Does immunodominance maintain the diversity of the common cold? William Koppelman University of Utah...
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Transcript of Does immunodominance maintain the diversity of the common cold? William Koppelman University of Utah...
Does immunodominance maintain the diversity of the common cold?
William KoppelmanUniversity of UtahMaster’s Oral Examination
Outline
Biological background Mathematical model Analysis/Simulations Results Conclusions
Biological Background
Rhinovirus characteristics Mutation Cross-reactivity Immunodominance
Human Rhinovirus (HRV)
Co-circulation of over 100 strains Cause ~50% of common colds
Limited to high level primates Adults average 2-3 colds per year Able to survive outside host for up to
3 days
HRV cont. Sufficient dose is 1-30 particles of the virus Attaches to ICAM-1 receptor of nasal cells Replication of the virus and rupture of the host cell
leads to infection of other nasal cells Incubation period of 8-12 hours
HRV Mutation RNA virus (typically have high mutation
rates Predicted to have 0.67 mutations per
genome per replication ~21 replications/infection
~14 mutations per infection Suggested that new serotype created in 2
to 4 years from mutation (Stott & Walker, 1969)
HRV Cross-Reactivity Cross-reactivity is the ability of B and
T cells to react with an epitope on the antigen that they are not designated for.
A single HRV serotype is, on average, related to 3.75 other serotypes (Cooney et al., 1975).
Therefore, related serotypes may elicit similar immune responses.
HRV Immunodominance A process in which the immune response focuses on
only a few of the many potential epitopes. Original antigenic sin is a process in which the
sequence a host encounters antigenic variants influences the specificity of the immune response.
Antigens Immune Response
Primary Exposure A a
Secondary Exposure A’ a
Mathematical Model
Discrete Stochastic Multiple Strain SIRS dynamics
Model Components
HRV strains exist in a 2-D genetic space.
Domain is a 10 x 10 grid with periodic boundaries
Each 1 x 1 square represents a strain (i.e. 100 strains)
Model Components cont.
Mutation is a distance in the genetic domain.
Strains differ by ~10% or 800 sites From derived mutation rate => ~50
infections to produce new serotype Therefore, a mutation distance of
1/50 per infection is reasonable for the domain.
Model Components cont. Serotypes will cross-react with related serotypes This corresponds to an area around a particular
strain in the genetic domain Equivalent to a circle (radius Xim) not including the
original serotype
23.175.4
75.31)( 2
Xim
Xim
Model Components cont. Immunodominance will
affect the transmission of HRV
The function of transmission will be related to the amount of variance from strains previously seen by the immune system
Step function is simplest, realistic form
Model components cont. Sub-population of environmental
surfaces obey SIS dynamics Stochastic elements
Random contact (uniform) Random mutation (normal) Random recovery time (log-normal) Random birth death (uniform)
Transmitting antigen compared against host’s immunity history
Analysis of continuous equivalent
RIdt
dR
N
SI
dt
dI
SNN
IS
dt
dS
)(
Continuous time, single strain, SIR model with births/deaths (constant pop.)
Assuming the birth rate is much smaller than the recovery rate then i* is the equilibrium prevalence
1*i
Endemic analysis Strain remains endemic if R0>1 Using estimated parameters from discrete
model Human birth rate is O(10-4)
0R
12.0
10.0
210 O
Sub-population analysis Model with hosts
following SIR dynamics and surfaces following SIS dynamics
System has two equilibria with the trivial solution never being unstable
*****2
5,4,3,2
1
1
,,,,
0
0
0,,0,0,
ddhhh
dh
ISRISE
NNE
Simulations (Infection)
Simulations (Immunity)
Simulations (Prev. & Div.)
Results In order to consider mechanisms influencing
serotype diversity, the virus must be endemic in hosts
Different functions of transmission should lead to endemic by increasing virus dynamics within cross-reactivity distance.
Conclusions Virus must be endemic to analyze
diversity Serotype interactions are crucial to
virus remaining endemic Once endemic, the diversity of
serotypes will evolve through serotype interactions
Serotype interactions are governed by immunodominance
Thanks
Dr. Adler Drs. Keener & Coley Dr. Guy Brynja Kohler John Zobitz Dr. Sherry