The Plague. By Joel Kent. Etiologic Agent: The plague, also known as the Black Death, is caused the bacterium Yersinia pestis.

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1 The Plague By Joel Kent Etiologic Agent: The plague, also known as the Black Death, is caused the bacterium Yersinia pestis. Transmission: Transmission occurs when a flea from a rodent bites a human. Fleas seek out new sources of blood when the rodent it is on dies. The fleas will often jump on humans, dogs or cats and promote transmission. Contact with infected fluids also transmits the disease. In addition to rodent fleas, skinning infected animals contributed to the spread of the bubonic plague. Pneumonic plague is There are three forms of the plague depending on the location of the infection. The bubonic plague is an infection of the lymphatic system, and is contracted through a flea or rodent bite. Y. pestis will enter the closest lymph node and propagate inside it. The bubonic plague rarely spreads from person to person. Pneumonic plague occurs when the bacteria enter the lungs in airborne droplets and cause pneumonia. It is considered contagious and will spread from person to person. Septicemic plague is an infection of the blood stream by Y. pestis. This can be a result of a flea or rodent bite, or as a progression from bubonic or pneumonic plague. Septicemic plague rarely spreads from person to person. Fleas acquire Y. pestis by ingesting infected blood, and can transmit the disease in two main ways. The first is an immediate transmission. The flea feeds from an infected source, and then feed from a second source and introduce the bacteria. This mechanical transmission is similar to using a dirty needle, because the bacteria will rest on the mouth of the flea before being transmitted. The second biological transmission involves the ingestion and regurgitation of the bacteria. When ingested, Y. pestis forms a biofilm between the esophagus and midgut of the flea. This creates a Bacot s block, a clot of blood and bacteria. This blockage prevents digestion, and is responsible for the transmission of the bacteria. A flea will attempt to ingest blood, and Y. pestis will mix with the blood before it is regurgitated by the flea into the victim s blood stream. Reservoirs: Rodents are the main long- term reservoir of Y. pestis globally. Prairie dogs and squirrels are the main reservoirs in the US, and domesticated cats dogs are also a significant reservoir. Transmission occurs through flea bites, and fleas are the main vector of transmission. General Characteristics of MO: Yersinia pestis is a gram negative, nonmotile, nonfspore- forming coccobacillus (Perry). Y. pestis is a facultative anaerobe of the Enterobacteriaceae family, and has an enterobacterial antigen common to enterobacteria. Y. pestis shows a bipolar staining through Giemsa, Wright s, or Wayson staining. For optimal growth it needs temperatures from 4-40 C, and a ph of It is possible for Y. pestis to survive in a ph from There is no true capsule, but a carbohydrate- protein envelope called fraction

2 1(F1) forms at temperatures above 33 C. Y. pestis is auxotrophic for L- isoleucine, L- valine, L- methionine, L- phenylalanine, and glycine. Key Tests for Identification: Yersinia pestis can be identified through physical and metabolic characteristics. First, a gram stain is performed to show Gram- negative rods. Then colony growth is assessed. A motility test will show Y. pestis to be non- motile. Y. pestis colonies are slow growing, pinpoint, opaque, smooth with irregular edges, and a hammered copper appearance. Colony morphology confirms a diagnosis, but takes two days to obtain. The colonies will grow on sheep blood agar after 24 hours, and are shown to be non- lactose fermenting on MacConkey agar at 48 hours. Biochemical tests can yield a presumptive identification and will show Y. pestis to be oxidase negative, catalase positive, urea negative, and indole negative. Further tests will show Y. pestis to yield a positive result of an o- nitrophenyl β- D- galactopyranoside (ONPG) test. Biochemical testing may be unreliable because of the slow growth of Y. pestis. In addition, a positive fluorescent antibody test against the F1 antigen gives presumptive evidence of Y. pestis. The CDC uses lysis of Y. pestis by a specific bacteriophage to confirm its presence. Signs and Symptoms: Patients with the bubonic plague develop a fever, headache, chills, and swollen and tender lymph nodes. Patients may also have nausea, vomiting, and diarrhea. Bacteremia or secondary plague septicemia is common. Untreated bubonic plague results in 40 60% fatalities. Patients with septicemic plague develop a fever, chills, weakness, abdominal pain, shock, and occasionally bleeding into organs. Skin can turn black and die, usually occurring in the extremities. Septicemic plague is fatal. Patients with pneumonic plague develop a fever, headache, weakness, and pneumonia with shortness of breath, chest pain, cough, and the production of bloody septum. Pneumonic plague is fatal. Historical Significance: The plague, Yersinia pestis, is likely responsible for three pandemics in recorded history. In total, the plague is estimated to have killed million people. The first was the Justinian plague (AD ). It originated in Ethiopia, spread to Pelusium, Egypt and then onward to the Middle East, Mediterranean basin and eventually the whole known world. From AD 558 to 654 the plague then continued in an epidemic cycle, occurring every 8-12 years. It is estimated that million people died because of the plague at this time, and the plague contributed to about a 50% population loss during this period. The second pandemic, the Black Death, spread around AD from Asia to Europe through the Silk Road trade route. The first epidemic is estimated to have killed 25 million Europeans from AD From 1361 to 1480 the plague occurred in 2 5 year cycles, and continued less frequently into the 1600 s. The third pandemic, the Modern Plague, originated in China around 1855 and spread worldwide through marine trade. It hit India specifically hard, and killed a million people per year. About 12.5 Indians were killed due to this plague. The plague was present in India from , and the last confirmed case was reported in 1994.

3 The Modern Plague led to discoveries about Yersinia pestis. Alexandre Yersin isolated Y. pestis by taking fluid from enlarged lymph nodes of people who died from the plague. He found a gram- negative bacillus, which he injected into guinea pigs. The guinea pigs died and had the same gram- negative bacillus in their lymph nodes. Because of the plague s association with dead rats, Yersin discerned that cause of the plague was this bacillus that infected humans and rats. Paul- Louis Simond is credited with discovering the mode of transmission of Yersinia pestis. He found that transmission only occurred when dead rats were still warm, and hypothesized that because fleas will leave when the rat becomes cold, that they are responsible for transmission. He examined fleas of infected rats and found the same microorganism in their intestine. This proved fleas transmit the plague. Virulence Factors: Yersinia pestis virulence comes from plasmids, and not its own microbial chromosome. A plasmid pcd1 encodes the Yersinia outer membrane proteins (Yop) and protein secretions. The protein secretions form a pore in the inner and outer membrane of Y. pestis, and Yops will form a pore in a eukaryotic cell after attachment. When Yops are transported to the eukaryotic cell, they are able to inhibit phagocytosis, inflammation, and induce apoptosis of macrophages. Another plasmid, ppcp1, encodes the protease Pla that interferes with blood coagulation and compliment activation. Plasmid pmt1 encodes for the capsular protein fraction 1 (F1), and a murine toxin. Once inside the lymph nodes, Y. pestis proliferates and eventually migrate through the blood stream and into the lungs. Its presence in the blood stream triggers septic shock. The blood vessels leak and decrease blood volume, resulting in dysfunctional blood clotting and organ failure. Control/Treatment: Nowadays, the plague is treatable with common antibiotics. If diagnosed in the US, patients will be isolated and given Gentamicin, Doxycycline, Ciprofloxacin, or Levofloxacin. As with any disease, the earlier treatment begins, the higher the chances of a full recovery. Prevention/Vaccine: Simple precautions can be taken to decrease the chance of transmission of Yersinia pestis. Remove possible rodent food supplies and rodent habitats from personal areas. Remove brush, rock piles, garbage, firewood, and pet food. Also, prevent transmission through infected tissue by wearing gloves when handling or skinning animals. Use flea repellent if flea exposure to self or pets is possible. If one s pets become sick, contact a veterinarian as soon as possible. Lastly, do not allow pets that are in an endemic area to sleep on your bed. Surveillance of wild and domestic animals helps to control the plague. Serological surveys of animals, and monitoring rodent population for sudden decreases are used. There is no commercially available vaccine for the plague, and the previously used vaccine has been shown to not be very effective. However, this short- term vaccine will be given to high - groups, like laboratory workers or members of the Peace Corps. Currently, an F1 subunit vaccine is in development. This relies on humoral immunity and booster would be required.

4 Local Cases and Outbreaks: The plague was introduced to the US in 1900 by rats on steamships. There have been 999 confirmed or probable human cases from The majority of the cases occur in the rural southwest. The two major areas of infection being northern New Mexico, northern Arizona, and southern Colorado; and California, southern Oregon and western Nevada. Eighty percent of the cases were the bubonic plague. Global Cases and Outbreaks: Globally, infections occur in small villages or agriculture areas in Africa, Asia, South America, and Western North America. Between 1000 and 2000 cases are reported annually. In the last 20 years the majority of cases that have been reported are from Africa, and currently 95% of reported cases are from sub- Saharan Africa and Madagascar. The Vietnam War contributed to a rise in incidence due to a disruption in human and rodent populations. In India in 1994 there was an influx of wild infected rodents searching for grain in compromised houses due to an earthquake. After early reporting, mass panic caused 600,000 of the city Surat s 2 million people to flea. Quick response by health officials prevented an epidemic. Almost a million people received tetracycline, flea- killing pesticides were greatly used, and house searches for suspect plague patients were done. There were deficiencies in the response by health professionals, but overall the outbreak only killed 54 people, which pales in comparison to other infections. References: 1. "Plague." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 03 Mar Web. 10 May < 2. "Plague." National Institute of Allergy and Infectious Diseases, 3 Feb Web. 10 May < 3. Perry, R D. Fetherston, J D. Yersinia pestis- - Etiologic Agent of Plague. Clinical Microbiology Reviews 10.1 (1997): Web. 10 May 2015 < 4. Hinnebusch, B. J. Erickson, D L. Yersinia pestis Biofilm in the Flea Vector and Its Role in the Transmission of Plague. Current topics in microbiology and immunology 322 (2008): Web. 10 May 2015 < 5. Olsen, Christopher M. "Modes of Transmission of Yersinia pestis." University of Wisconsin- Madison, n.d. Web. 11 May < 6. Sciulli, Rebecca. "Yersinia Pestis." Public Health & Environmental Laboratories. State of Hawaii Department of Public Health, n.d. Web. 11 May <

5 7. Rollins, Sarah. Rollins, Sean. Ryan, Edward. Yersinia pestis and the Plague. Pathology Patterns Review. American Society of Clinical Pathology (2003);119 (Suppl 1):S78- S85. Web. 10 May 2015 < 8. Chamberlain, Neal R. "Plague: Yersinia pestis." A.T. Still University, 2 Nov Web. 11 May < 9. "Plague." Mayo Clinic, 26 Mar Web. 11 May < conditions/plague/basics/treatment/con > 10. Feodorova, Valentina. Motin, Vladimir. Plague Vaccines: Current Developments and Future Perspectives. Nature. Emerging Microbes and Infections, 7 Nov Web. 11 May < 11. "Plague." WHO. World Health Orginization, Nov Web. 12 May <