When someone mentions the plague, the Black Death often leaps to mind: an infamous, decimating disease that we tend to associate with the medieval period. However, since the beginning of recorded history the plague has sinisterly spread across the globe and wiped out up to 30-40% of the world’s population three times, as well as hundreds of smaller outbreaks. The most recent pandemic (a worldwide outbreak of disease) was less than two hundred years ago, and is arguably still going on. Several thousand cases of plague occur worldwide each year, and the plague has now been classified as a reemerging disease. While we may view the plague as an ancient disease, when we consider the facts that we lack a vaccination, there are antibiotic resistant strains, and the pathogen has been utilized for biological warfare, it is very much a modern issue.
Meet the Microbe
The causative agent behind the plague is a bacterium by the name of Yersinia pestis. It was first isolated in 1894 by Alexandre Yersin, who proudly named one of the deadliest pathogens after himself (a bit of a dubious honor). Since then, these bacteria have been found on all continents except Antarctica[1,2]. It is a gram negative, non-motile bacterium that has the ability to enter and live inside of host cells. There are seventeen species in the Yersinia genus, with only a handful being pathogens. Two of these, Y. enterocolitica and Y. pseudotuberculosis, both cause mild food and water borne illnesses that have little in common with the devastation wrought by their plague-causing relative. Y. pestis is a clone that diverged from Y. pseudotuberculosis only a scant 1,500 to 20,000 years ago[1,4,13]. That is pretty young—especially as Y. pestis evolved both an increased pathogenicity and an entirely new method of entering hosts. Y. pestis can infect over 200 mammal species through wounds, ingestion, or inhalation. It has a handful of rodent host species which are variably resistant to the disease along with fleas, and both of these are the main players in the multi-phase life cycle of Y. pestis.
Rats have long since been associated with the plague, and by 1910 the primary role of fleas in the life cycle and transmission of the plague was widely acknowledged. The plague is foremost a disease of rodents and is transmitted between rodent hosts via fleas. Humans and other mammals are, in fact, completely accidental hosts (that’s almost insulting when you consider the disaster it causes in us!)[1,4,5]. Consequently, the life cycle of Y. pestis consists of a cycle between rodents and fleas. When their rodent hosts die, the fleas abandon the corpses and seek new hosts, inadvertently infecting other mammals, such as humans.
There are over 2,000 species of fleas, but only 80 of these transfer Y. pestis. These insects are intimately associated with their hosts, requiring their blood to survive. Surprisingly, very few pathogens are actually transmitted by fleas, which suggests their midgut is relatively inhospitable. When a flea feeds on an infected rodent, bacteria from the rodent’s blood is taken into the flea’s midgut. Y. pestis does not enter the cells of fleas or adhere to the flea’s digestive tract, resulting in half of fleas actually removing all of the bacteria through their feces. In order to overcome this, Y. pestis must build up an incredibly high density within the blood of its host rodent. When bacteria manage to persist in the flea’s midgut, they rapidly reproduce and form clusters that are too large to be excreted. The bacteria proceed to form a biofilm on the proventriculus, a valve in the flea connecting the esophagus to their midgut. This causes the flea to regurgitate when it attempts to feed, spewing the bacteria into the bite and passing them onto a new host, where they once again begin to proliferate[2,4].
When a human has the misfortune of being bitten by an infected flea, having direct contact with infected animal tissues, or eating undercooked, infected meat they will likely get struck by the plague [2,5]. As the main source of infection is through flea bites, outbreaks in human populations tend to correlate with seasonal and geographic distributions of rodents and fleas, and are often preceded by high mortality rates in rodent populations[1,9]. These cycles occur irregularly, can result in up to 99% mortality in rodent-host populations, and may lead to human outbreaks. There are roughly 2,000 cases of human plague a year, with the majority of the cases being in Africa (in 2000-2001, 41% of world cases were in Madagascar, which is apparently more vulnerable in the real world than in Pandemic). The number of infections is currently on the rise, resulting in the plague being considered a reemerging disease and being one of the six infectious diseases that requires notification of the World Health Organization.
Once Y. pestis infects a human host, the resultant plague has an “explosive” spread pattern which quickly leads to epidemics. After an incubation of 3 to 6 days, the infection presents with a very sudden onset of malaise, chills, a fever, headache, aches, insomnia, indistinct speech, loss of coordination, and vomiting. Delirium and violent behavior can also occur, and the symptoms vary between types of plague. Depending on the method of transmission, three different types of plague can occur. These forms are not isolated; the disease can progress from one type of plague to another due to the spread of Y. pestis within the host’s body. If Y. pestis spreads into the blood and enters the lungs it can cause pneumonic plague, and if it enters the blood it will cause septicemic plague.
The most common form is bubonic plague, as it results from the most frequent form of transmission: a flea bite, or direct contact of a wound to infected material. Bubonic plague accounts for 80-95% of human cases, and it has a mortality of 10-20% if treated and up to 60% if untreated[1,2]. Upon being bitten, a pustule or ulcer may develop around the bite. The bacteria enter the lymphatic vesicles, causing inflammation and swollen “buboes” which often occur in the groin, armpits, or throat. Malaise, fever, and painful buboes are accompanied by a heightened pulse and low blood pressure. Eventually, a collapse of the circulatory system, hemorrhaging, and thrombosis can lead to death[1,2].
Pneumonic or pulmonary plague is the most dangerous form, with a 100% mortality rate if untreated and a mortality rate well over 50% even if treated. While it is rarer than bubonic plague, occasionally outbreaks of pneumonic plague do occur: in Manchuria in 1910, 60,000 people became infected. This form of plague is transmitted through respiratory droplets, or as a complication of a different type of plague. It has the most rapid onset of any type, with symptoms presenting within 24 hours in the form of fever, chills, headache, malaise, and coughs producing clear, bloody, or purulent sputum. These symptoms rapidly progress to breathing difficulties, wheezing, and cyanosis (tissue/skin discoloring due to lack of oxygen). Once the lungs are densely populated by the bacterium, internal bleeding and fluid buildup can occur, resulting in respiratory failure, circulatory collapse, and death[1,2].
The final and rarest form of plague is septicemic plague, with a 100% mortality rate if untreated but ‘only’ 22% if treatment is available within the first 24 hours. When bacteria proliferate at high levels with the blood, septicemic plague arises. The blood-infection causes small blood clots to occur, cutting off circulation to parts of the body and depleting the clotting molecules in the blood. This leads to uncontrolled bleeding, nausea, fever, vomiting blood, abdominal pain, and diarrhea. The blood clots result in cyanosis and necrosis due to a lack of oxygen reaching the tissues, with gangrene as a secondary effect[1,2].
These delightful forms of plague come about due to the high density of bacteria in the body and the chemicals secreted by the bacteria. A single flea bite will transfer thousands of bacteria into the skin, through which they enter the lymphatic system. Many of these bacteria will be killed by the immediate immune response: neurophils, a type of white blood cell. The body takes 4-5 days to produce Y. pestis specific immune T-cells and B-cells. However, the bacteria survive the immune response by invading macrophages (longer-lived white blood cells). Inside of the macrophages, the bacteria proliferate safely and, in a poorly-understood biological phenomenon, acquire resistance to being consumed by immune cells as well as gain an ability to inactivate T-cells. Once sufficiently armed, the bacteria population inside the macrophage kill their host cell and are unleashed into the body once more. The bacteria then migrate to the lymph nodes and proliferate further. This is the pathology behind bubonic plague, where the bacteria damages the lymphatic system and causes endotoxic shock. If the lymphatic system is overwhelmed and the bacteria spread into the blood and other organs, the proliferation and toxic effects cause septicemic plague. If it spreads to the lung, it progresses to pneumonic plague[2,11].
History of the Plague
Y. pestis has an impressive resume for a pathogen. Along with thousands of outbreaks worldwide, the bacteria has caused three pandemics that resulted in millions of deaths, decimation of cities, and the collapse of governments and entire civilizations all in the past 1500 years[2,13]. These pandemics spread the pathogen across the globe, to every continent except Antarctica (there’s not much there to infect except penguins, anyway). Luckily for us, the probability of a pandemic of such proportions occurring naturally today has been reduced thanks to better living conditions, public health, and antibiotics.
The most ancient record of an outbreak of the plague is found in the Bible, in the book of Samuel. The description dates the disease to 1320 to 1,000 BC, in the Philistines. While there is no proof that this plague was caused by Y. pestis, the description of tumors and the association with rats leads us to believe it was indeed the bubonic plague. Six hundred years later in 430 BC, the Plague of Athens broke out. Descriptions of the symptoms recorded in Thucydides’ The Peloponnesian War once again suggest the outbreak was bubonic plague, which began in Ethiopia and spread to Athens. In this outbreak, Y. pestis supposedly helped Sparta reach victory by decimating enemy troops. The next major plague occurred in the 2nd century AD, under the Roman Emperor Marcus Aurelius. This disease swept across the Roman Empire and slaughtered a third of the population. However, descriptions of the symptoms have led many modern historians and scientists to believe the disease was actually smallpox, rather than the plague. While all of these were large, influential outbreaks, they did not manage to reach pandemic proportions. The dubious honor of the three pandemics goes to Justinian’s Plague, the Black Death, and the Modern Pandemic.
Justinian’s Plague broke out in 541 AD, under the Roman Emperor Justinian. Barely 300 years after smallpox had cut down the population by a third, another pathogen reared its head. Y. pestis crossed over into human hosts in Egypt, the main source of grain for the entire Empire and an important center of trade. Diseases in the Roman Empire spread with an eager ferocity through the mobile population and dense cities. Soon the pathogen had spread throughout the empire and east into China (some recent genetic studies suggest the source was actually China, and it then entered the Empire through Egypt)[9,10]. Over the extended course of the pandemic, city populations across the globe were reduced by 40% to 60%. The exact numbers are uncertain, with estimates ranging from 25 million upwards. At the height of the outbreak, the historian Procopius wrote that up to 5,000-10,000 people died each day in the city of Constantinople. This plague, along with a rich variety of other factors, is thought to be a major contributing factor to the fall of the Roman Empire.
Nearly 800 years after Justinian’s Plague, the Black Death struck in 1346. In merely four years, this outbreak of bubonic plague wiped out 25 million people, a third of Europe’s population (If that number is reflected on today’s European population, it would be 250 million people!)[5,9]. Over the next 50 years, it killed a further 20 million people. The Black Death began in China and traveled along trade routes back to Italy (the plague in Europe may have been jumpstarted by early biological warfare, which will be mentioned in the next section). Y. pestis gleefully spread throughout the city and countryside of Italy within days, wreaking economic, political, and social chaos. Governments, trade, and commerce all came to a screeching halt as populations in the world were decimated. In Europe, the disease worsened or initiated recessions and uprisings. Socially, everyone started pointing fingers at each other; Christians blamed it on Muslims who blamed the Christians right back, and then they both pointed fingers at the Jews. The unfortunate Jewish population became a prime target; in the city of Strasbourg, 16,000 Jewish residents were killed. By 1351, 210 Jewish communities had been massacred. This was, understandably, a main factor in the movement of Jewish populations east into Poland and Russia.
The final pandemic lacks a catchy name and is simply referred to as the Modern Pandemic or Third Pandemic. Once again, the pandemic started in China (that’s quite a trend!) in 1855 before spreading to all inhabited continents. Within the first two months, 100,000 people had been killed in China alone. By the end of height of the outbreak, over 12 million people had been killed in China and India (for some odd reason, there is no worldwide mortality number, possibly because China and India were the worst-hit.)[9,10]. During this pandemic, the pathogen was finally identified and the connection to rats and fleas elucidated. When the deaths fell to under 200 a year, the pandemic was declared finished. However, as the number has increased to over 2,000 cases a year some argue that the pandemic is still ongoing[10,13]! Next time you need a conversation starter, try telling your partner that we’re in the midst of a plague pandemic.
Unsurprisingly, Y. pestis is classified as an agent of bioterrorism. As much as I’d like to say that no one wants to inflict plague on another person, cursing plagues upon each other’s houses has been part of human culture for thousands of years. While most of us say it mostly in jest, the fact that the pathogen can be found worldwide, can be easily mass produced and dispersed via aerosol , has a high fatality, and has the potential for self-propagation make Y. pestis a prime specimen for the deranged. It is listed at the top of the CDC’s Critical Biological Agent list, as 50 kg worth of the pathogen released over a city of 5 million would cause over 150,000 to fall ill[2,9]. The bacteria would survive for about an hour and reach a distance of up to 10 kilometers, with the dispersal method resulting in an outbreak of pneumonic plague; onset would occur within 2-4 days and death within 2-6 days of exposure . The low cost and simple production have given biological weapons the name “weapons of the poor,” and they have been used throughout history.
The first known occurrence of plague-warfare dates back to 1346, incidentally the same year that the Black Death struck. In the midst of the Siege of Caffa, the Tatar army was suffering from the plague and one Tatarn had the bright idea of catapulting the infected corpses at their enemies, Genoese sailors. The infected and traumatized sailors then fled to Italy, spreading the plague from Asia to Europe and kicking off the Black Death[10,12]. Thanks guys.
A century later during the Battle of Carolstein in 1422, the Lithuanians decided to play copy-cat and catapulted the bodies of plague-infected soldiers (and their feces, to add insult to injury) at their enemies as well. It must have worked well enough, because a few hundred years later in 1710 the Russians also tossed their infected cadavers at Swedish troops in a battle in Reval[10,12]. That was the end of plague-cadaver-catapulting, although in World War II the plague once again came into the spotlight.
During the Second World War, both the United States and the Soviets were running biological weapons units in direct competition, as they tended to do with everything during that time. Taking tips from history, they attempted to utilize the plague as a weapon. As there was no plague outbreak to utilize (and catapults are less effective across oceans), they resorted to attempting to develop methods of aerosolizing the bacteria directly. The United States shut down their program before reaching any success with Y. pestis, but the Soviets marched on and managed to manufacture large quantities that were ready to be deployed into weapons. In fact, they had missiles with warheads containing plague and smallpox available for launch before 1985 to use “against enemy population centers.” Luckily, since then they’ve been pressured to shut down their program[1,9,10]. Meanwhile, the Japanese in World War II had no such restraint on utilizing the plague. They actually used biological weapons several times on the Chinese. The Japanese Unit 731 dropped mixes of rice, wheat, and plague-infected fleas on the Chinese cities and provinces of Chuhsien, Ningpo, Suiyuan, Ninghsia, and Changteh between 1940 and 1941. All of these resulted in outbreaks of plague[9,10].
While the USA and Russia have supposedly stopped their biological warfare programs, there are indications that China, Syria, Iran, Egypt, Libya, Taiwan, North Korea, and Israel all are developing offensive biological weapons.
Apart from countries trying to infect each other, there has been one report of an individual attempting to utilize Y. pestis; in 1995 in Ohio, a microbiologist was arrested after acquiring Y. pestis with ‘suspect motives.’
As much as I’d like to console everyone after the previous section, there is currently no accepted vaccination for the plague. Two vaccinations exist, one in Russia and one in Australia, but both cause “unacceptable side effects” and are banned in the US. While vaccinations are currently being investigated, it is not likely that they would be widely used as preemptive measures as plague cases are rare. Consequently, one major problem is that it takes approximately a week for a vaccine to become effective; if someone has pneumonic plague they will be dead in under a week, rendering vaccination use rather pointless post-exposure.
On the bright side, antibiotics are currently relatively effective treatments for plague infections. Y. pestis is susceptible to many antimicrobial drugs. It is vital to start these antibiotics as soon as possible, and to be cautious of resulting shock: many of the drugs cause the bacteria to die and lyse, breaking open and releasing endotoxins that can be life-threatening. Unfortunately, there is a recent emergence of drug-resistant and multiple-drug-resistant strains of Y. pestis. Due to the rise in antibiotic resistance, scientists are investigating alternative therapies, including immunotherapy, phage therapy using bacteria viruses, bacteriocin therapy utilizing proteins created by bacteria to target the pathogen, inhibition of virulence factors, and more effective symptomatic treatment.
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