Lecture 10: Plague - Principles of Infectious Disease

Principles of Infectious Disease Lecture 10: Plague  Plague: History Our first historical account of plague begins with an outbreak in the port of Pelusium near what is now Suez in Egypt in 541 CE. It quickly spread to Alexandria, and because Egypt was the “bread basket” of the...

Principles of Infectious Disease Lecture 10: Plague  Plague: History Our first historical account of plague begins with an outbreak in the port of Pelusium near what is now Suez in Egypt in 541 CE. It quickly spread to Alexandria, and because Egypt was the “bread basket” of the Byzantine Empire, it rapidly expanded along the routes of grain ships Emperor Flavius Justinian throughout the Empire, arriving in the capitol, Constantinople within the year. Much of what we know of the plague comes from Procopius, Court Archivist to the Emperor Justinian, as well as Syriac Church Historians John of Ephesus and his successor, Evangrius Scholasticus.  Plague: History Procopius writes……. A “sudden fever…but the body showed no change in its original color, neither was it as hot as expected when struck by a fever, nor did any inflammation occur…but the fever was of such a lethargic kind….[within a couple of days] a bubonic swelling developed there in the groin of the body, which is below the abdomen, but also in the armpit, and also behind the ear and at different places on the thighs… Up to this point, then, everything occurred in the same way all who had taken the disease. But from then on very distinct differences developed for there ensued for some a deep coma, with others violent delirium…For those who were under the spell of the coma forgot all who were familiar to them, and seemed to lie, sleeping constantly. And if anyone cared for them, they would eat without waking, but some were neglected, and these would die directly through lack of sustenance. But those who were seized with delirium suffered from insomnia and were victims of distorted imagination, for they suspected men where coming to them to destroy them, and they would become excited and rush off in lague: History rocopius continues……. “They also had great difficulty in the matter of eating, for they could not easily take food. And many perished through lack of any man to care for them, for they were overcome with hunger, or threw themselves from a height. And in those cases where neither coma nor delirium came on, the bubonic swelling became worse and the sufferer, no longer able to endure the pain, died. … In some cases death came immediately, in others, after many days; and with some the body broke out with black pustules about as large as a lentil and these did not survive even one day, but all succumbed immediately. Vomiting of blood ensued in many, without visible cause, and immediately  Plague: History Procopius continues……. “Now in those cases where the swelling rose to an unusual size and a discharge of pus had set in, it happened that they escaped from the disease and survived for clearly the acute condition of the swelling found relief in that direction, and this proved in general, and indication of returning health….And with some of them the tight withered, in which case, though the swelling was there, it did not develop the least suppuration. With others who survived, the tongue did not remain unaffected, and they lived on Second pandemic: The black Death (mid 1300s CE) Like the first pandemic, the Black Death probably had its ultimate origin in China. It is thought to have spread Westward along the route of Mongol invasion. Prior to coming to Europe, it heavily depopulated India. It was probably introduced to Europe via a number of ways, but one possible avenue started with the siege of Caffa in 1347. nd pandemic: The black Death (mid 1300s CE) Remains of Genoese Fortress at Caffa The Republic of Genoa (Italy) maintained a prosperous trading outpost on the Crimean Peninsula (on the Black Sea) named Caffa. It was a major trading post between Asia and Europe. Jani Beg, a self-crowned king and leader of a Mongol/Turkic army laid siege to Caffa in order to expand his empire. During the Siege, bubonic plague began to ravage his army. Not wishing to keep all the fun to himself, it is said that he ordered the catapulting of plague-infected corpses over Jani Beg the Caffa city walls. Many Genoan expatriates fled on ships back to Italy and France, facilitating the spread of disease. Caffa  Plague: History witness to history: The account of vanni Boccaccio of Florence, Italy 1348 …It began both in men and women with certain swellings in the groin or under the armpit. They grew to the size of a small apple or an egg, more or less, and were vulgarly called tumors. In a short space of time these tumors spread from the two parts named all over the body. Soon after this the symptoms changed and black or purple spots appeared on the arms or thighs or any other part of the body, sometimes a few large ones, sometimes many little ones. These Note similarities to Procopious’s descriptions!  Plague: History ovanni Boccacciocontinues…… “No doctor's advice, no medicine Could overcome or alleviate this disease, an enormous number of ignorant men and women set up as doctors in addition to those who were trained. Either the disease was such that no treatment was possible or the Doctors were so ignorant that they did not know what caused it, and consequently could not administer the proper remedy. In any case very few recovered; most people died within about three days of the appearance of the tumors described above, most of them without any fever or other symptoms.  Plague: History ovanni Boccaccio continues…… “The violence of this disease was such that the sick communicated it to the healthy who came near them, just as a fire catches anything dry or oily near it. And it even went further. To speak to or go near the sick brought infection and a common death to the living; and moreover, to touch the clothes or anything else the Plague: Histor Giovanni Boccaccio continues “Such was the multitude corpses brought to the c every day and almost ev hour that there was not consecrated ground to g them burial, especially s they wanted to bury eac person in the family grav according to the old cus Although the cemeteries full they were forced to huge trenches, where th buried the bodies by hun Here they stowed them like bales in the hold of and covered them with a earth, until the whole tr was full." ing Social Consequences of the Black Death rope depopulated by ¼ to 1/3. me urban areas by 50% or more! th population drop, food prices ashed while wages skyrocketed. eviously, peasants were bound to eir lord and their lands through udal system, but labor shortages ve lower classes power to demand gher wages, buy land and means production, and shatter the udal system. The inability of both urch and Nobility to stem the plague eakened their authority and some y these conditions paved the way the Enlightenment.  Terminology Endemic: Describes a disease that is always present at relatively stable levels in human population. Enzootic: Like endemic, but in non-human anim Epidemic: Unusually high incidence of disease in humans that is spreading rapidly. Pandemic: An epidemic spanning multiple continents. Zoonosis: A disease that spreads naturally from animals to hum Epizootic: An “epidemic” among non-human animals. or: A living intermediary, usually an arthropod, that transmits a pathogen from o to another.  Plague: General ue is an ancient disease that is now endemic in many of the world, and is caused by Yersinia pestis. e are three historically-recorded pandemics. 1st was in entury CE (Plague of Justinian), 2nd was in the 14th www.genome.gov ury (European Black Death-wiped out ¼ -1/3 population), began in China in 1860. ng 3rd pandemic Alexandre Yersin isolated in Hong Kong for rst time the plague organism that bears his name. ng this pandemic, infected rats were transported to , Africa and the New World, where it established itself cal rodent populations and remains today. Alexandre Yersin www.wikipedia.org  Rattus norvegicus Plague: General ts are the reservoir hosts for Yersinia pestis. mportant species for transmission to man are the estic black rat (Rattus rattus) and the brown sewer Rattus rattus Rattus norvegicus). f yearly plague cases occur in Africa, but a handful n each year in the southwestern the United States of Mississippi river) Here the reservoir hosts www.cdc.gov are nd squirrels and prairie dogs. ector for Y. pestis is the flea, most commonly Xenopsylla psis. Xenopsylla cheopsis  Plague: Microbiology Yersinia pestis is a small Gram-negative coccobacillus. Yersinia sp. www.cdc.gov Exhibits pleomorphism (different shapes) in Infected American Rock clinical specimens. Squirrel coughing up blood-tinged sputum Grows aerobically on many common nutrient agars. www.misc. medscape.com Somewhat susceptible to adverse environmental conditions (killed by heating to 56oC for 15 min, 4h exposure to sunlight, can survive desiccation for only a few days. Prairie dogs in Western U.S. They can survive months in cool moist soil of are also reservoir hosts gue: Clinical manifestations Can be one of the most virulent infections known to man. However, both mild and sub-clinical cases are not uncommon. www.bbc.com Incubation period usually 2-5 days, but can be up to 2 weeks. Disease usually manifests in either of two types: bubonic and pneumonic (although other clinical presentations do exist, including septicemic, plague meningitis and pharyngeal or tonsillar plague). Extremely high mortality rates are associated with plague. onic Plague: Clinical manifestations This is the most common form. Presents first with fever, malaise, anorexia and headache. Sometimes there is a dull, aching sensation at www.Wikipedia.org sites where buboes will begin to form 24h later. Primary buboes will be found in various locations, depending on site of inoculation (flea bite). Buboes are swollen lymph nodes that may enlarge to the size of hen’s eggs. They are tender and develop necrotic centers. Untreated they will suppurate and form  Clinical manifestations of bubonic plague the-travel-doctor.com Wikipedia.org Involvement of femoral/ Involvement of posterior cervical inguinal lymph node lymph node Suppurating bubo http://intranet.tdmu.edu.ua Axillary bubo www.emergency.cdc.gov  Bubonic Plague: Clinical manifestations set of fever is often rapid with temperature ng to 39-40oC or higher. ually prostration and lethargy are seen and ere is sometimes agitation and delirium. miting and diarrhea sometimes seen. hough not always present, a patchy, rpuric (subcutaneous bleeding) dermal crosis may arise, which is one reason e disease earned its sobriquet, ack Death”.  Septicemic Plague: Clinical manifestations Episodes of bacteremia are common in bubonic plague and culture of small volumes of blood can reveal Y. pestis perhaps 40% of time at a density of perhaps 102/ml. However, the term “septicemic plague” refers to a particular acute clinical syndrome with very high densities (107/ml) of plague organisms in the blood in the absence of clinically-apparent buboes. Symptoms include fever, rigors, malaise and headache. Nausea, diarrhea vomiting and abdominal pain are more frequent than bubonic form. Duration of disease is shorter  Septicemic Plague, cont. Another clinical manifestation of septicemic plague is the development of acral necrosis (“acral” meaning “of the extremities). The www.cdc.gov blackening as a result of the necrosis may also be a reason plague became known as “Black Death”. Acral necrosis is also seen with pneumonic plague. http://hardinmd.lib.uiowa.edu/cdc/ monic Plague: Clinical manifestations “Pneumonic” denotes an infection in the lungs. Pneumonic plague is of two types: Primary, where the lungs are the initial and main focus of Pneumonic plague CDC.com infection, and secondary, where the infection spread to the lungs after initial bubonic or septicemic presentation. First symptoms are intense headache with malaise, fever, vomiting and prostration. Usually patients have impaired consciousness. There is little to suggest classical pneumonia, changes in lung sounds are usually slight. There is often production of watery, eumonic Plague: Clinical manifestations rtality rate for both primary and secondary nic plague are very high, and if any impact on y is to be made, antibiotic therapy must begin www.cdc.gov 4h of onset of symptoms. onic plague is the only type that can be easily itted from person-to-person through infected droplets. s close contact with patient having productive cough. imate is cool and humid, allowing infectious droplets st, epidemics of pneumonic plague have occurred Lung of primary pneumo nchuria, 1911). plague victim. Note necr foci throughout lung  Less common plague manifestations Plague meningitis: Usually a complication of inadequately treated bubonic form. Although seemingly associates with presence of axillary buboes (suggesting lymphatic spread) bacteremia is also the likely route of spread. Symptoms are similar to other bacterial meningitis with fever, headache, neck stiffness and vomiting. Mortality rate is higher than with uncomplicated bubonic plague. Pharyngeal or tonsillar plague: Transmission  Virulence factors: Type III secretion How system does Y. pestis do its damage? As we shall see, it produces a series of powerful toxins. However, like other enterobacteriaceae, it possesses a Type III secretion system EM of assembled Type III system that allows it to inject toxins directly into target cells! The type III system contains 3 kinds of proteins. The first is STRUCTURAL, and form the base, Inner rod, and needle components. The second is EFFECTOR, and consists of the actual toxins that get injected. The third are the CHAPERONES. These are proteins  Y. Pestis virulence factors/toxins E: I will NOT ask you to memorize ANY of these toxins. There are too many-but D note of the fact that almost all of these are directed against one general target yadBC: a gene that encodes 2 proteins. Appears to be involved in adherence and invasion of epithelial cells. Loss of gene has large impact on virulence for bubonic, but not pneumonic plague (Forman Infec. Immun. 2008). Plasminogen activator: A membrane serine protease that activates host plasminogen. It can dissolve blood clots(facilitating spread) and can also inhibit chemotaxis of PMN.  Y. Pestis virulence factors/toxins V antigen (LcrV). A multifunctional virulence factor that has been implicated in facilitating the transfer of other effector proteins across the Type III secretion system but has also been linked to pore formation on target cells, and is actually itself translocated into the target leukocyte where it exerts immunomodulatory effects. Yop (Yersinia Outer proteins) proteins. These represent the primary group of effector proteins that are injected into the host cell via the type III secretion system. There are 6 known Yops. YopE: A Rho GTP-ase activating protein that inhibits reactive oxygen species generation as well as phagocytosis.  Y. Pestis virulence factors/toxins YopH is a protein tyrosine phosphatase, also with anti-phagocyte function. Disrupts cytoskeleton to inhibit phagocytosis, disrupts PI3K pathway to down-modulate ROI production, and IL-12 production (a proinflammatory cytokine) as well as TNF-alpha and IL-1B. YopO/YopA and YopJ are co-expressed from a single transcript YopA is is a serine threonine kinase that disrupts actin-based cytoskeletal system. YopJ inhibits MAP kinase and NF-kB signaling systems to limit pro-inflammatory cytokine release. It also causes apoptosis in macrophages. YopT is a cytotoxin that disrupts actin filaments and inhibits t is this general cellular target? Yersinia toxins take out phag In general, Yops disrupt intracellular signaling and cytoskeleton to prevent leukocyte activation and phagocytosis. Most of the virulence factors of Y. pestis are directed against phagocytic cells of the innate immune system. Not only is the direct killing capacity of these cells disrupted, but if the innate immune system is taken out, the adaptive immune system is also compromised. If these important immune system cells are inhibited, Y. pestis can grow and spread unopposed. Ultimate death is often  Yersinia pestis: Treatment ause disease progression is generally rapid, therapy ds to begin as quickly as possible. ough were practicable, screening for antibiotic stance is helpful. Gentamycin bsence of sensitivity information, first line drugs include eptomycin, Gentamycin, as well as chloramphenicol, Chloramphenicol racycline and doxycycline. avenous administration is warranted in pulmonary or anced cases. Tetracycline biotic prophylaxis should be offered to patient contacts. Doxycycline  Yersinia pestis: Transmission Y. pestis-infected flea (note dark mass in gut Normal flea after blood meal representing replicating bacteria). When Xenopsylla cheopsis takes a blood meal from a Y. pestis-infected host, the organisms are capable of multiplying to great numbers in the flea gut. Y. pestis is capable of growing as a biofilm that blocks the proventriculus-a structure that forms the transition between esophagus and gut. When the flea tries to take a subsequent blood meal, it finds that it cannot swallow due to the obstruction. The hungry and frustrated flea bites again and again, regurgitating the leftovers of each attempt back into  Yersinia pestis: evolutionary origins Y. pestis is the oddball of the enterobacteriaceae because it is not transmitted via ingestion of contaminated food or water, but via an arthropod vector. Its closest relative is Y. pseudotuberculosis, which causes a relatively benign enteric disease. How do these two organisms differ? Genetic analysis has revealed shocking similarity between Y. pestis and Y. pseudotuberculosis, including perfect homology between the 16s rRNAs. More sophisticated genomic sequencing has suggested that they are so closely  Yersinia pestis: evolutionary originssequencing revealed the following: Complete genomic Y. Pestis has acquired 32 new chromosomal genes and two extra-chromosomal plasmids. The plasmids appear to encode genes that adapt the organism for flea transmission. One plasmid encodes the Yersinia murine toxin (Ymt) which promotes survival and growth in the flea midgut. The other plasmid encodes Y. pestis plasminogen activator (Pla). This protein has different function at low temperature environment of flea midgut and might help block Yersinia pestis: evolutionary origins Also of great interest was the fact that there were 317 genes found in Y. pseudotuberculosis that were no longer present in Y pestis. This large loss of genes results in elimination or modification of pre-existing expression pathways. This suggests that most of the genetic differences accounting for the changes in pathogenicity between Y. pestis and Y. Pseudotuberculosis are explained by a LOSS of genes rather than an acquisition!  How do we know that Y. pestis caused either the Justinian plague or the Black Death? Ever since the discovery of Y. pestis, a controversy has existed as to whether the historical plagues were caused by this or other pathogens. Jani Beg In the “pro” category, many of the historical accounts of clinical manifestations are highly consistent with plague. However, there are some confusing inconsistencies. Among these: Norwegian rats did not appear in England until 60 years after the plague. A similar situation in Iceland: hard-hit but no known rodent reservoirs, and besides Iceland is too cold for the flea vectors. Epidemiologists note that the plague spread much faster than would be expected by a rat-borne disease. Historical accounts indicate a widespread belief that person-to-person spread ow do we know that Y. pestis caused either e Justinian plague or the Black Death? It appears that modern molecular techniques may have definitively solved the controversy. Mass grave sites for both Justinian and Black Death plagues have been excavated, and DNA from dental pulp has been extracted. Multiple groups have reported PCR amplification of Y. Pestis DNA. But how to account for some of the inconsistencies? First, infectious agents can change over time, and plague of antiquity may not behave Plague mass graves in Italy  Strategies to evade or circumvent bodily defenses Breaching anatomical barriers Speed Evading phagocytosis and its consequences Stable strain variability Antigenic “quick change” artists Microbial stealth technology Immune subversion Which ones are used by Y. Pestis?