The Plague - Yersinia pestis

Question 1

What is the Yersinia sp?

Answer 1

3 human pathogenic Yersinia species

Yesinia pestis
= the plague

Yersinia pseudotuberculosis
= far east scarlet-like fever
= self limiting acute gastroenteritis
= mesenteric lymphdenitis that mimics acute appendicitis

Yersinia enterocolitica (yersiniosis)
= fever, abdominal pain, bloody diarrhoea
= symptoms develop 4-7 days after exposure
= may last 1-3 weeks (or longer)

Question 2

What is Yersinia pestis?

Answer 2

= γ-proteobacterium (4.6-4.65 Mb genome)

= aerobic gram negative bacillus or coccobacillus

= non-motile

= non-sporulating

= grows within 24 to 72 hr at 4-40 oC
(optimum 28-30 oC at pH7.4)

= exhibits numerous insertion sequences, intragenomic recombination and lateral gene transfer events + remnants of an enteric life cycle

Question 3

What are the symptoms?

Answer 3

Bubonic plague
= most common type
= causes buboes (swollen, painful lymph nodes under arms, in neck /groin)
= without treatment, bacteria can spread to other parts of the body
= 60-70% fatality rate

Septicemic plague
= more dangerous type
= bacteria moved into blood
= bleeding under skin from mouse, nose, anus
= blackened skin on nose, fingers, toes
= abdominal pain, diarrhoea, vomiting and shock
= 100% fatality rate

Pneumonic plague
= rarest form (5-10%)
= fatal without treatment
= bacteria in lungs
= very contagious via aerosols
= cough, sometimes with blood
= trouble breathing
= nausea and vomiting
= 100% fatality rate

Meningitis Plague
= 10% of people with bubonic plague will develop plague meningitis
= stiff neck, fever, headache, coma

Question 4

What was the evolution of Yersinia pestis?

Answer 4

Spread since ancient times
(e.g. plague of athens, antoinine plague, the great plague)

Re-emergic of pneumonic plague in Madagascar
= 1954-2018

Consensus that bubonic plague was first, followed by evolution of pneumonic plague

Y.pestis evolved from GI pathogen: Y. pseudotuberculosis

Modern strains acquired single gene encoding protease: Pla
= optimises protease activity
= BUT unnecessary for pneumonic plague
= needed for inducing invasive infection associated with bubonic plague
(indicated Y. pestis was capable of causing pneumonic plague before evolving further

Question 5

What are the environmental transmission / reservoirs?

Answer 5

Reservoirs
= soil (virulent up to 285 days)
= protozoa (Dictyostelium discoideum, Acanthamoeba castellani)
= animals (200 species - mainly rodents)

Transmission
= soil to animals
= flea-borne to animals and humans
= aerosols (person to person)
= food / meat handling

Question 6

What is the life cycle of infection?

Answer 6

1. Flea life cycle
   = fleas lay eggs in moist soil of rodent burrows
   = larvae feed on rodent faeces, develop into fleas
   = adult fleas parasitise rodents and become infected with Y. pestis
2. Enzootic cycle
   = rodents act as hosts and reservoirs for Y. pestis, vectored by fleas
3. Epizootic cycles occur when fleas infect mammals which are not natural hosts of Y. pestis
4. Newly infected mammals spread plague to new areas BUT die from Y.pestis
5. Humans can become infected via flea bite
6. Bubonic plague can develop into pneumonic plague = direct transmission between humans

(may be additional step in transmission)
= addition of pPCP1allows colonisation of flea gut
= Y. pestis persists longer during transmission

= Y. pestis is associated with Amoebae

Question 7

What are some factors affecting re-emergence?

Answer 7

Resistance of rodents
= low resistance = fleas jump to new host including humans
= high resistance = act as reservoir

Resistance of fleas to insecticides

Resistance of Y. pestis to antibiotics

Rodent distribution
= urbanisation
= deforestation

Social inequality

Cultural behaviour
= ritual exhumation

Question 8

What are the 3 plasmids in the Y. pestis CO92 reference strain?

Answer 8

= (biovar Orientalis) = contains 3 plasmids

Plasmid 1
= designated pCD1, pYV
= common to the three human-pathogenic Yersinia species
= encodes:
a. type III secretion system (T3SS)
b. Yersinia outer proteins, or Yops (prevents host’s immune response)
c. the V antigen (LcrB) (implicated in immunosuppressive activity)
d. Yersinia bactin siderophore system gene (ybt) (acquires iron from blood)

Plasmid 2
= designated pFra, pMT1
= encodes:
a. capsular F1 glycoprotein antigen
b Yersinia murine toxin Ymt - allowing survival of Y. pestis in flea gut

Plasmid 3
= designated pPla / pPCP1
= encodes:
a. plasminogen activator Pla a = major virulence factor promoting systemic spread from peripheral sites
b. pesticin, a bacteriocin

= plasmids contents can be altered by successive subcultured

= additional plasmids have also been characterised
(plasticity and ongoing evolution of Y. pestis)

Question 9

How does Y. pestis spread within body?

Answer 9

Bite may provoke discrete local inflammation at skin portal of entry
= spreads via lymphatic route towards regional lymph nodes
= pathogen growth results in development of bubo

Y. pestis further spreads via lymph and blood vessels to spleen and liver
= causes rapidly fatal speticemia
= dissemination in the lungs (= secondary pneumonic plague)
= to meninges and CSF (= meningitis)

Blood dissemination of bacteria
= may cause intravascular coagulation and endotoxic shock

Y. pestis rapidly multiplies in tissues
= protected from immune system by serum resistance
= evasion of innate function
= including neutralisation of immune cells , mediated by T3SS (encoded by pCD1 plasmid)

= Y. pestis is facultative intracellular bacterium that multiplies in macrophages

Question 10

How does Y. pestis obtain virulence?

Answer 10

Requires 3 virulence plasmids
= pYV/pCD1
= pPla/pPCP1
= pFra/pMT1
(+ chromosomally encoded virulence factors)

Cytoplasmic, cell-surface associated + secreted virulence factors
= adhesion to host cells mediated by Braun lipoprotein Lpp and protein (e.g. Ail, PsaA, Pla)

Yop effectors
= delivered through T3SS to trigger apoptosis, inhibit phagocytosis and block cytokine production
= e.g Yop H,E,T,J,A,M,K

LPS modification and the capsular antigen F1
= encoded by caf gene
= further contribute to Yersinia immune escape

Expression of virulence determinants
= induced during transition from temperature of flea midgut (26oC) to mammalian host (37oC)

Y. pestis survival in host requires efficient metal acquisition systems
= yersiniabactin-dependent iron uptake system is encoded in high-pathogenicity island within pigmentation chromosomal locus pgm

Other metal transport systems
= e.g. YbtX, ZnuABC, Yfe and Feo
(play role in infection)

Additional virulence factors
= e.g. YMPY1.66c, Brn1, RbsA, GspE (+ more)

Question 11

What are some medieval cures?

Answer 11

Vicary method

Treacle

Leeches

Spoonful of emeralds

Human excrement paste

Bathing in urine

Question 12

What are current cures / prevention?

Answer 12

Cure
= Antibiotics
(e.g. Ciprofloxacin, Doxycycline, Gentamicin, Levofloxacin)

Prevention
= Isolation
= Flea control (contact with animals / repellents)
= Vaccine
(inactivated / attenuated)
(not yet licensed in many countries)