Lecture 7- antigenic variation and diversity Flashcards
what is the basic reproduction number R0?
The basic reproduction number (sometimes called basic reproductive ratio, R0,
r nought) of an infection can be thought of as the number of cases one case
generates on average over the course of its infectious period, in an otherwise
uninfected population.
When R0 < 1 the infection will die out in the long run.
But if R0 > 1 the infection will be able to spread in a population.
The larger the value of R0, the harder it is to control the epidemic.
The proportion of the population that needs to be vaccinated to prevent
sustained spread of the infection is given by 1− 1/R0.
R0 is affected by several factors including
- duration of infectivity of affected patients,
- infectiousness of the organism,
- the number of susceptible people in the population that the affected
patients are in contact with.
What is the evolutionary success of an infectious agent and R0
R0 = βcD
β is the inherent transmissibility of the agent,
c is related to the number of transmission opportunities
D is the duration of infectiousness of the disease.
Any mechanism by which a pathogen can increase one or more of these factors
will provide a selective advantage.
Successful evasion of host immunity results in an increased value for D.
Antigenic variation is a very widespread means of immune evasion
- disarm the effect of acquired immunity by changing antigens.
what is the structure of a virion?
- Lipid envelope with 2 projecting
glycoproteins: - haemagglutinin (HA), a trimer
- neuraminidase (NA), a tetramer.
- Envelope inner side is lined by
matrix protein (M1). - Inside are 8 ribonucleoprotein
(RNPs) genome segments.
Lacks RNA proof-reading enzymes.
Not a retrovirus – no DNA step, no genome
integration.
what is the differences between antigenic drift and shift?
Drift
Minor changes in HA and NA
RNA-dependent RNA polymerase that copies the viral genome makes
an error ~every 10 thousand nucleotides
Amino acid substitutions in the HA and NA may permit the virus to
escape from immune control
If so, a fitness advantage and emergence as a novel epidemic strain,
replacing the circulating strain
Driven by immune selection (like antigenic variation, e.g. HIV-1?)
Shift
Reassortment of HA, NA (or both) gene segments between strains
Can result in a new pandemic strain, infective to new host (e.g. us)
(Not really like antigenic variation?)
what pathogens evolve?
165: Antonine plague (Smallpox, we think)
11th century: Leprosy (Mycobacterium leprae or Mycobacterium lepromatosis)
1350: The Black Death (Yersinia pestis)
1817: First (of seven!) Cholera pandemic (Vibrio cholerae)
1918: ‘Spanish’ Flu (H1N1 Influenza)
2019-23(?): Covid-19 (SARS-CoV-2)
Above are pandemic outbreaks
Can be caused by movement of people, or by cross-species movement of pathogen
Only some controlled by vaccination/treatment
Other pathogens are endemic; e.g. has there been a syphilis pandemic; malaria?
All pathogens must adapt (evolve?) to host immune pressure – within or between
hosts and species (over years or days)
what are notably successful pathogens in human history?
165: Antonine plague (Smallpox, we think)
11th century: Leprosy (Mycobacterium leprae or Mycobacterium lepromatosis)
1350: The Black Death (Yersinia pestis)
1817: First (of seven!) Cholera pandemic (Vibrio cholerae)
1918: ‘Spanish’ Flu (H1N1 Influenza)
2019-23(?): Covid-19 (SARS-CoV-2)
where foes antigenic variation occur?
viruses, bacteria and eukaryotic parasites
how do VIsE antigens change?
by recombination
The B. burgdoferi genome is very unusual for a bacterium:
Genome is a linear chromosome
10 circular and 12 linear plasmids
Linear replicons are terminated by covalently closed hairpins
VlsE only expressed from a single
vlsE locus
Many silent vls genes
Recombination copies segments
of the silent vls genes into the
variable region of the transcribed
vlsE gene
what is the antigenic diversity in Trypanosoma cruzi?
Distant relative of Trypanosoma brucei
Intracellular parasite
Causes decades long infections
T. cruzi contains a huge repertoire of genes for surface antigens, including mucins and
mucin-like proteins; evidence for variation between strains by recombination
Homogeneous mucin ‘coats’ are expressed in the insect stage
Heterogeneous mucins ‘coats’ are expressed in the mammal:
- impairment of T and B-cell function?
- immune evasion?
- host cell binding?
what is the antigenic diversity in influenza A?
Two surface glycoproteins:
Haemagglutinin (HA), attaches the virion to cells
(attachment, invasion)
Neuraminidase (NA), releases the virion
(spread)
what is the antigenic variation in HIV-1 due to mutation?
gp120 (part of gp160) needed for
host cell entry
Antibodies raised against gp120
Mutations in gp120 gene, caused
by reverse transcriptase, allow
immune evasion
what is the antigenic variation in plasmodium?
Plasmodium express PfEMP1 and transport it
to the RBC surface; forms a ‘knob’
Needed to stop infected RBCs entering the
spleen, by mediating adherence to blood
vessel walls
Antibodies are raised against PfEMP1
~60 var genes encode PfEMP1 variants,
switching between the single gene transcribed
what is malaria?
caused by plasmodium
300-500 million cases per year
40% of the global population
exposed
1.5 - 2.4 million deaths per year,
90% of them in Africa
85% of fatalities occur in children
<five years old
Characteristic fluctuating fever
symptoms occur when Plasmodium
invades red blood cells
when does VSG transcription occur?
from a very complex telomeric
transcription site
Only one VSG gene (and hence coat) is expressed at a time in a
single cell but there are ~15 transcription sites
what is the Pilin antigenic variation in Neisseria by recombination?
Pili only expressed from a single
pilE locus
Many silent pilS genes
Recombination copies segments
of the silent pilS genes into the
pilE gene
what is the major route for VSG switching involving recombination?
T. brucei has thousands of silent VSG genes (a far bigger family that found
elsewhere)
Antigenic variation is catalysed by copying of silent genes, or parts of silent genes,
into the VSG transcription site(s)
what is antigenic variation?
Clonal phenotypic variation.
Reversible.
Uninduced.
One variant at a time expressed by each cell.
Often based on a library of variable antigens genes.
Allows part of the infecting population to escape host
immune-mediated killing.
Viruses, bacteria and eukaryotic (protist) pathogens
what is antigenic diversity?
Irreversible genome modification.
Mutation and immune selection for survivors that transmit.
Typical of viruses, especially those with RNA genomes, but also protists
what is the antigens variation in Neisseria?
Neisseria spp. are obligate human commensal bacteria; live in the nasopharynx
Can result in disease:
Neisseria gonorrhoeae
Neisseria meningitidis
Antigenic variation involves the
pilus (type IV)
Pilus acts in cell and tissue
adhesion, twitching motility,
DNA transformation
Antigenic variation can change
the amount of pili
