yersinia pestis the plague micro exam

Types of plague

- Bubonic -Septicemic-- primary and secondary pneumonic- primary and secondary

Septicemic

-fatality rate of 30-50% in treated cases, 50-90% in untreated cases causes severe blood infection throughout the body and gangrene of acral regions (nose and digits) if untreated Primary: occurs when a flea inserts y. pestisdirectly into the bloodstream Secondary: occurs as a severe development from bubonic or pneumonic (when y pestismigrates to bloodstream)

Pneumonic

100% death rate if not treated within first 24 hrs can be transmitted via direct inhalation of the germs least common, yet most dangerous form Primary: occurs via inhalation of pneumonic respiratory droplets Secondary: occurs when bubonic or septicemic plagues spread to the lungs

septicemic plague

1º septicemic plagueis due to spreading of Y. pestis by way of the bloodstream from the site of inoculation without bubo formation Septicemic plague may also follow an initial presentation of bubonic plague, thereby becoming 2º septicemic plague. Spreading of Y. pestis to all organs including liver, spleen, heart, kidneys and CNS occurs, leading to septic shock and death.

treatment in a contained casualty setting

Adults Preferred choices:Streptomycin, 1g IM twice daily Gentamicin, 5 mg/kg IM or IV once daily or 2 mg/kg loading dose followed by 1.7 mg/kg IM or IV three times daily† Alternative choices:Doxycycline, 100 mg IV twice daily or 200 mg IV once daily Ciprofloxacin, 400 mg IV twice daily‡ Chloramphenicol, 25 mg/kg IV 4 times daily§ Children|| Preferred choices:Streptomycin, 15 mg/kg IM twice daily (maximum daily dose 2 g) Gentamicin, 2.5 mg/kg IM or IV 3 times daily† Alternative choices:Doxycycline, If >= 45 kg, give adult dosage If < 45 kg, give 2.2 mg/kg IV twice daily (maximum 200 mg/dl) Ciprofloxacin, 15 mg/kg IV twice daily‡ Chloramphenicol, 25 mg/kg IV 4 times daily§ Pregnant Women¶ Preferred choice:Gentamicin, 5 mg/kg IM or IV once daily or 2 mg/kg loading dose followed by 1.7 mg/kg IM or IV three times daily† Alternative choices:Doxycycline, 100 mg IV twice daily or 200 mg IV once daily Ciprofloxacin, 400 mg IV twice daily‡

pathogenesis bubonic

Flea --> Skin --> Lymphatic vessels --> Forms buboes (ark 1)Blood Organs 2°septicemic2°pneumonic (ark 2) Blood Lungs

1 pneumonic

inhaled infected respiratory droplets (from either can or human) --> lungs

costume worn by plague doctor to protect against 'miasmas" of poisonous air

long uggy beak with black robe and weird shaped hat

differential diagnosis

pneumonic plague-•bilateral pulmonary infection, with greater infection in the left lung. inhalation of anthrax-widened mediastinum, resulting in less available space for lungs

Reservoirs

•Urban and domestic rats •Ground squirrels •Rock squirrels •Prairie dogs •Deer mice •Field mice •Gerbils •Voles •Chipmunks •Marmots •Guinea pigs •Kangaroo rats ...over 200 identified reservoirs

bubonic

-most common form (-85% of all cases) -causes swollen lymph nodes (buboes) -can only spread form person to person via direct contact with bubo drainage -1%-15% death rate if treated : if not treated, 40%-60% death rate -the backbone of the survival of y. pestis because it can develop into both secondary septicemic and pneumonic types

Septicemic transmission `

-•Bites from flea vectors where Y pestisis inserted directly into bloodstream -no discernible bubo present ---•Develops as a complication of bubonic or 1º pneumonic plague -When Y pestisenters the bloodstream

Pneumonic transmission

-•Inhalation of respiratory droplets from infected animals such as cats •Inhalation of respiratory droplets from a person with primary or secondary pneumonic plague •Handling Y pestiscultures in the laboratory setting --•Bubonic and 1°septicemic spread plague bacilli hematogenously to the lungs

description yersinia pestis

0.5-0.8 μm in diamete r1-3 μm long Grows optimally at 28ºCand a pH of 7.2-7.6 Bacterial cell wall F1 Protein Envelope

Genome

1 chromosome -4.65Mb Orientalis and Medievalis strains have been sequenced3 plasmids pMT1 -96.3kb pYV -70.3kb pPla -9.6kb The plasmids are crucial to the virulence

Enzymes and Toxins

1. catalase 2. coagulase and clumping factor -clots oxalated or citrated plasma. Coagulase binds to prothrombin, polymerize fibrin. Hyaluronidase -spreading factor; staphylokinase -fibrinolysis; lipase .Toxic shock syndrome toxin -TSST-1 is the superantigen; binds to MHC class II.

Pathology

Furuncle or other localized abscess Accumulation in a hair follicle→tissue necrosis. Coagulase coagulates fibrin, resulting in fibrous tissue. Center of the lesion turns to liquefaction of the necrotic tissue→granulation tissue→healing. Suppuration via lymphatics or veins Spreading of toxins, eg. TSST-1.

yersinia Pestis

Gram negative coccobacillus Non-motile Enterobacteriaceae family Non-spore forming (unlike Anthrax)Facultative anaerobe Obligate parasite

Staphylococci

Normal flora of the skin, nose, throat, and mucous membranes; cause suppuration, abscess, pyogenic infections, fatal septicemia .Hemolyze blood, coagulate plasma and produce a variety of extracellular enzymes and toxins At least 30 species: S aureus, S epidermidis, S saprophyticus-UTI in young women Staphylococci are non-motile; aerobic or microaerophilic and relatively resistant to drying and heat S aureusis catalase +, coagulase +; form grey to golden yellow colonies, ferment mannitol.

Plasmids crucial to virulence of Y. pestis

Plasmid Name Size (kb) Virulence determinants Role in disease pMT1* 96.2 F1 capsule antigen Bacterial transmission by Fleas pYV 70.3 Several Yops, Type III Toxicity. Avoidance secretion system of immune system pPla* 9.6 Plasminogen activator Dissemination from intra-dermal site of infection *unique to Y. pestisonly

plasmids crucial to virulence of y.pestis

Plasmid Name, Size (kb) ,Virulence determinants, Role in disease pMT1*, 96.2,F1 capsule antigen, Bacterial transmission by Fleas pYV ,70.3 ,Several Yops, Type III secretion system,, Toxicity. Avoidance of immune system pPla*, 9.6, Plasminogen activator, Dissemination from intra-dermal site of infection *unique to Y. pestisonly

Precautions for Dealing with Plague Victims

Since the only form of human to human spread occurs by respiratory droplet from a patient with pneumonic or secondary pneumonic plague, surgical masks, gloves, gowns, and goggles should be worn at all times All patients with pneumonic plague should be strictly isolated (as required by law) until they have received 48 hours of antibiotic treatment and show signs of improvement Labs should operate at biosafety level 2, unless they are performing tests that may aerosol or produce droplets in which case biosafety level 3 should be observed No environmental decontamination is necessary as the bacteria is quite fragile outside of the host environment

Medically Important Gram + Bacteria

Staphylococci StreptococcusBacillus Clostridium Listeria Erysipelothrix Lactobacillus Actinobacteria Streptomyces Proprionibacterineae Corynebacterium Nocardia Mycobacterium

Staphylococci

Staphylococci are resistant to drugs: 1. β-lactamase production makes them resistant to penicillins (including ampicillin) 2. Independent β-lactamase production in resistant to nafcillin.mecAgene in chromosome. 3. Resistant to vancomycin. Due to increased cell wall synthesis or alterations of cell wall, or the resistant vanA. 4.Plasmid mediated resistance to tetracyclines, aminoglycosides.

Toxins and Enzymes

Streptokinase (fibrinolysin): human plasma→plasmin (active proteolytic enzyme that digests fibrin and other proteins). Causes pulmonary embolism. Hyaluronidase splits hyaluronic acid. Acts as a spreading factor Hemolysins: streptolysin O (SLO)-inactivated in O2, anti-SLO level increases following infection (ASO serum titer of 160-200 units); and streptolysin S (SLS) -zones around colonies, elaborated in the presence of serum

Weaponization

The CDC ranks the plague as a Category A disease "Agents in Category A have the greatest potential for adverse public health impact with mass casualties, and most require broad-based public health preparedness efforts (e.g., improved surveillance and laboratory diagnosis and stockpiling of specific medications). Category A agents also have a moderate to high potential for large-scale dissemination or a heightened general public awareness that could cause mass public fear and civil disruption."

Machinery of this "Biological Syringe"

The Type III secretion system consists of : The core apparatus for secretion through two bacterial membranes The "needle" YopB, YopD, YopK, LcrV Control elements YopN, TyeA, LcrG The "poison" (Anti-host effector proteins) YopE, YopH, YopM, YpkA and YopJ

Mechanisms that allow spreading of Y. pestis in mammalian host

Plasminogen activator protease (Pla) Genes located on smallest plasmid pPla Pla is required for the migration of Y. pestis from the subcutaneous infection site into the circulation Pla derives its name from the fact that it can activate the mammalian plasma enzyme plasminogen to plasmin. Plasmin is responsible for the breakdown of fibrin Main virulence role of Pla: Cleaves fibrin deposits that trap Y. pestis, thereby promoting plague infection

World History

*The first record of plague was an outbreak among the Philistines in 1320 B.C. when God enacted his vengeance upon them for capturing his Ark, which belonged to Israel: "He [the Lord] brought devastation upon them and afflicted them with tumors. And rats appeared in their land, and death and destruction were throughout the city...The LORD'Shand was against that city throwing it into great panic. He afflicted the people of the city, both young and old, with an outbreak of tumors." I Samuel 5:6-12 "The Philistines asked, "What guilt offering should we send to Him? They replied, "Five gold tumors and five gold rats because the same plague has struck both you and your rulers." I Samuel 6:4

How Antibiotics Work

Antibiotics inhibit prokaryote protein synthesis by preventing the transition from initiation complex to chain-elongating ribosome and causes miscoding.

Staphylococci -Antigenic Structure

Antigenic peptidoglycans (polysaccharides) stimulate production of interleukin-1 and opsonic antibodies; chemoattractant; endotoxin-like and activate complement. Teichoic acids elicit anti-teichoic acid antibodies in endocarditis patients Protein A binds to the Fc portion of IgG molecules, agglutinate bacteria. Capsules inhibit phagocytosis Coagulase is a clumping factor on cell wall surface, binds to fibrinogen and yield bacterial aggregation.

Differential diagnosis of plague

Bubonic•Tularemia •Cat Scratch Disease •Chancroid •Lymphogranuloma venereum •Bacterial adenitis •Tuberculosis •Scrub Typhus Septicemic •Septicemia caused by other Gram Negative bacteria •Meningcoccemia •Rocky Mountain Spotted Fever Pneumonic •Inhalational anthrax •Tularemia •Viral Pneumonia (Influenza, Hantavirus, CMV) •Q fever

Bacillus anthracis

Characteristics Capsule Spore: central endospore Nonmotile Reservoir, zoonotic Hoof stock (sheep, cattle, goats) Fur, hides (textile workers) Soil contaminated with spores Virulence Capsule Spore Exotoxin (anthrax toxin) Necrosis Edema Protective Ag Lethal factor Edema factor PA + LF = Lethal Toxin PA + EF = Edema Toxin

B. anthracis

Diagnosis Culture/Isolation Treatment Antibiotic (cipro) Prevention Vaccination (AVA)Proper disposal Chemical disinfection Burn carcasses

Clinical AspectsSigns and Symptoms of Plague

Differential Diagnosis Laboratory Diagnosis Treatment

Y. pseudotuberculosisvs. Y. pestis

Disease: Enteric infection Transmission: enters mammals through food and water Chromosomal DNA -4.74MbExtrachromosomal DNApYV "Two thousand years ago, it only gave you a tummy ache"-Brendan Wren, geneticist Disease: Bubonic Plague Transmission: rodent to humans through flea vector Chromosomal DNA -4.65Mb 90% chromosomal DNA relatedness with Y. pseudotuberculosisExtrachromosomal DNA pYV pPla pMT1 "Within a few hundred years -an evolutionary eye blink-Y. pestislearned to leap between fleas and mammals, to live in the blood instead of the intestine, and to cause the swelling, coughing and hemorrhaging of medieval nightmares."http://www.nature.com/nsu/011004/011004-12.html

Hms is temperature dependent

Experiments indicate that fleas do not become blocked at higher temperatures (above 28ºC = 82.4ºF) It is not known however whether it is the expression of the Hmsgene that is affected by temperature, or rather its protein product is affected by temperature. For instance, if held at 30ºC, fleas survive Y. pestis infections in an unblocked state, perhaps explaining why human bubonic plague epidemics often end after the onset of warmer temperatures. In addition, if you refer to the World Distribution of Plague Map, you will notice that plague does not occur in the equatorial regions, evidence which further supports this theory.

B. anthracisdiseases

Exposure Inhalation Inoculation Ingestion meat Diseases Gastrointestinal Hemorrhage/death Cutaneous Eschar/toxemia Inhalation Toxemia/death

Mechanisms that allow extracellular lifestyle in the mammalian host

F1 antigenGenes located on largest plasmid pMT1 Exposure to temperatures of around 37ºC in mammalian host results in production of large amounts of F1 antigen, which is exported to Y. pestis surface to assemble into an antiphagocytic envelope .Yersiniabactin (Ybt)-siderophore Genes located on chromosome Used to obtain nutritional iron necessary for bacterial growth from eukaryotic proteins transferrin and lactoferrin Bacteria requires iron in order to cause infectionType III secretion systemGenes located on the middle-sized pYV plasmid In extracellular environment, this is the weapon used by Y. pestis to kill macrophagesIt is the key virulence mechanism that allows Y. pestis to protect itself from phagocytosis.

Septicemic plague symptoms

Fever 100% Nausea & Vomiting 50% Altered mental status common Abdominal pain 39% Diarrhea 39% Chest x-ray Patchy bilateral infiltrates

Can be transmitted from

Flea bite

Manner in which fleas transmit plague

Flea feeds on Y. pestis-infected blood Y. Pestis enters flea's midgut & multiplies logarithmically Clump of Y. pestis forms in the midgut, blocking fleas foregut During next meal, blood cannot enter the midgut & flea gets very hungry Flea bites vigorously & regurgitates the contents of its midgut into the next wound

1 speticemic

Flea-->Blood vessels-->organs

Streptococci

Grow in blood or tissue fluids, 5% CO2at 37°C. Group D enterococci grow well at 15°C and 45°C. Classification is based on: group-specific cell wall Ag; M-protein; T-antigen and nucleoproteins. -cell wall Ag by Lancefield grouping, by extraction of centrifuged culture with hot HCl, nitrous acid or formamide; by enzymatic lysis of strep cells (eg. Pepsin or trypsin).chemical structure of cell wall rhamnose acetylglucosamine. -M-protein -virulent factor, able to resist phagocytosis by polymorphs. There are more than 100 serotypes of M proteins. M protein molecule rod-like coiled-coil structure.-T antigen -not virulent, acid-labile and heat-labile.

y.pestis mechanisms that contribute to flea blockage

Hemin storage proteins (Hms)Genes located on chromosome Necessary for flea blockage, which is essential for efficient transmission of plague from flea to mammals Hms play a very important role in the transmission of plague, changing the Y. pestis from a harmless inhabitant in the flea vector's midgut to one that amasses in the foregut, causing the blockage. In the flea, the Hms proteins alter the hydrophobicity of the bacterial cell, thereby promoting aggregation and clumping of bacteria within the blood meal. This is one of the main mechanisms by which blocking of fleas occur.

The Streptococci

Heterogenous group of bacteria, characterized by colony growth characteristics, hemolytic patterns on blood agar, antigenic composition of group-specific cell wall. Spherical cocci in chains, Gram +. Most group A, B and C produce hyaluronic acid capsules .Cell wall contains proteins (M, T antigens), carbohydrates and peptidoglycans, . M-protein is hair-like fimbriae.

plague in the usa

Human plague has been reported most often from the four western states of New Mexico, Arizona, Colorado andCalifornia 341 casesof human plague were reported during 1970-1995 The overwhelming majority of cases were bubonic plague Reported human plague cases by county. u.s 1970-1997

Treatment

In a contained casualty setting, parenteral antibiotic therapy, especially streptomycin or gentamycin, is suggested. In a mass casualty setting, intravenous or intramuscular therapy may not be possible, so oral therapy, preferably with doxycycline (or tetracycline) or ciprofloxacin, should be administered. Patients with pneumonic plague will suffer from complications and therefore require substantial advanced medical supportive care.

Clinical findings

Localized staph infection appears as "pimple" hair follicle infection, or abscess. Dissemination of S. aureus→endocarditis, meningitis, pulmonary infection. 2°infection: symptoms like organ dysfunction or intense focal suppuration Food poisoning due to staph enterotoxin presented with short incubation (1-8 hr); violent nausea, vomiting, diarrhea, rapid convalescence, no fever. TSS manifested by abrupt onset of high fever, vomiting, diarrhea, scarlatiniform rash, cardiac/renal failures. Women with tampons, or men and children with injured wounds. Virtually never in bloodstream.

Methicillin -Resistant S. aureus (MRSA)

MRSA -methicillin-resistant S aureus, because the organisms rapidly develop resistance to many antimicrobial drugs, drugs cannot act in the central necrotic part of a suppurative lesion. Emergence resistant to erythromycin group -not used singly for treatment of chronic infection .Sometimes called multiple -resistant S. aureus.

Treatment in a Mass Casualty Setting and Postexposure Prophylaxis

Mass Casualty Setting and Postexposure Prophylaxis# Adults Preferred choices:Doxycycline, 100 mg orally twice daily** Ciprofloxacin, 500 mg orally twice daily‡ Alternative choices: Chloramphenicol, 25 mg/kg orally 4 times daily§,†† Children|| Preferred choices:Doxycycline,**If >=45kg give adult dosage If <45 kg then give 2.2 mg/kg orally twice daily Ciprofloxacin, 20 mg/kg orally twice daily Alternative choices:Chloramphenicol, 25 mg/kg orally 4 times daily§,†† Pregnant Women¶ Preferred choices:Doxycycline, 100 mg orally twice daily and Ciprofloxacin, 500 mg orally twice daily Alternative choices:Chloramphenicol, 25 mg/kg orally 4 times daily§,††

Yersinia Pestis as a Weapon

Pros It is relatively easy to obtain and mass produce.It can be delivered in aerosol form Pneumonic plague causes a rapid onset of illness with a high fatality rate Pneumonic plague has a high potential for secondary spread of cases during an epidemic 100-500 bacteria are enough to cause pneumonic plague Cons Plague is fragile and dies after about 1 hr Manufacturing an effective weapon using Y. pestiswould require advanced knowledge and technology

Regulations of Virulence Determinants

Protein expressions depend on the bacterial growth phase. Accessory global regulon gene, agrhas 2 operons: 1stencodes RNA III that induces up-regulation of the secreted proteins and down-regulation of surface proteins.

Streptococcusspecies

S. pyogenes-Group A; β-hemolytic; human pathogen only; diseases such as local tonsillitis, necrotizing fasciitis and post-streptococcal glomerulonephritis. S. agalactiae-group B; β-hemolytic; NF of female genital tract, neonatal sepsis and meningitis. Enterococcus faecalis-normal enteric flora; γ-or α-hemolytic .S. pneumoniae-α-hemolytic; growth is inhibited by optochin and colonies are bile-soluble .Viridans streptococci -α-hemolytic typically; growth not inhibited by optochin and colonies are not bile-soluble; NF of the upper resp T; Viridans such as S. mutanssynthesize large polysaccharides (dextrans) contribute to dental caries.

Mechanisms that allow intracellular lifestyle in the mammalian host

The determinants which allow survival and growth of in the macrophage are not known However, Y. pestis has been shown to possess a two-component regulatory system called Pho/PhoQ which is associated with protection from macrophage killing mechanisms. The ability of Y. pestis to survive in macrophages is critical to the early pathogenesis of the disease.

Summary

The plague has a long history as a killer, and due to its notoriety can be used to inspire fear. The plague is a very real threat, and the USA is taking it very seriously, and steps are being taken to increase our defensive preparedness for such an attack. Perhaps the best thing that can be done is to have an early detection system, and scientists are rapidly making efforts to do just that.

The Oldest Bioweapon

The plague has a long history as an agent of biological warfare

evolution of y.pestis

There are 11 species of Yersinia 3 pathogenic species of Yersinia Yersinia enterocolitis -enteropathogen Yersinia pseudotuberculosis -enteropathogen Yersinia pestis-systemic pathogen Y. pestis evolved from Y. pseudotuberculosis 1500-15,000 years ago

Biovars of Y . pestis

There are 3 biovars of Y. pestis, each named for the pandemic that it is thought to have caused They are named based on their ability to convert nitrate to nitrite and ferment glycerolGlycerolNitrite Antiqua (1stpandemic)++ Medievalis (2ndpandemic) +-Orientalis (3rdpandemic)-+The 3 biovars exhibit no difference in their virulence or pathology in animals or humans.

Additional Dangers of Yersinia Pestis as a Weapon

There is no currently available pre-exposure prophylaxis or vaccine for plague Biological attack with plague might employ antimicrobial-resistant strains that circumvent clinical efforts to deal with the disease In 1995 a patient in Madagascar was found who had a Y. Pestis with a transferable multidrug resistance plasmid (natural) Additionally, there are reports that the bioweapons operations of the former Soviet Union engineered multidrug resistant and fluoroquinolone resistant Y. Pestis

Type III secretion system

Type III secretion system is upregulated at 37ºC, i.e. within the mammalian host .This system allows Y. pestis that are in contact with a macrophage to inject a range of effector proteins called Yersinia Outer Proteins (Yops) into the macrophage through a "syringe-like" apparatus. The Yops essentially function as a poison that destroys a macrophage's phagocytic and signalling capabilities, ultimately inducing its apoptosis.

Benefits of Treatment

Type of Plague 1.Untreated Fatality Rate 2.Fatality Rate with Treatment Bubonic 1. 50-90% 2. 5-20% Septicemic 1. 50-100% 2. 30-50% Pneumonic 1. 100% and death occurs rapidly usually within 48 hours of onset 2. Unknown (too few cases for accurate results)

importance of flea blockage

Unblocked, uninfected flea on the left (A) and blocked, infected flea on the right (B). •The ensuing blockage causes the starving flea to go into a "blood-feeding frenzy," in which it regurgitates the mass of Y. pestis and transmits it to a mammalian host. http://www.asm.org/ASM/files/CCLIBRARYFILES/FILENAME/0000000467/nw20030086p.pdf •Experiments indicate that only blocked fleas effectively transmit plague to mammals. •After flea feeds on Y. pestis infected blood, the bacteria enter the midgut of the flea, where it will grow and multiply, eventually forming a large mass that can lodge in the flea's foregut. During next meal, blood cannot enter midgut

Yops

When placed in environment that is around 37ºC and with a low Calcium concentration, Y. pestis ceases to grow and expression of Yops is induced. Altogether, there are 29 Yops but not all play a role in Type III secretion system. There are at least 6 Yops which directly contribute to the killing of a macrophage :Yops E, H, J, O, MYops B and D Required for pore formation in the macrophageLow Calcium Response V antigen (LcrV) Important for the activation of the Type III secretion system

Effectiveness of Y. Pestis as a Weapon

While antibiotic treatment of bubonic plague is usually effective, pneumonic plague is difficult to treat and often results in death regardless of treatment Most experts agree that "intentional dissemination of plague would most probably occur via an aerosol of Y pestis, a mechanism that has been shown to produce [pneumonic] disease in nonhuman primates...The size of the outbreak would depend on the quantity of biological agent used, characteristics of the strain, environmental conditions, and methods of aerosilization...people would die quickly following the onset of symptoms." -JAMA May 3, 2000 Vol 283, No. 17 In 1970, the WHO estimated that "if 50 kg of Y pestis were released as an aerosol over a city of 5 million, plague could occur in as many as 150,000 persons, 36,000 of whom would be expected to die." And this does not take into account the people who would die from secondary contraction of the disease. According to the CDC, "The fatality rate of patients with pneumonic plague when treatment is delayed more than 24 hours after symptom onset is extremely high."

Pathogenesis of plague

Within the bubo, by an unknown mechanism, the bacteria then escapes from the infected macrophages to adopt an extracellular lifestyle, where they further grow and replicate. The organisms, with their newly formed antiphagocytic F1 envelope, can now resist phagocytosis by the leukocytes. In addition, Y. pestis can actually kill macrophages with an apparatus called the Type III secretion system. Eventually, the infection can spill out into the bloodstream, leading to involvement of the liver, spleen, and lungs (which leads to 2°septicemicand 2°pneumonicdevelopment). 1°Septicemic Flea inserts directly into the bloodstream causing migration of y. pestis to organs 1°Pneumonic Inhaled Y. pestisbacilli would enter into lungs

Vectors

Xenopsylla cheopis(the oriental rat flea; nearly worldwide in moderate climates) •Oropsylla montanus(United States) •Nosopsyllus fasciatus(nearly worldwide in temperate climates) •Xenopsylla brasiliensis(Africa, India, South America) •Xenopsylla astia(Indonesia and Southeast Asia) •Xenopsylla vexabilis(Pacific Islands) ~30 identified flea vectors

Pathogenesis of plague

Y. pestis within the macrophages are then trafficked to the local draining lymph node. The massive infiltration of phagocytic cells within the lymph nodes cause them to become hot, swollen and hemorrhagic. This gives rise to the characteristic black buboes responsible for the name of this disease.

molecural biology of yersinia pestis

characteristics Biovars of y.pestis Evolution of Y. Pestis pathogeisis of plague

pneumonic plague transmitted by

cough, sneezing, inhaled by

Bubonic plague symptoms

incubation period 2-6 days ' Fever 100% Headache 85% Severe exhaustion 75% Vomiting 25-49% Altered mental status 38% Abdominal pain 18% Cough 25% Skin rash 23% 2º septicemic plague 23% 2º pneumonic plague 5-15%

epidemiolgy

the bodies were left everywhere becuase they didnt have a way to take them out, the bodies just started decomposing and becoming time bombs, spreading the virus further when people stepped the decomposed bacteria and liquids X0

septicemic plague signs

the toes, fingers and nose and lips turn black as the skin dies.

Modes of transmission

•*BITES FROM FLEA VECTORS* •Direct contact with infectious body fluids or tissues while handling an infected animal (which can be dead or alive) •Ingestion of raw or uncooked meat from an infected animal (marmots, prairie dogs, goats, camel) •Inhalation of infectious droplets

the 3rd pandemic hongkong/china

•Beginning in the Yunnan province of China in 1885, the 3rdpandemic spread to all inhabited continents excluding Australia •It spread to Canton and Hong Kong in 1894 and Bombay in 1898 •By 1900, it had spread via steamship to the rest of the world •By 1903, India was losing an average of 1 million people per year •Ultimately, it killed more than 12 million people in India and China alone in the period from 1898-1918 •Small outbreaks of plague continue to occur as a result of the stable enzootic foci found round the world from the 3rdpandemic (except, of course, in Australia) •This pandemic was the least severe of the three due to understanding its nature and the advent of effective public health measures (100→25→12 million) •Most importantly, antibiotics were discovered during this outbreak, and some patients were actually cured, which is why it is sometimes referred to as the modern pandemic

Bubonic transmission

•Bites from flea vectors •Bites or scratches from infected animals, such as cats •Direct contact with infected animal carcasses, such as rodents (especially marmots), rabbits, hares, carnivores (eg, wild cats, coyotes), and goats

Pathogenesis of plague(focus on Bubonic plague)`

•Colonization of Y. pestis in the flea •Transmission of the Y. pestis from flea to mammalian host. A flea bite transfers 25,000 -100,000 organisms to host. •While growing in the flea, Y. pestisloses its antiphagocytic F1 capsular layer (inactivated at lower temperatures), and so many of the pathogenic organisms are phagocytosed and killed by mammalian leukocytes. •However, not all engulfed Y. pestis are killed. Bacteria that are ingested by neutrophils appear to be readily killed, but bacteria within macrophages are able to survive. •The macrophages provide a protected environment for Y. pestis to resynthesize their F1 capsular layer and other virulence antigens (activated by the warm 37ºC body temperature). The ability of Y. pestis to survive and grow in macrophages is critical to the early pathogenesis of plague.

Signs and Symptoms(Septicemic Plague)

•Complications •Hemorrhagic changes in skin called "purpuric lesions" •Disseminated intravascular coagulation (DIC) •Extremity gangrene •It is the blackened gangrene characteristic of advanced septicemic plague that gave the pandemic of Medieval Europe the name "Black Death."

Signs and Symptoms Pneumonic Plague

•Incubation period of 1-3 days •Productive cough •Hemoptysis •Rapid, shallow breathing •Cyanosis •Nausea and vomiting •Abdominal pain •Chest x-ray with alveolar infiltrates

Discovery of plague bacterium

•June 1894: Alexandre Yersin successfully isolates the plague organism which he calls Bacterium Pestis. Kitasoto makes the same discovery independent of Yersin; however, his data shows discrepancies, thus Yersin is credited. He develops a treatment (an antiserum) to combat the disease and cures a plague patient in 1896 He is the first to suggest that it may be caused by the rodent/flea pathway, and he also identifies the black rat as the reservoir for the Manchurian outbreak 1897: Masanori Ogata and Paul-Louis Simond independently discover the role of the flea in plague transmission 1910: W.M. Haffkine demonstrates the efficacy of his vaccine Post-1911: L-T. Wu recognizes the Manchurian outbreak as the pneumonic form and establishes measures to prevent the spread of disease via aerosolization 1970: After 3 name changes, plague bacterium is renamed Yesinia Pestisin honor of Alexandre Yersin

the tree plague pandemics

•Justinian's Plague (~540-700AD) •The Black Death (1346-1350) •The China Epidemic (~1855-1908) AKA "The Modern Pandemic"

signs and symptoms of bubonic plague

•Pain/tenderness at regional lymph nodes enlarge to become "buboes" •Extremely painful •occur in groin , axilla or cervical areas •Ulcer or skin lesions at site of flea bite in <10% of cases

The black death

•The 2ndpandemic is thought to have originated in the Gobi desert in the 1330's where the bacillus was active and abundant •China was a major player in trade, thus it took less than a decade for the plague to spread across western Asia and into Europe •In Oct 1347, Italian merchant ships returned to Sicily from a trip to the Black Sea, and by the time they docked, many of the merchants were already dying from the plague •It is believed to have been spread via fleas embedded in the fur they traded •By the following August (1348), it spread all the way north to England •The disease lay dormant in winter (due to flea inactivity), but within 5 years of its onset, 25 million people were killed in Europe (1347-1352) •25 million = 1/3 of the population; however, these numbers could be askew due to the presence of other diseases that may have assisted in depopulation of Europe •After the first 5 yr cycle, the death toll lessened; however, for the next 130 years, outbreaks occurred in 2-5 year cycles •A period of rest was seen from 1480-17thC., then the Great Plague struck killing ~100,000 more people in London •The plague caused major political, cultural, and religious ramifications •It is also responsible for the introduction of hospitals as care centers rather than quarantine locations as it catalyzed the movement toward more effective health care and a cleaner, healthier style of living •17th Century London(plague locations + death toll in London)

Justinian's Plague

•The first recorded and confirmed pandemic •Occurred during the reign of the Roman Emperor Justinian •It spread from Egypt through the known world •Population losses of 50-60% occurred in North Africa, Europe, and central and southern Asia for an approximate total of 100 million deaths Justinian the Roman Emperor

20th century plague .2

•There are 7 countries that have been affected by plague every year: Brazil, Democratic Republic of the Congo, USA (with the exception of 1955, 64, 68), Madagascar, Myanmar, Peru, and Vietnam •There have been three periods of increased plague activity from 1954-97: 1) During the mid-60's 2) Between 1973-19783) mid-80's-present •The rise of reported plague morbidity has increased worldwide in the 90's, especially in Africa GEOGRAPHICAL SHIFTS: ASIA→AMERICAS→AFRICA •In the 1950's, plague was a problem primarily in Asia, with little activity in the Americas •By the early 60's, plague activity in the Americasincreased, and in Africa, it began to play a role •The mid-60's-early 70's show a magnificent increase in plague activity in Asia which is primarily due to the Vietnam War •For the past 15-20 years (since~1982), a dramatic rise in activity can be seen for Africa

20th century plague

•World Health Organization reports ~ 1000-3000 cases/year worldwide w/ an average of ~1700/yr •For the period of 1954-1997, a total of 80,613 cases were reported with 6,587 deaths •The maximum number of reported plague cases (6004) occurred in 1967 and the minimum (200) occurred in 1981 •This is vastly underreported due to lack of proper surveillance and laboratory capabilities in many countries •There are only 38 countries that report plague activity •Generally occurs in rural areas where enzootic foci and rodent populations abound (L.A. outbreak in 1924 was last urban outbreak)

Incidental Hosts

•humans •Domestic and feral cats •Dogs •Lagomorphs (rabbits and •hares) •Coyotes •Camels •Goats •Deer •Antelope *http://www.cidrap.umn.edu/cidrap/content/bt/plague/biofacts/plaguefactsheet.html#_Reservoirs/Vectors/Modes_of_Transmissio