Emerging Infections

Emerging Infections

1. What is an emerging virus?

   • A) A virus which has newly appeared in a host (humans)
   • B) A virus which has existed previously but has changed geographic range
   • Emergence happens in both under and well developed countries - does not depend on economic status
   • Most emerging viruses that have infected humans over the past 40 years are RNA viruses, and usually infect only one other host
   • Most emerging viruses come from animals (are zoonotic)

2. Why do viruses emerge?

   • Mutation
     • RdRp error
       • Copies RNA genome into new progeny genome. Vast majority of viruses have RNA genomes and therefore need RdRp
       • Has a high error rate ~1 mistake per 10,000nt. If 10,000 viral progeny particles are produces, each one will be different in 1 mutation, giving rise to 'quasispecies'. These mutations may change coding in a number of effects such as receptor specificity, polymerase activity or new transmission characteristics that may allow emergence
       • DNA polymerases also produce errors
         • E.g. In parvoviruses - Encode VP1 and 2 which form the viral capsid. Feline parvovirus causes fatal infection cats. 2 coding changes in VP2 resulted in the emergence of canine parvovirus
           • The VP2 receptor, transferrin, is different by 3 AA's in cats and dogs
             • Mutations in the VP2 protein allowed a switch of receptor specificity from feline to canine transferrin
     • Reassortment of segmented RNA genomes
       • If 2 different segmented viruses co-infect the same cell, the reassortment of their genomes can give rise to a new virus genotype
         • Flu (8 segments), bunyaviruses (3 segments) and arenaviruses (2 segments) can all do this
         • If the different viruses have different specificities, reassortment can give rise to a virus with new tropism
     • Recombination
       • Also depends on a cell being co-infected by 2 viruses
         • Occurs when the RdRp switches the template strand when copying the genome. Happens when there are areas of sequence homology between the genomes This gives rise to a new recombinant strand which contains sequences from both templates
         • e.g. Western equine encephalitis virus (WEEV) serological analysis showed a mixture of 2 alphaviruses, eastern equine encephalitis virus and sindbis virus. Crossover happened at a conserved signal sequence in E3 protein.
         • If the different viruses have different specificities, reassortment can give rise to a virus with new tropism
   • Change in contact between humans and infected host
     • Weather
       • Results in a change of food supply for the reservoir host, followed by a change in its territory. e.g. Sin nombre virus infect the deer mouse as a reservoir. Warm wet weather (el nino) caused increased food supply. The mouse population exploded, all the food was eaten. Mice then had to move into human dwellings for food
         • Causes enterohemmorhagic fever and pulmonary disease
     • Bush meat markets
       • Widespread in rural sub-Saharan Africa. Allows new contact between humans and infected wild animals. Meat sold is unprocessed. Responsible for transmission of ebola, HIV etc
     • Live animal markets
       • Widespread in China, Vietnam and Hong Kong. Most common animals involved are chickens, dogs, pigs, ducks, cats, cows and rabbits. Responsible for new strains of highly pathogenic influenza
     • Farming and land development
       • Humans moving into environments that have never been developed. e.g. Nipah virus in Malaysia, 1998. Caused by deforestation - Removed food supply of fruit bat (primary host), bats migrated and ate fruit at urban farms and dropped it near pigs (2nd host), pigs vet infected via bat saliva and transmit to humans via farm contact. Fatality ~50%
     • Global travel and commerce
       • 100,000 passengers travel by air per year. Virus spread can be caused by either an infecter human or vector on flights
         • E.g. Air dissemination of SARS coronavirus. Horseshoe bat and civet cat (sold at live animal markets) are the stable hosts. Disease was initially identified in china, but reached 17 countries in 4 weeks.
           • All possible transmission events were identified
             • Came back to 16 people who stayed on the same hotel floor for a global conference in china - all of whom were infected (virus is very contagious). All flew home to different countries to disseminate the virus.
               • One of the individuals went to hospital and had a viisitor who became infected and flew from HK to Beiijing. 1/4 of people on his flight were subsequently infected
                 • Mapping of interactions lead to a total of 28,000 people being quarantined - SARS declared over in 2013

3. West Nile Virus

   • Life Cycle
     • Culex mosquito are main vectors - Feed on an infected bird (stable host)
       • Infected mosquitos feed on uninfected birds
       • Rarely, infected mosquitos feed on humans/horses (dead end host)
   • Timeline of emergence
     • 1937 - Virus firrst isolated in West Nile District of Uganda
       • 1937-1993 - Endemic throughout africa/southern europe - Rate of serious illness very low
         • 1993 - New strain emerged in Senegal, highly pathogenic to humans
           • Isolate found in Isreal, subsequently found in birds, humans and horses in NY in 1999
             • 2012- Drastic increase in cases and fatalities - a majority in Texas, where a particularly warm summer encouraged increased CUlex populations. Texas declared a state of emergency
   • Why did it spread so fast?
     • Moved 3,000 miles in 4 years - yet no spread in Europe?
       • Suggests novel factors involved in spread across US
     • 1. New virulent Senegalese strain emerged in 1993 - An isolate of this strain was found in 1998 in Isreal, almost identical to the NY isolate in 1999. Therefore, the virus in NY was one of the highly pathogenic, Senegalese strain
     • 2. Naive population of hosts. The USA had never encountered the virus before, bird and human hosts had no immunity, therefore the entire population was susceptible
     • 3. Many susceptible bird species - Some of which migrate. Receptor specificity was suitable for many US bird species, virus was isolated from over 320 US bird species, whose migratory routes cover the nation
     • 4. The vector - USA has a susceptible mosquito vector, culex pipens, which has 3 novel features: It feeds on both birds and humans, it hibernates and can therefore survive the winter and females pass virus onto all progeny (verticel transmission. This lead to increased contact between vector and hosts
     • 5. USA geography - No natural protective boundaries (seas/high mountain ranges) to prevent migration of virally infected birds/mosquitos - easily spread
   • Unresolved features
     • How did it arrive/cross the Atlantic?
       • Infected mosquito on a flight?
       • Infected bird smuggled into NY zoo where first isolated?
       • Infected bird crosses the Atlantic? - Carrier pigeons have been known to do it
     • How did it spread so far westwards so quickly, when all USA bird migration routes are North/South?
   • Small +sense RNA genome. Enveloped, icosahedral
   • Flavivirus - Same family as dengue, yellow fever and japanese encephalitis viruses
   • Emerged in USA in late 1990s
   • 75% of infections are asymptomatic, 24% give mild encephalitis/fever, 1% cause serious disease (neuroinvasiveness) - 0.1% of infections are fatal overall - 10,000 people per year

4. Types of host

   • Reservoir/stable host - Organism that supports viral replication and transmission (does not necessarily cause disease in this host)
   • Dead end host - Organism that supports viral replication but no or limited further transmission (usually humans)
   • Some viruses may be transmitted between a reservoir and dead end host via a vector. A vector is not necessarily a host, as the vector must support viral replication to be considered a host