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Does immunodominance maintain the diversity of the common cold?

Does immunodominance maintain the diversity of the common cold?. William Koppelman University of Utah Master’s Oral Examination. Outline. Biological background Mathematical model Analysis/Simulations Results Conclusions. Biological Background. Rhinovirus characteristics Mutation

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Does immunodominance maintain the diversity of the common cold?

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  1. Does immunodominance maintain the diversity of the common cold? William Koppelman University of Utah Master’s Oral Examination

  2. Outline • Biological background • Mathematical model • Analysis/Simulations • Results • Conclusions

  3. Biological Background • Rhinovirus characteristics • Mutation • Cross-reactivity • Immunodominance

  4. 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

  5. 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

  6. 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)

  7. 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.

  8. 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.

  9. Mathematical Model • Discrete • Stochastic • Multiple Strain • SIRS dynamics

  10. 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)

  11. 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.

  12. 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

  13. 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

  14. 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

  15. Analysis of continuous equivalent • 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

  16. Endemic analysis • Strain remains endemic if R0>1 • Using estimated parameters from discrete model • Human birth rate is O(10-4)

  17. 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

  18. Simulations (Infection)

  19. Simulations (Immunity)

  20. Simulations (Prev. & Div.)

  21. 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.

  22. 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

  23. Thanks • Dr. Adler • Drs. Keener & Coley • Dr. Guy • Brynja Kohler • John Zobitz • Dr. Sherry

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