Yersinia pestis

• 1. Introduction

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  Yersinia pestis looks like a safety pin under the microscope. Stain gathers at both ends of the tiny rod and leaves the middle pale. This bacterium cannot swim, and it forms no spores. Even so, it causes plague. That disease produced the Plague of Justinian and the Black Death, two of the deadliest pandemics in recorded history.

  Plague takes three forms, called pneumonic, septicemic, and bubonic. The microbe lives on the oriental rat flea, which itself lives on rats. Because it is a parasite of a parasite, scientists call it a hyperparasite.

  Three questions run through this story. Who first pinned the organism down, and how did a flea come to matter so much? How does such a small cell disarm the defenses of a human body? And how far back do its traces reach in human graves?

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• 2. Anatomy of a Killer

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  The KIM strain of Yersinia pestis carries a genome of 4,600,755 base pairs, which encode 4,198 proteins. The CO92 strain, taken from a clinical isolate in the United States, runs slightly longer at 4,653,728 base pairs. Strain 91001, whose sequence was published in 2004, is non-pathogenic. Not every member of the species harms people.

  The bacterium grows best at 28-30 degrees Celsius and at a pH of 7.2-7.6, though it tolerates a wide range of both. It dies very quickly under UV light, when dried out, or above 40 degrees Celsius.

  Of the 11 species in the genus Yersinia, only three cause human disease. The other two are Yersinia pseudotuberculosis and Yersinia enterocolitica. People usually catch either one from contaminated food or water.

  DNA studies show that Y. pestis and Y. pseudotuberculosis are 83% similar, which is high enough to count as a single species. In 1981 someone proposed demoting Y. pestis to a subspecies of its relative. The Judicial Commission of the International Committee on Systematic Bacteriology declined. Y. pseudotuberculosis usually causes only mild diarrhea, and the commission feared that merging the names would confuse people about two very different diseases.

  Three plasmids, which are loops of extra DNA, shape the bacterium's career as a pathogen. One of them, pCD1, is shared with its two relatives. The other two, pPCP1 and pMT1, belong to Y. pestis alone. The pMT1 plasmid codes for a phospholipase D that matters for transmission by fleas. The pPCP1 plasmid codes for a protease called Pla, which activates plasmin in human hosts and is a major virulence factor for pneumonic plague.

  Deep sequencing of the bacterium's small noncoding RNAs turned up some 63 novel candidates. One of them, Ysr141, regulates the synthesis of an injected protein called YopJ. In 2006, a proteomics analysis of the KIM strain compared its growth under four sets of conditions designed to model flea and mammal hosts.

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• 3. Race in Hong Kong

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  In 1894, plague broke out in Hong Kong, and two bacteriologists went hunting for its cause. Alexandre Yersin, a Swiss/French physician from the Pasteur Institute, belonged to the Pasteur school of thought. Kitasato Shibasaburō, a Japanese bacteriologist, followed Koch's methodology.

  Both men isolated the bacterium independently. A series of confusing and contradictory statements from Kitasato eventually tipped acceptance toward Yersin as the primary discoverer. Yersin named the organism Pasteurella pestis, honoring the Pasteur Institute where he worked. It was later moved to a new genus and renamed Yersinia pestis in his honor.

  Yersin also watched the rats. He noticed that rats died of plague not only during human epidemics but often before them. Many locals regarded plague as a disease of rats. Officials in China, India and Australia reported that large numbers of dead rats were soon followed by outbreaks.

  In 1898, the French scientist Paul-Louis Simond found the vector that drives the disease. He had also come to China to battle the Third Pandemic. Simond noticed that people who fell ill did not need to be in close contact with each other.

  In Yunnan, China, inhabitants fled their homes as soon as they saw dead rats. On the island of Formosa, now Taiwan, residents treated the handling of dead rats as a high-risk activity. People caught plague only if they touched rats that had died less than 24 hours earlier. That pattern led Simond to suspect the flea as a go-between.

  His classic experiment settled the matter. Infected fleas jumped from a rat that had just died of plague onto a healthy rat, and the healthy rat died of plague too.

  Plague later spread to Chinatown in San Francisco, from 1900 to 1904, and then to Oakland and the East Bay from 1907 to 1909. Authorities feared the effect on trade and hid the dead of Chinatown. That delay gave the disease time to pass into native rodents in outlying areas. It has lived in the rodents of western North America ever since.

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• 4. Fleas and Rodents

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  More than 200 species of rodents act as reservoirs for Y. pestis, and the main ones change from continent to continent. On the steppes, the marmot is believed to be the principal reservoir. In North America the common reservoirs are ground and rock squirrels, chipmunks, and prairie dogs. In Asia they are susliks and gerbils. In Africa they are gerbils and Mastomys natalensis, and in South America the short-tailed field mouse is a reservoir of note.

  Spread follows two cycles. In the sylvatic, or forest, cycle the rodents are wild. In the urban cycle the rodent is primarily the brown rat, Rattus norvegicus, and the bacterium can move from the urban setting back out again. Humans are usually infected through the bite of an infected flea. If the disease reaches the pneumonic form, people can pass it on through airborne respiratory droplets, and those who catch it this way mostly develop the pneumonic form themselves.

  Over 125 species of flea can transmit Y. pestis. A flea picks up the bacterium while feeding on an infected animal. Yersinia murine toxin, or Ymt, is highly toxic to rodents. Scientists once thought it existed to ensure reinfection of new hosts. In fact it is essential for colonizing fleas and for surviving inside them.

  The hemin storage system handles the handoff back to a mammal. Its genes induce a biofilm in the proventriculus, a valve connecting the flea's midgut to its esophagus. Clotted blood and bacteria form a mass that blocks feeding. The entomologist A.W. Bacot was the first to describe this, so it is called Bacot's block.

  The starving flea makes futile attempts to feed. Blood is pumped into the esophagus, where it dislodges bacteria from the proventriculus. The bacteria are then regurgitated into the circulation of the host.

  Fleas are not the whole story. In the black-tailed prairie dog, Cynomys ludovicianus, plague can cause colony collapse with a massive effect on prairie food webs. Yet transmission there does not follow the blocked-flea pattern. Carcasses, unblocked fleas, or another vector may matter instead.

  Y. pestis has also killed camels, chickens, and pigs. Domestic dogs and cats are susceptible, and cats are more likely to become ill. People can be exposed through contact with an infected animal, dead or alive, or by inhaling droplets that a sick dog or cat has coughed. In some regions the reservoir is not clearly identified, which complicates prevention and early-warning programs. A 2003 outbreak in Algeria was one such case.

  The CO92 strain came from a patient who died of pneumonia after catching the infection from a cat.

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• 5. Disarming the Immune System

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  Two antigens, called F1 and V or LcrV, help Y. pestis resist the cells that would normally swallow it. The bacterium makes both at normal human body temperature. It survives and keeps producing them even inside white blood cells called monocytes, though not inside neutrophils. Natural or induced immunity comes from antibodies against F1 and V, which make neutrophils engulf the bacterium.

  A flea bite lets the bacteria past the skin barrier. The type-III secretion system then lets Y. pestis inject proteins, called Yersinia outer proteins or Yops, into macrophages and other immune cells. YopB and YopD form pores in the host cell membrane and are linked to cell rupture. YopO, YopH, YopM, YopT, YopJ and YopE pass through that pore into the cytoplasm. Together they limit phagocytosis and the signaling pathways of the innate immune system.

  YopE and YopT are proposed to restrain the rupture that YopB and YopD can cause. A burst cell would spill its contents and attract immune attention, which the bacterium does not want.

  YopH is an enzyme, a protein tyrosine phosphatase, that helps the bacterium evade immune cells. Its ability to block phagocytosis lets Y. pestis grow in lymph nodes and cause swelling known as lymphadenopathy.

  YopJ is an acetyltransferase that is activated inside host cells by phytic acid. It modifies MAPK kinases and disrupts the host cell's protein kinase activity. That disruption causes macrophages to die by apoptosis, which is proposed to help establish infection. YopO, also called YpkA, is a potent inducer of apoptosis in human macrophages.

  Some strains can even interfere with immune signaling, for example by preventing the release of certain cytokines. It has also been suggested that a bacteriophage named Ypφ may have increased the virulence of this organism.

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• 6. Reading Ancient Graves

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  In 2010, researchers in Germany used PCR evidence from samples taken from Black Death victims. They definitively established that Y. pestis caused the medieval Black Death. In 2011, the first genome of Y. pestis isolated from those victims was published. It showed that the medieval strain was ancestral to most modern forms.

  In 2016, the bacterium was identified from DNA in teeth found at a Crossrail building site in London. The remains belonged to victims of the Great Plague of London, which lasted from 1665 to 1666.

  Three main strains are recognised. Y. p. antiqua caused a plague pandemic in the sixth century. Y. p. medievalis caused the Black Death and the epidemics of the second pandemic wave. Y. p. orientalis is responsible for current plague outbreaks.

  On the 15th of January 2018, researchers at the University of Oslo and the University of Ferrara made a suggestion about spread. They proposed that humans and their parasites, most likely fleas and lice at the time, were the biggest carriers of the plague.

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• 7. Bronze Age Origins

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  In 2015, the journal Cell published a study of ancient graves. Plasmids of Y. pestis were detected in the teeth of seven Bronze Age individuals. They came from the Afanasievo culture in Siberia, the Corded Ware culture in Estonia, the Sintashta culture in Russia, the Unetice culture in Poland, and the Andronovo culture in Siberia.

  DNA evidence published that year indicates that Y. pestis infected humans 5,000 years ago in Bronze Age Eurasia. The genetic changes that made it highly virulent came only about 4,000 years ago. The flea-borne version was found in two individuals of the Srubnaya culture from the Samara region of Russia, around 3,800 years ago. A third came from an Iron Age individual from Kapan, Armenia, around 2,900 years ago. At least two lineages were therefore circulating in Bronze Age Eurasia.

  The bacterium carries many nonfunctioning genes and three "ungainly" plasmids. Those traits suggest an origin less than 20,000 years ago. A strain from about 4000 BP, called the LNBA lineage, was identified in western Britain. It shows that the highly transmissible form spread from Eurasia to the far north-western edge of Europe.

  A study published in 2018 pushed the story back to the Neolithic decline, as far back as 6,000 years ago. A site in Sweden supplied the DNA evidence. Trade networks, rather than migrating populations, were proposed as the likely avenue of spread. There is also evidence that Y. pestis may have originated in Europe, in the Cucuteni-Trypillia culture, rather than in Asia as is more commonly believed.

  In 2021, researchers found a 5,000-year-old victim in hunter-gatherer remains in the modern Latvian and Estonian border area. It is the oldest known victim in the world.

  Between 5,300 and 4,900 years ago, the population of Neolithic farmers in northern Europe declined sharply. Nobody had determined whether agricultural recession or plague was responsible. A 2024 study of Neolithic graves in Denmark and western Sweden concluded that plague was widespread enough to be the cause. It found three outbreaks between 5,200 and 4,900 years ago, the last caused by a strain with reshuffled genes.

  Another study contests that idea. A Kiel University team examined 133 individuals from gallery graves of the Wartberg Culture and found Y. pestis in only two. That points to no large-scale outbreak in that cultural setting. A dog was infected as well.

  In August 2025, researchers recovered an LNBA lineage genome from the tooth of a domesticated sheep in modern-day Russia, about 4,000 years old. It confirms sheep as an ancient host and suggests livestock may have helped carry the pathogen toward humans.

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• 8. Plague Today

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  Between one thousand and two thousand cases of plague are still reported to the World Health Organization every year. Proper antibiotic treatment gives victims a far better prognosis than they had before antibiotics existed. The disease is now most common in the Democratic Republic of the Congo, Madagascar, and Peru. In 2008, sub-Saharan Africa and Madagascar accounted for over 95% of reported cases.

  Cases in Asia rose five- to sixfold during the Vietnam War. The suggested reason is disruption of ecosystems and closer contact between people and animals.

  Between 1970 and 2020, 496 cases were reported in the United States. They were found mostly in New Mexico, Arizona, Colorado, California, Oregon, and Nevada. Wildlife suffers too, including the endangered black-footed ferret.

  A formalin-inactivated vaccine was available in 1993 to high-risk adults in the United States, until the Food and Drug Administration removed it. It was of limited effectiveness and could cause severe inflammation. Experimental vaccines based on F1 and V antigens show promise, but bacteria lacking F1 are still virulent. The V antigens also vary enough that such vaccines may not fully protect.

  The United States Army Medical Research Institute of Infectious Diseases found that an experimental F1/V vaccine protects crab-eating macaques but fails to protect African green monkeys. The Cochrane Collaboration found no studies of sufficient quality to judge the vaccine's efficacy.

  In September 2009, Malcolm Casadaban, a molecular genetics professor at the University of Chicago, died. His death was linked to his work on a weakened laboratory strain of Y. pestis. Hemochromatosis was hypothesised to be a predisposing factor.

  On the 3rd of November 2019, two cases of pneumonic plague were diagnosed at a hospital in Beijing's Chaoyang district. The patient was a middle-aged man with fever who had struggled to breathe for about ten days. His wife, who came with him, had similar symptoms. Police quarantined the emergency room, and controls were placed on Chinese news aggregators. On the 18th of November, a third case was reported in a 55-year-old man from Xilingol League in northern China. He received treatment, and 28 symptomless contacts were placed in quarantine.

  In July 2020, a case of bubonic plague was confirmed in Bayannur, a city in China's Inner Mongolia autonomous region. The patient was quarantined and treated, and a second suspected case was investigated. A level 3 alert was issued and stayed in effect until the end of the year. It forbade hunting and eating animals that could carry plague.

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