Emerging and re-emerging infectious diseases

Question 1

why is the prevalence of infectious diseases constantly changing?

Answer 1

due to changes in the pathogen, the environment and the host population
- Some of these changes result in the identification of apparently “new pathogens”, sometimes after an epidemic outbreak for the first time
- BUT the pace of identification of serious “new” pathogens increased dramatically in the 20th century and now we have the problem of the re-emergence of infectious diseases that were formerly well controlled

Question 2

what factors are responsible for the emergence of new pathogens and the re-emergence of old pathogens?

Answer 2

1. globalisation and environmental changes
2. new ways of growing and handling food
3. natural disasters
4. breakdowns in public health
5. changes in pathogens
6. recognition of new pathogens

Question 3

how has globalisation and environmental changes led to the emergence and re-emergence of pathogens?

Answer 3

• Increased urbanisation in tropical countries has led to massive increases in insect-borne viral diseases like Dengue virus – easy to transmit due to close contact.
• Clearing forests in Africa has led to the re-emergence of Ebola virus by new zoonotic transfer to humans as people come in contact with infected apes more frequently, and then return to cities where spread occurs fast
• Climate change (global warming) allows vector-borne diseases to spread into new areas.
• Increased international travel and commerce - Long-haul flights with air re-circulation may lead to transfer of respiratory diseases, and transport disease from one part of world to another very quickly and cheaply

Question 4

how has new ways of growing and handling food led to emergence and re-emergence of pathogens?

Answer 4

• “New” food-borne pathogens like Campylobacter, E. coli 0157 and other strains take advantage of modern high-volume meat production methods and inadequate cooking.
• Food production is so fast that it is difficult to control spread of pathogen - industrialisation means spread of infection is far easier
• Unwashed veg are a major cause of spread of pathogens to humans, as infected animal faecal matter may get on lettuce leaves - major cause of diarrhoea infections
• More examples of increased zoonotic transfer of pathogens from animals to humans is occurring (e.g. COVID-19)

Question 5

how have natural disasters lead to emergence and re-emergence of pathogens?

Answer 5

• Earthquakes, floods, tsunamis, political upheaval etc. will lead to outbreaks of many otherwise well controlled diseases.
• war in Syria led to breakdown of their healthcare system
• Without clean water, cholera will become a problem e.g. Haiti earthquake
• Inadequate takeup or effective vaccination programmes will lead to outbreaks – Diphtheria and whooping cough rates increase after natural disasters or civil wars etc

Question 6

how have breakdowns in public health led to emergence and re-emergence of pathogens?

Answer 6

In the UK, the MMR (measles-mumps-rubella) vaccine scare led to lower uptake of the vaccine and outbreaks of measles

Question 7

how have changes in pathogens led to their emergence and re-emergence?

Answer 7

• Development and spread of antibiotic resistance has been increasing and is now a major problem for treatment.
• High mutation rates in some viruses (HIV).
• Acquisition of novel toxin genes by specific bacterial strains, from other bacteria, gain of virulence.

Question 8

what is an example of a re-emerging pathogen/disease?

Answer 8

Some “old” diseases have been discovered to be caused by “new” pathogens (e.g. Helicobacter pylori)

Question 9

what is an example of an emerging pathogen/disease?

Answer 9

epidemic outbreaks of new diseases are attributed to previously unknown pathogens (e.g. Legionella pneumophila)

Question 10

what is Lyme disease?

Answer 10

• caused by Borrelia burgdorferi
• sourced by Tick bites
• re-emergence via increase in deer and human population
• flu-like symptoms, rashes

Question 11

what does Campylobacter cause?

Answer 11

most common cause of infectious diarrhoea worldwide due to people not cooking things properly
- Enteritis

Question 12

what does E. coli 0157 cause?

Answer 12

E. coli 0157 strain causes serious diarrhoea, as it picked up Shiga toxin from Shigella, causing kidney failure
- acquisition of toxin

Question 13

why is there an increased incidence of TB today?

Answer 13

• M. tuberculosis re-emergence is caused by more immunosuppressed individuals in the world
• 2 billion people are asymptomatically infected with TB (senescent) which can be reactivated in a small %
• Where TB is endemic in Africa, HIV infection incidence is highest
• Those immunosuppressed with HIV have a larger chance of TB reactivating

Question 14

what does Helicobacter pylori cause?

Answer 14

gastritis
gastric ulcers
duodenal ulcers
gastric cancer

Question 15

how was H. pylori discovered to be causing gastric ulcers?

Answer 15

• before 1980s, it was thought ulcers were cuased by diet, stress and genes
• in early 1900s, a spiral-shaped bacteria was seen in human stomach, but was not cultivated successfully
• 1983: Warren and Marshall discovered association between spiral bacteria and gastric ulcers, as they isolated and grew the bacteria in pure cultures
• after 1983, people didnt believe bacteria could cause ulcers due to stomach acid, so Marshall drank a culture of H. pylori and developed acute gastritis - confirmed Koch’s postulates

Question 16

what is Helicobacter pylori?

Answer 16

The bacteria seemed similar to campylobacters and they originally called these bacteria “Campylobacter pyloridis”. Subsequently reclassified as Helicobacter pylori
- Spiral shaped rod with polar flagella
- Flagella end in distinctive bulb shapes – unique to Helicobacter

Question 17

how is Helicobacter pylori cultured?

Answer 17

prolonged incubation on rich media in an atmosphere of low oxygen and increased carbon dioxide

Question 18

is human infection of Helicobacter pylori common?

Answer 18

Human infection is common – up to 30% prevalence in western countries and up to 80% or more in developing countries

Question 19

what are the properties of helicobacter pylori?

Answer 19

• Gram-negative spiral shaped bacterium, closely related to Campylobacter. H. pylori only found in humans, but various animals have their own species, e.g. H. felis (cat), H. canis (dog).
• A fastidious bacterium with complex nutritional requirements and a small genome (1.7 Mb) typical of a highly host-adapted bacterium – relies on host to survive
• It is microaerophilic – cannot grow at 21% oxygen, and must be cultivated at 5-10% oxygen and 5% carbon dioxide.
  -Cannot grow outside a human host – transmitted person-to-person, often mother to baby in families, but exact details of transmission still unclear.
• Highly motile and chemotactic – polar flagella
• Produces a highly active and abundant UREASE enzyme (nickel cofactor)
• Urease protects against stomach acid

Question 20

how does the urease enzyme of Helicobacter pylori help its survival in the host?

Answer 20

urease can degrade urea to ammonia and CO2
- Urea -> NH3 (alkaline) + CO2
- Alkaline of ammonia protects Helicobacter against stomach acid

Question 21

what is Helicobacter pylori mechanism of pathogenesis?

Answer 21

1. When it reaches mucosal epithelia of the stomach, the Helicobacter can sense the nutritional gradient at the epithelia
2. Helicobacter swims through the mucus towards the nutritional environment of the epithelia, using their polar flagella and corkscrew shape
3. At the epithelial cell surface, Helicobacter secretes urease enzyme to neutralise the gastric acid and protect themselves in the viscous mucus
   - Maintains comfortable environment proximal to epithelium
4. They grow here and form colony on epithelial surface
5. they produce enzymes to degrade mucin for nutrients like proteins and carbohydrates
6. This results in a gap forming in the mucus layer, enabling the stomach acid to reach the epithelium and cause stomach ulcer
   - Stomach acid eats lining of the stomach
   - If untreated, can perforate the stomach and kill the patient

Question 22

what is the pathogenicity island of H. pylori?

Answer 22

H. pylori has a pathogenicity island that encodes a vacuolating cytotoxin (VacA) and a type IV secretion system (TFSS)

Question 23

what is the role of VacA in Helicobacter pylori?

Answer 23

VacA is a pore forming toxin with multiple effects
- it punches holes in epithelial cells to leak nutrients for the bacteria to use
- induces apoptosis of epithelial cells, leading to damage

Question 24

what is the role of the type IV secretion system (TFSS)/CagA of Helicobacter pylori?

Answer 24

TFSS acts like a syringe to inject proteins into host cells
CagA is an effector protein that is injected into epithelial cell and remodels the host cell cytoskeleton and impacts many signalling pathways

Question 25

what are the 3 possible outcomes for someone infected with H. pylori?

Answer 25

1. 80% of people who carry Helicobacter have mild gastritis, which is then overcome and then they are just carriers (no significant disease)
2. In a 10-15% of people, there is increased acid damage as bacteria colonise the stomach, leading to duodenal ulcer
3. In 2-5% of people, they cause gastric ulcer and possibly cancer

Question 26

how is Helicobacter pylori infection treated?

Answer 26

• For successful eradication, a combination of TWO antibiotics PLUS a drug to stop acid production is given, for 1-2 weeks.
• e.g. Amoxycillin + metronidazole + omeperazole (proton pump inhibitor)
• This “triple therapy” is about 90% successful and the ulcers do not recur

Question 27

why may a declining incidence of H. pylori be bad?

Answer 27

• Since the 1950s, big rises in Esophageal cancer and gastro-esophageal reflux disease (GERD).
• over the same period, Helicobacter infection rates have decreased.
• Evidence has been emerging to suggest that H. pylori might protect against these diseases….Thus, in hp positive patients, should it be eradicated if it is not causing symptoms? Is hp more like a commensal that has co-evolved with us?

Question 28

what are the key virulence factors used by Helicobacter pyrloi?

Answer 28

1. flagella - chemotaxis to colonise under mucosa
2. urease - neutralise gastric acid, causing gastric mucosal injury
3. LPS - adhere to host cells and induce inflammation
4. effector CagA - actin remodeling, IL-8 induction, host cell growth and apoptosis inhibition
5. exotoxin VacA - leads to gastric mucosal injury
6. Outer proteins - adhere to host cells
7. secretory enzymes: mucinase, protease, lipase, causing mucosal injury

Question 29

when did the first Legionnaire disease outbreak occur?

Answer 29

• Legionnaires’ disease acquired its name in 1976 when an outbreak of pneumonia occurred among people attending a convention of the American Legion in a hotel in Philadelphia.
• On January 18, 1977 the causative agent was identified as a previously unknown bacterium, subsequently named Legionella.
• The air-conditioning system at the Bellvue Stratford Hotel was found to be responsible for spreading the bacterium in an aerosol form to many rooms. Among the 182 persons infected, 147 required hospitalization, and 29 died.

Question 30

what bacterium causes Legionnaire’s disease?

Answer 30

Legionella pneumophila

Question 31

what is Legionella pneumophila?

Answer 31

• Legionella was a new genus of Gram-negative bacteria from the gamma sub-division of the proteobacteria.
• They are motile with polar flagella, and have fastidious nutritional requirements.
• Growth is best on “charcoal agar” which absorbs toxic compounds and reactive oxygen species.
• It is very common in water bodies, both natural and man-made and survives by entering amoebae and growing intracellularly
• It can also survive in biofilms in aquatic environments.

Question 32

how was Legionella pneumophila cultured?

Answer 32

• Samples were taken from patients’ lungs and observed under microscope
• Initially cultured in eggs, and then developed charcoal agar to culture
• Infected guinea-pig model organism with the pure culture to replicate the Legionella disease phenotype
• Could then re-isolate the bacteria (they completely addressed Koch’s postulates)

Question 33

what is the life cycle of Legionella pneumophila?

Answer 33

1. Amoebae consumes the Legionella but cannot digest it
2. The Legionella grows and divides in the amoebae by using it like an incubator
3. It then kills the amoebae and is released back into the water

Question 34

where are Legionella pneumophila normally found and spread?

Answer 34

• Water cooling towers
• Air-conditioning systems
• Shower-heads
• Windscreen wiper wash bottles in cars

All these sources create aerosols that spread the bacteria/amoebae

Question 35

how do Legionella pneumophila cause disease in humans?

Answer 35

Legionella can subvert the macrophage and grow in a vacuole
- The bacteria use a type IV secretion system (Dot/Icm) to deliver effector proteins into the macrophage cytoplasm that prevent phagolysosome formation but instead allow them to replicate inside a vacuole – the Legionella containing vacuole (LCV)
- Remodel the macrophage vacuole as a replication site
- Strips macrophage of its nutrients
- Macrophage will burst and release the legionella into the infected tissue

Question 36

how can the spread of Legionella pneumophila be controlled?

Answer 36

• Biocides can now be added to air-conditioning systems to prevent legionella growing.
• Chlorine dioxide treatment is effective.
• Hot water systems should be maintained above 60C

Question 37

how is Legionella pneumophila infection treated?

Answer 37

• For respiratory infections, fluoroquinolone antibiotics like ciprofloxacin, or macrolides like azithromycin are effective.
• Mortality rates in new outbreaks (up to 5%) are now lower than the early outbreaks as we have more experience of successful treatments