1. Immunity and pathogen competition Dominik Wodarz Department of Ecology and Evolution 321 Steinhaus Hall University of California, Irvine CA 92697 Immune system / evolutionary aspects pathogen competition and evolution on epidemiological level

2. Immunity and pathogen competition Immune system / evolutionary aspects pathogen competition and evolution on epidemiological level 1

3. Immunity and pathogen competition Immune system / evolutionary aspects pathogen competition and evolution on epidemiological level 1 2

4. Outline 1 Effect of immunity on competition between wild-type and drug resistant rhinoviruses in a population of hosts 2 Effect of pathogen competition for hosts on the evolution of immune protection and immunological memory

5. Effect of immunity on pathogen competition 1 Context: Drug resistance in rhinovirus infections Rhinoviruses basics: in 75% of cases: leads to common cold symptoms incubation period: 1-2 days virus shedding increases with onset of symptoms, and falls sharply as patient recovers infection lasts on average 7 days

6. Rhinoviruses – immunological aspects rhinoviruses consist of about 100 serotypes (i.e. recognized by different immune specificities) no geographic or temporal pattern observed in strain distribution strains may have different transmissibility infection leads to immunity (memory -> protection) protection is largely strain-specific -> people get colds many times number of colds per year decreases with age, since people become immune to more strains (kids vs adults)

7. Rhinovirus treatment: pleconaril originally developed by ViroPharma in 2002, rejected by FDA because company did not demonstrate adequate safety Now, further developed and in phase II clinical trials with Schering-Plough

8. Will treatment result in a significant increase in the prevalence of drug resistant virus strains? Two types of drug resistance in rhinoviruses: 1.“Acquired resistance”: mutations during viral replication can give rise to virus strains that are resistant to the drug

9. Will treatment result in a significant increase in the prevalence of drug resistant virus strains? Two types of drug resistance in rhinoviruses: 1.“Acquired resistance”: mutations during viral replication can give rise to virus strains that are resistant to the drug 2. “Natural resistance”: Rhinovirus population exists as about 100 serotypes. Some serotypes are more susceptible to the drug than others

10. Natural resistance: different serotypes have different susceptibility Will treatment result in a significant increase in the proportion of less susceptible or resistant virus strains? What is the effect of immunity? Because they are different serotypes, it is not likely that there is much immunological cross-reactivity between “susceptible” and “resistant” virus strains. -> Analyze mathematical model that describes spread of two virus strains in a population of hosts, assuming a varying degree of immunoligical cross-reactivity.

11. Mathematical model treatment: reduce the transmission parameter,  t <  1, and speed up the rate of recovery,  t >  1. cross-immunity parameter  : if  =0: recovered individuals completely protected against 2 nd strain. if  =1: recovered individuals receive no protection against 2 nd strain.  = fraction of infected people treated

12. Outcomes of the model complete cross-immunity (  =0) no cross-immunity (  =1) partial cross-immunity strain 1 = sensitive strain 2 = resistant

13. Impact of treatment on equilibrium prevalences treatment reduces basic reproductive ratio of sensitive strain (strain 1) extent to which differences in competitiveness affect equilibrium behavior depends on the strength of cross-immunity between strains no cross-immunity or partial cross-immunity  =0.1  =1

14. Impact of treatment on equilibrium prevalences treatment reduces basic reproductive ratio of sensitive strain (strain 1) extent to which differences in competitiveness affect equilibrium behavior depends on the strength of cross-immunity between strains no cross-immunity or partial cross-immunity  =0.1  =1 strong cross-immunity  =0.001  =0.0001

15. Impact of treatment on equilibrium prevalences treatment reduces basic reproductive ratio of sensitive strain (strain 1) extent to which differences in competitiveness affect equilibrium behavior depends on the strength of cross-immunity between strains -> Prediction: drug use is not likely to lead to a major change in the relative frequency of drug-sensitive and drug-resistant strains no cross-immunity or partial cross-immunity  =0.1  =1 strong cross-immunity  =0.001  =0.0001

16. Treatment dynamics and time scales for different levels of cross-immunity and fraction treated Oscillatory behavior: time taken to reach equilibrium can be long Implication: levels of resistance seen in short term may exceed the equilibrium value. Thus, care must be taken in analyzing any short-term data on the prevalence of resistant virus, as it may take some time for the underlying trend to be revealed.

17. What about “acquired resistance”? With “natural resistance”, the prevalence of resistant strains is unlikely to increase significantly because there is not much cross-immunity With acquired resistance: data indicate that there is high degree of cross-immunity -> model predicts that prevalence of resistant strains will increase significantly in population of hosts. But: Look at in vivo dynamics.

18. Acquired resistance and in vivo dynamics Similar in principle to HIV: mutation gives rise to a resistant strain, and data indicate that resistant strain is likely to have a fitness cost. Rise of drug resistance in HIV is big problem. Difference with rhinovirus infection: intact immune responses fight rhinoviruses, and this might significantly reduce the risk of resistance emerging in vivo.

19. In vivo dynamics, immune responses, and the rise of resistance F(y w,y r,z) susceptible host cells wild-type virus resistant virus specific immune response

20. In vivo dynamics, immune responses, and the rise of resistance F(y w,y r,z) susceptible host cells wild-type virus resistant virus specific immune response The two virus strains share an enemy: the immune response -> concept of apparent competition in ecology R W I (fitness cost) if wild-type virus induces higher levels of immune responses (because it grows faster in in absence of treatment), then it can drive the resistant virus extinct via the shared immune response

21. In vivo dynamics, immune responses, and the rise of resistance early start of treatment: wild-type has not grown enough to induce sufficient levels of immunity. -> resistant strain not suppressed later start of treatment: wild-type virus has grown more and induced a sufficient level of immune resposnes. -> resistant strain is suppressed

22. Start of treatment and suppression of resistance In general: the resistant strain is not likely to rise to significant levels that can be transmitted if treatment is started after a time threshold, once immune responses have expanded sufficiently. This is likely to be the case with rhinovirus infection because symptoms occur only after significant virus spread and may even by caused in part by the immune responses themselves

23. Start of treatment and suppression of resistance In general: the resistant strain is not likely to rise to significant levels that can be transmitted if treatment is started after a time threshold, once immune responses have expanded sufficiently. This is likely to be the case with rhinovirus infection because symptoms occur only after significant virus spread and may even by caused in part by the immune responses themselves  Even though “acquired resistance” would spread quickly on an epidemiological level, it is not likely that a newly generated resistant mutant in the host would replicate sufficiently for it to be transmitted. Note: if treatment is started very early after infection, and little immunity exists, the prediction is that a resistant mutant will not be suppressed. However, the probability that a resistant mutant will have been generated during this time is extremely small!

24. Rhinovirus conclusion Treatment of rhinovirus infection is might not lead to an increase in the prevalence of resistant relative to wild-type strains, because of the patterns of immunity.

25. Effect of pathogen competition on evolution of immune system  Immunological memory = protection of host against a second infection by the same pathogen. Lasts for a very long time, in some cases for life. Is it advantageous to have long lasting protection against re-infection? At first, the answer seems obvious…

26. Simple mathematical model one host – one virus susceptible hosts infected hosts recovered hosts pathogen

27. Simple mathematical model one host – one virus susceptible hosts infected hosts recovered hosts pathogen Parameter g: rate at which immunity is lost and host returns to being susceptible G = 1/g = average duration of memory-mediated protection

28. Simple mathematical model one host – one virus susceptible hosts infected hosts recovered hosts pathogen Parameter g: rate at which immunity is lost and host returns to being susceptible G = 1/g = average duration of memory-mediated protection To which g does the system evolve to? G = ∞, i.e. maximum memory duration ( discounting things like metabolic tradeoffs that could limit memory )

29. One host – 2 virus strains Susceptible Infected with Pathogen 1 Infected with Pathogen 2 Immune to 1 Infected with 2 Immune to both Immune to 2 Infected with 1 Immune to Pathogen 1 Immune to Pathogen 2 As before, the immune or recovered individuals become susceptible again with a rate g. In which direction does the duration of memory protection evolve now?

30. Equations

31. Assumptions Two virus strains: strain 2 is competitively inferior and more virulent  interesting behavior: remember rhinovirus model: absence of immunological cross-reactivity between strains allows coexistence if there is no such separation, we observe competitive exclusion

32. Duration of memory and outcome of competition Short memoryLong memory(a) (b) Duration of memory (arbitrary units) Abundance of inferior pathogen Time (arbitrary units) Abundance of pathogens superior pathogen inferior pathogen The longer the duration of memory, the better the inferior and more virulent pathogen can persist.

33. Tradeoffs: Longer duration of memory: longer protection against re-infection but higher prevalence of virulent pathogen Shorter duration of memory: shorter protection against re-infection but lower prevalence or of virulent pathogen (or absence)

34. Evolutionary dynamics: two stable states 0 8 G thr suboptimal memory outcome maximum memory outcome Longer memory winsShorter memory wins Longer memory wins Duration of memory (G)

35. Properties of G thr – the threshold memory duration that separates the 2 outcomes The threshold moves up as the virulence increases. i.e. as virulence increases, the system is more likely to evolve to the suboptimal memory outcome. This is because it is more important to exclude the virulent strain than to be protected against re-infection in this situation

36. Evolutionary cycles? one pathogen strain => maximum memory duration allows invasion of more virulent strain(s). costly for the host reduce duration of memory exclude virulent strain(s)

37. Some thoughts on biological implications difficult to test because duration of memory not well studied Need to compare pathogen that exists as a diverse population to pathogen that exists as a homogeneous population  Perhaps the common cold, with its 100 serotypes Immune protection relies largely on IgA in nasal secretions But: the titer of rhinovirus specific IgA declines faster than other antibody titers, and protection is may not last for life but for a few years -> perhaps it helps exclude more virulent strains?? Vaccination may backfire: if protection is increased by vaccination, it may allow for the emergence of more virulent strains, and this could be costly for the host population

38. Final thoughts: How can duration of memory be modulated? Experiments indicate that infection with a heterologous virus can lead to a decline of previously established memory against a first infection  If pathogen exists as a diverse population and the host can frequently be infected by different strains of the pathogen, memory may be relatively short lived. Adaptive??

39. People Alun Lloyd (NC State) on the models of rhinovirus drug resistance Marc Collett (Viropharma) Dan Pevear (Viropharma)