Download The Plague

The Plague
(Y. Pestis)
Eti Mezei, Elodi Dielubanza, Clara Boyd
Overview - 3 Types of Plague
Bubonic
Pneumonic
- Most common form
- Generally secondary
complication of
- Responsible for most bubonic plague
though can be a
plague epidemics
primary infection
- Diagnosis is more
difficult
Septicemic
- Generally secondary
complication of
bubonic plague
though can be a
primary infection
- Poses the greatest
burden to the human
system of the 3 types
- Easily communicable
All types of plague are caused by the gram-negative bacteria Yersinia
Pestis
Epidemiology
Historical & Modern Aspects
Reservoirs, Vectors
Transmission
World History
Discoveries
Modern Plague
Trends in the USA
Reservoirs & Vectors
Reservoirs
Vectors
Urban and
domestic rats
Ground squirrels
Rock squirrels
Prairie dogs
Deer mice
Field mice
Gerbils
Voles
Chipmunks
Marmots
Guinea pigs
Kangaroo Rats
Xenopsylla cheopis (the oriental rat Humans
flea; nearly worldwide in moderate
Domestic and feral
climates)
cats
Dogs
Oropsylla montanus (United
States)
Lagomorphs
Nosopsyllus fasciatus (nearly
(rabbits and hares)
worldwide in temperate climates)
Coyotes
Xenopsylla brasiliensis (Africa,
Camels
India, South America)
Goats
Xenopsylla astia (Indonesia and
Deer
Southeast Asia)
Antelope
Xenopsylla vexabilis (Pacific
Islands)
Incidental Hosts
Modes of Transmission
■ Fleabite
■ Inhalation of salivary droplets of infected humans
or cats
■ Cat’s scratch
■ Ingestion of the bacillus
■ Contact with infected body fluids
Transmission & Type of Plague
1
Bubonic
Septicemic
Y. Pestis enters the
lymphatic system
through the skin
Direct inoculation of Y. Direct inhalation or
Pestis into
ingestion of Y.Pestis
bloodstream
Bite from infected flea
2
-----------------
Bite from infected flea;
Scratch from infected
cat; Contact with
Infected Fluids
As a complication of
bubonic or 1
pneumonic plague
Pneumonic
Inhaling droplets from
cough of infected
human/cat; Eating
infected animal; Inhaling
Y. Pestis in the lab
Via hematogenous
spread, as a
complication of
bubonic or septicemic
plague
Transmission Cycles
Plague and World History

1320 B.C. -- 1st mention of plague is in the Bible
Philistines stole the ark of the covenant from the
Israelites and plague ensued:
[t]he Lord’s hand was heavy upon the people of Ashdod and its vicinity. He
brought devastation upon them and afflicted them with tumors. And rats
appeared in their land, and death and destruction were throughout the
city…[T]he Lord’s hand was upon that city, throwing it into great panic. He
afflicted both young and old with and out break of tumors in the groin.
Plague and World History
541-700 A.D. – 1st Pandemic, Justinian Plague
■ Began in Pelusium Egypt and
spread to the middle East
& Europe with estimated population
losses of 50-60% in N. Africa,
Europe & S. Asia.
■ A.D. 558-654: The 2nd through 11th epidemics occurred
in 8-12 year cycles.
Plague and World History
1346-1666 – 2nd Pandemic, Black Death

Plague believed to have entered Europe along trade
routes from central Asia by fleas in bundles of imported fur.

1347-1351: 1st 5-year epidemic killed an estimated 17-28
million people, 30-40% of Europe’s population at the time.

Epidemics continued throughout the period in 2-5 year cycles
until 1480 and then with less frequency until late 17th century.

The plague stimulated significant
advance in medical practice including
the beginnings of clinical research,
reorganization of hospitals.
A Plague Doctor
NOTE: other epidemics existing at the time of the 1st and 2nd Plague pandemics may
have contributed to depopulation figures
Plague and World History
1855 – 3rd Pandemic, China
■
Began in the Yünnan province and troops from the war in that area
helped to spread plague down the southern coast to Hong Kong and
Canton by 1894 and Bombay by1898.

By 1900 steamships had helped to spread the disease to Africa,
Austrailia, Europe Hawaii, India, Japan, the Middle East, the
Phillipines, the U.S, and S. America. By 1903, 1 million people/year
were dying of plague in India.
Mukden, China, 1910-11:
Workers in a plague
hospital hose off an autopsy
table with carbolic spray
Plague and World History
1855 – 3rd Pandemic, China (cont’d)

Stable enzootic foci were established on every inhabited continent
except Austrailia and outbreaks continue until today though greatly
reduced because of advances in public health practices and drugs.

Significantly, it is during the 3rd Pandemic that the bacterium
responsible for plague as well as its vectors and reservoirs were
identified.
History of Yersina Pestis

First discovered in 1894 during the Hong Kong Plague by two
independent investigators (Alexandre Yersin and Shibasaburo
Kitasato) within days of each other.

Kitasato was initially credited for the discovery but Yersin’s bacillus
proved to be the infecting bacillus.

Yersin drained buboes of deceased plague victims and identified the
bacillus with microscopy.

Confirmed the involvement of the bacillus in infection by injecting
healthy rodents with infected lymph isolates. Healthy animals
developed plague symptoms and dissection showed blood and
organs to be filled with the isolated bacillus.
Y

Nomenclature: the plague bacillus has had four name
changes.
Classifications:
Bacterium Pestis until 1900
Bacillus Pestis until 1923
Pasturella Pestis (after Yersin’s mentor)
Yersinia Pestis in 1970 until present day
Identification of Vectors and
Reservoirs
■ Yersin also confirmed the Black rat (Rattus rattus) as the
reservoir after local suspicion implicated its involvement in
the transmission of the plague.
■ In 1897 during the Indian outbreak, Paul- Louis Simond
and Masanori Ogata identified the oriental rat flea
(Xenopsylla Cheopis) as the transmission vector by
exposing healthy rodents to fleas collected from the
corpses of rats which had died recently from plague.
Early Prevention and
Treatment Methods

Yersin isolated serum from horses immunized with the
bacillus for treatment of human plague in 1896.

W.M Haffkine created and used an effective
preventative vaccine for the Plague containing killed
bacteria during the Manchurian outbreak (1910).

L.T Wu characterized pneumonic plague during the
1910 Manchurian outbreak and helped to institute
protective measures against aerosol spread of the
disease.
Modern Plague

For most of the 20th century the occurrence of plague
has sharply decreased though not disappeared. Plague
remains an enzootic infection of rats, ground squirrels
and other rodents in every inhabited continent except
Austrailia.

Why has Plague decreased so sharply?
The WHO credits public health prevention protocols and
the development of effective antibiotics.
Modern Plague

WHO reports 1000-3000 cases of plague worldwide annually
(avg.1700cases/year for the last 50 years) (conservative estimate)

Plague is largely underreported in countries with limited surveillance
and laboratory capabilities.

Modern plague is primarily occurrent in rural areas with poor
sanitation and large rodent populations.

Urban cases are increasingly rare. Los Angeles1924 was the last
U.S urban outbreak.
Modern Plague - Distribution
* largest enzootic foci are in the Southwestern &Pacific U.S and the
former USSR.
Modern Plague –
# Cases Reported to WHO 1954-1997
Modern Plague - Timeline

1900 - Plague officially arrives in the U.S. Infected corpse of
Chinese Laborer found in San Francisco hotel basement.

1924 - Los Angeles. 33 cases, 31 fatal. 1st case, Mexican
American male, misdiagnosed with STD, family and neighbors
contract plague and die with in two weeks. Many die before public
health measures were taken.

1967-72 - Vietnam. Defoliation, disturbance of the ecosystem and
economic losses during the war contributed to outbreak. Singular
contributor to the 1967 jump in worldwide plague vases.

1992 - Arizona. 1 confirmed case, 1 fatality. Misdiagnosis of
pneumonia. Post-mortem lab tests confirmed Y. Pestis. Family
cat identified as source.
Timeline Cont’d
■
1994 – India.
Bubonic plague begins when rats arrive
because of stockpiles of relief grain.
Pneumonic form shortly follows.
5150 suspected pneumonic and bubonic
cases from 26 states. 163 confirmed with
serology, 53 confirmed deaths, 300
suspected.
Mass panic; 600,00 flee Surat including 110
plague cases.
Timeline Cont’d
■ 1997
Zambia- Jan. Namwala region 90 cases of bubonic plague, 22 fatal.
Heavy rains drove rats into inhabited regions.
Mozambique - Aug. Tete province. 115 reported cases of bubonic.
No reported deaths.
Malawi - Oct. Southern region, 43 reported cases, 17 of which were seropostive.
>60% cases were children. No reported deaths.
Mozambique - Nov. August outbreak continues and extends to 225 cases.
No reported deaths.
■ 1999
Namibia - May Northwest region, 39 reported cases, 8 deaths.
Malawi - July Reported cases in 22 villages, 74 suspected cases total.
No reported deaths.
Timeline Cont’d
■ 2001
Zambia - Mar. Nyanje and Petauke regions 436 suspected cases,
11 deaths. Y. Pestis postively identified.
■ 2002
India - Feb. Hat Koti village. 16 cases of pneumonic plague
including 4 deaths. Cases linked to one villager.
Malawi- June. Nsanje region and 26 nearby villages. 71 reported
cases of bubonic plague.
■ 2003
New York - Nov. 2 cases. Couple contracts plague in Santa Fe, NM
and travels to New York. Neither case fatal but man required
double foot amputation.
Plague Patient Returns Home
NEW YORK, Feb. 10, 2003
A New Mexico man who was hospitalized in
New York City for more than three months
with bubonic plague left the hospital to fly
home on Monday, a spokesman said.
John Tull left Beth Israel Medical Center at
about 7 a.m., hospital spokesman Mike
Quane said. Tull was admitted to Beth Israel
on Nov. 5.
Tull, whose feet were amputated due to
extensive tissue damage, will begin physical
therapy in Albuquerque, N.M., Quane said.
John Tull at the Beth Israel
Hospital in New York City with his
wife Lucinda Marker.
Disease investigators believe Tull and his
wife, Lucinda Marker, contracted plague from
infected fleas on their Santa Fe, N.M., ranch.
They became ill after arriving in New York on
Nov. 1 for vacation.
CBSNEWS.com
Trends in Human Plague
in the U.S.

From 1899-1926 Plague in the U.S. was an urban
epidemic involving domesticated rats with cases most
prevalent in California and Hawaii.

Late 1940’s saw a jump in infection in the Southwestern
states which remain hotspots for infection.

Static annual infection levels from 1925-1964 (avg.<2
cases/year). 1965 saw increases that would carry into
the 80’s.
Trends in Human Plague
in the U.S

Seasonal distribution: 1926-1979 81.5% of plague cases
occurred in May-September. Prior to 1926 most were
Sept.-Oct.

1970-1980
53% cases ♀
59% were < 20 years old.
Similar age distribution from 1926-1969

Racial dist.: 1970-79 35% of cases were in Indians (1.4
Indians per 100,00 compared to 0.1non-Indians).
Simplified Pathogenesis
(Focus on Bubonic Plague)
Pathogenesis
“Blocked” Flea
Flea feeds on Y. Pestis-infected blood
Y. Pestis enters flea’s midgut & multiplies
logarithmically
Clump of Y.Pestis & fibronous material forms
in the midgut,
blocking flea’s proventriculus
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
Pathogenesis
ENTRY:
Flea bite -- regurgitation of blood
containing Y. Pestis
(≈ 25,000 -100,000 organisms) into
interstitial space of subcutaneous
tissue
DISSEMINATION:
Superficial lymph vessels drain skin
& subcutaneous tissue --Y. Pestis
enters the lymphatic system
Pathogenesis
DISSEMINATION:
Y. Pestis migrates through lymph
vessels to regional lymph node
Massive inflammatory response obliterates
underlying lymph node architecture -leads to painful swellings (Buboes)
Pathogenesis
HEMATOGENOUS DISSEMINATION:
Y. Pestis may enter the blood stream
at the lymph node, and can then travel
to other organs (liver, spleen).
(= 2 Septicemic Plague)
HEMATOGENOUS DISSEMINATION:
Once in the bloodstream,
Y. Pestis also has the opportunity
to enter the lungs.
(2 Pneumonic Plague)
Molecular Biology
of Yersinia Pestis
Bacteriological Characteristics
Evolution
Biovars
Genome
Molecular Pathogenesis
Proteins/Virulence Factors/
Immunology
Bacteriological Characteristics

Gram negative

Non-motile

Enterobacteriacae

Non-spore forming
coccobacillus

Facultative anaerobe

Obligate parasite
Bacteriological Characteristics

.5-.8 uM in diameter

1-3 uM long

Grows optimally at 28° C
and a pH of 7.2-7.6

Bacterial cell wall

Protein Envelope (F1)
Evolution of Y. Pestis
There are 11 species of Yersinia
3 pathogenic species of Yersinia


Yersinia Pseudotuberculosis - enteropathogen
Yersinia Enterocolitis - enteropathogen
Yersinia Pestis - systemic pathogen




Y. Pestis evolved from Y.pseudotuberculosis
1500-4000 years ago


90% chromosomal DNA relatedness
Physiological and antigenic similarities
Y. Pseudotuberculosis

Disease
 Enteric infection

Transmission
 Enters mammals through
food and water

Genes
 YadA, Inv, O antigen

Extrachromosomal DNA
 pCD1
Y. Pestis

Disease
 Bubonic Plague

Transmission
 Flea, mammal, never
found in free environment

Pseudogenes
 YadA, Inv, O antigen

Extrachromosomal DNA
 pCD1
 pFra
 pPst

Pathogenicity Islands
Biovars of Y.Pestis

3 biovars named based
on their ability to convert
nitrate to nitrite and
ferment glycerol



Glycerol
Antiqua (1st pandemic)
+
+
Medievalis (2nd pandemic)
Orientalis (3rd pandemic)
Nitrite
+
+
Genome

4500 genes

One chromosome- 4.6Mb
 Pathogenicity islands (pgm locus)

Three plasmids
 pFra – 96.2 kb
 pPst1- 9.7 kb
 pCD1- 70.3kb
Chromosome Pgm locus

102 kb pathogenicity island in the chromosome

contains three hemin storage genes (Hms)



These genes only found in Y.pestis
They are essential for flea blockage
Allow Y. Pestis to store large quantities of hemin (iron source) in its outer
membrane

Bacteria requires iron in order to cause infection

An inorganic iron transport system (ybt) (a sidephore) is
encoded within Pgm locus

Ybt chelates iron bound to eukaryotic proteins and
transports them to the bacterium
pFra

60-280 kb (depending on the strain)

Found only in Y. Pestis

Contains gene for murine toxin (Ymt)

Two forms of a protein toxic for mice and rats

Proposed as B-adrenergic antagonist

Ymt transcription is threefold higher at 26°C(flea) than at
37°C(mammal).

This gene is believed to be essential for flea colonization
pFra

Contains structural and regulatory genes that
encodes F1 protein capsule (caf1)

F1 is a proteinacious capsule that forms at 37°C
(mammal) but not 26°C (flea)

F1 capsule makes bacterium resistant to
phagocytosis by monocytes

Resistance to phagocytosis by monocytes allows
journey from dermis to viscera