assumed that prenyl groups facilitate attachment to cell membranes, similar to lipid anchor like the GPI anchor, though direct evidence is missing...

, which is important for localizing the protein to the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

. It has been proposed that YopE and YopT may 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
Acetyltransferase
Acetyltransferase is a type of transferase enzyme that transfers an acetyl group.Examples include:* Histone acetyltransferases including CBP histone acetyltransferase* Choline acetyltransferase* Chloramphenicol acetyltransferase...

 that binds to a conserved α-helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...

 of MAPK kinases. YopJ acetylates MAPK kinases at serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

s and threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...

s that are normally phosphorylated during activation of the MAP kinase cascade
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...

. YopJ is activated in eukaryotic cells by interaction with target cell Phytic acid
Phytic acid
Phytic acid is the principal storage form of phosphorus in many plant tissues, especially bran and seeds. Phytate is not digestible to humans or nonruminant animals, however, so it is not a source of either inositol or phosphate if eaten directly...

 (IP6). This disruption of host cell protein kinase activity causes apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 of macrophages, and it has been proposed that this is 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 (YpkA). YopO is a potent inducer of human macrophage apoptosis.

Immunity


A formalin-inactivated vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 once was available for adults at high risk of contracting the plague until removal from the market by the U.S. Food and Drug Administration. It was of limited effectiveness and may cause severe inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

. Experiments with genetic engineering
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...

 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, such that vaccines composed of these antigens may not be fully protective. United States Army Medical Research Institute of Infectious Diseases
United States Army Medical Research Institute of Infectious Diseases
The U.S. Army Medical Research Institute of Infectious Diseases is the U.S Army’s main institution and facility for defensive research into countermeasures against biological warfare. It is located on Fort Detrick, Maryland and is a subordinate lab of the U. S...

 (USAMRIID) have found that an experimental F1/V antigen-based vaccine protect cynomolgus macaques but fails to protect African green monkeys.

Symptoms and disease progression

  • Bubonic plague
    • Incubation period of 2–6 days, when the bacteria is actively replicating.
    • Universally a general lack of energy
    • Fever
    • Headache
      Headache
      A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

       and chills occur suddenly at the end of the incubation period
      Incubation period
      Incubation period is the time elapsed between exposure to a pathogenic organism, a chemical or radiation, and when symptoms and signs are first apparent...

    • Swelling of lymph nodes resulting in buboes, the classic sign of bubonic plague. The inguinal nodes
      Superficial inguinal lymph nodes
      The superficial inguinal lymph nodes form a chain immediately below the inguinal ligament.They lie deep to Camper's fascia which overlies the femoral vessels at medial aspect of the thigh....

       are most frequently affected ("boubon" is Greek for "groin.")

  • Septicemic plague
    • Hypotension
      Hypotension
      In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

    • Hepatosplenomegaly
      Hepatosplenomegaly
      Hepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...

    • Delirium
      Delirium
      Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...

    • Seizures in children
    • Shock
    • Universally a general lack of energy
    • Fever
      Fever
      Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

    • Symptoms of bubonic or pneumonic plague are not always present
    • Note: Patient may die before any symptoms appear

  • Pneumonic plague (Spread person to person)
    • Fever
    • Chills
    • Coughing
    • Chest pain
    • Dyspnea
      Dyspnea
      Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...

    • Hemoptysis
      Hemoptysis
      Hemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...

    • Lethargy
    • Hypotension
      Hypotension
      In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

    • Shock
    • Symptoms of bubonic or septicemic plague are not always present


If this occurs with the classic bubo
Bubo
Bubo may refer to:* A bubo, a rounded swelling on the skin of a person afflicted by the bubonic plague.* Bubo, the horned owl and eagle-owl genus.* Bubo, a mechanical owl in the 1981 film Clash of the Titans...

es, this is considered primary, while secondary occurs after symptoms of bubonic or pneumonic infection. Since the bacteria are blood-borne, several organs can be affected, including the spleen and brain. The diffuse infection can cause an immunologic cascade to occur, leading to disseminated intravascular coagulation
Disseminated intravascular coagulation
Disseminated intravascular coagulation , also known as disseminated intravascular coagulopathy or consumptive coagulopathy, is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases. DIC leads to the formation of small blood clots inside the blood...

 (DIC), which in turn results in bleeding and necrotic skin and tissue. Such a disseminated infection increases mortality to 22%.

With the exception of the buboes, the initial symptoms of plague are very similar to many other diseases, 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


Gram's stain
Gram staining
Gram staining is a method of differentiating bacterial species into two large groups ....

s can confirm the presence of gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

 rods, and in some cases the identification of the double-curved shape. An anti-F1 serology test can differentiate between different species of Yersinia, and Polymerase chain reaction (PCR) can be used to identify Y. pestis.

Treatment


The traditional first line treatment for Y. pestis has been streptomycin
Streptomycin
Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...

, chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...

, tetracycline, and fluoroquinolones. There is also good evidence to support the use of doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...

 or gentamicin
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...

. 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
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

 support.

In an emergency department setting, Harrison's Principles of Internal Medicine
Harrison's Principles of Internal Medicine
Harrison's Principles of Internal Medicine is an American textbook of internal medicine. First published in 1950, it is presently in its eighteenth edition...

  outlines the following treatment course. Antibiotics within the first 24 hours are very beneficial, with intravenous being preferred in pulmonary or advanced cases. Streptomycin or gentamicin are the first-line drugs, with chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...

 for critically ill patients, or rarely for suspected neuro-involvement.

Recent events


In September 2009, the death of Malcolm Casadaban
Malcolm Casadaban
Malcolm Casadaban was Associate Professor of Molecular Genetics and Cell Biology and of Microbiology at the University of Chicago...

, a molecular genetics
Molecular genetics
Molecular genetics is the field of biology and genetics that studies the structure and function of genes at a molecular level. The field studies how the genes are transferred from generation to generation. Molecular genetics employs the methods of genetics and molecular biology...

 professor at the University of Chicago
University of Chicago
The University of Chicago is a private research university in Chicago, Illinois, USA. It was founded by the American Baptist Education Society with a donation from oil magnate and philanthropist John D. Rockefeller and incorporated in 1890...

, was linked to his work on a weakened laboratory strain of Y. pestis. Hemochromatosis was found to be a strongly predisposing factor in Dr Casadaban's demise from this attenuated strain used for research. A final report about his autopsy, which came out in February 2011, strengthened this premise, and its final conclusions proved the late doctor did indeed suffer from hemochromatosis. One in 400 people carries the genetic defect that causes iron build-up in the body and especially the liver, and those of European descent are twice as likely to possess it, due to the protection it offered to their populations in their recent past. Those having carried the defect had a much better chance of surviving bubonic plague, and their specific populations became much larger due to their higher survival rate. However, individuals carrying this gene possess high to toxic amounts of iron in their livers that becomes worse with age, which gives this modified plague bacteria the iron they've been genetically deprived of. Dr. Casadaban's old age, combined with his untreated hemochromatosis, made him a prime candidate to be infected, regardless of the most stringent lab safety protocols.

External links