The Evolution of Antigenic Diversity among Pathogens

1. The Evolution of Antigenic Diversity among Pathogens Caroline Buckee Omidyar Fellow, SFI Sir Henry Wellcome Fellow, University of Oxford

2. Pathogen antigens: targets of the immune response Human antibody Measles virus

3. Y Y Y Y Y Pathogen antigens: targets of the immune response Measles

4. Pathogen antigens: targets of the immune response Streptococcus Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

5. Pathogen antigens: targets of the immune response Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Influenza Time

6. HIV1 Shankarappa et al. ‘99 Plasmodium falciparum Pathogen antigens: targets of the immune response

7. Pathogen trade-offs Virulence versus transmissibility Functionality versus immune escape Massad (1987) Evolution. Tolia et al. (2005) Cell.

8. Plasmodium spp Annual cases: ~300 million Annual deaths: ~1-3 million

10. Ross-MacDonald model (1911, 1957) Susceptible Infected (y) r HUMAN ab ac Infectious (w) Infected (v) Susceptible MOSQUITO   

11. Susceptible Infected (y) r ab ac Infectious (w) Infected (v) Susceptible   

12. Mosquito feeding rate Infectiousness of mos Ratio mos:hum Infectiousness of hum Mos death*parasite incubation recovery Mos death Biting rate squared (two bites per transmission) Exponential relationship between R0 and 

13. Malaria eliminated in many parts of the world in the 1950’s

14. 1 0 0 9 0 8 0 7 0 PREVALENCE OF PARASITAEMIA 6 0 5 0 4 0 3 0 2 0 1 0 0 0 - 1 1 - 4 5 - 9 1 0 - 1 4 1 5 - 1 9 > 2 0 > 4 0 A G E G R O U P Naturally acquired immunity to P. falciparum does occur, and requires repeated infections From Snow and Marsh (1990)

15. 200 150 NUMBER OF CASES 100 50 0 0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 9-10 AGE CLASS (years) Immunity to disease is acquired rapidly From Snow and Marsh (1990)

16. Severe malarial anemia Cerebral malaria O’Meara et al. 2008 Lancet

17. Adult serum Newbold et al 1992 Agglutination of P. falciparum infected erythrocytes by naturally acquired antibodies Y Y Y Y antibody binding photos by Paul Horrocks

18. 1 HB3 PROPORTION SEROPOSITIVE 1935 0 . 5 1776 ISOLATE 1934 1917 0 5 - 9 10 - 14 15 - 19 20 - 30 >30 1 - 4 AGE GROUP Isolate-specific responses - different strains? From Gupta et al. Science (1994)

19. “Common” parasites independently associated with young host age and severe disease Bull et al. 2000

20. Gupta et al., 1994

21. Implications of many different strains: Normally: R0 = adult lifespan / avg age first infection Proportion to vaccinate > 1 - 1/R0  avg age infection very low, R0 high and p close to 1 Many strains: Avg age first infection = adult lifespan / Sum of R0s  R0 lower than thought, vaccination possible?

22. PfEMP1 inserted into the erythrocyte membrane mediate adherence to a range of host cell types IE binding to endothelium (ICAM-1, CD36 etc) Infected erythrocyte (IE) IE binding to erythrocytes IE binding to dendritic cell (CD36) EM courtesy of D. Ferguson, Oxford Univ.

23. Infected blood cells sequester in tissue capillaries EM courtesy of D. Ferguson, Oxford Univ.

24. 106 Number of Parasites 104 102 40 80 120 160 200 Days of infection Blood-stage antigenic variation sustains infection Chronic infections following treatment for neurosyphilis (Wagner von Jauregg Nobel Prize 1927 for “malaria therapy”)

25. Each parasite has a repertoire of approximately 60 var genes encoding PfEMP1 Gardner et al. (2005) Nature.

26. Model Framework for more than one locus Gupta et al., 1996,1998

27. Model Framework

29. How are var genes structured? Var gene structure DBL1 CIDR1 DBL2 DBL3 CIDR2 Semi-conserved Variable domains

30. Kraemer & Smith 2006 (Lavstsen et al. 2003)

31. Short sequence tags from wild isolates: High rates of non-homologous recombination DBL1 CIDR1 DBL2 DBL3 CIDR2

32. Recombination Mutation Phylogenetic techniques: the problem of recombination

33. 1. Networks Bull, Buckee, et al. 2008 Mol. Micro.

34. Bull, Buckee, et al. 2008 Mol. Micro.

35. Group A var genes Bull, Buckee, et al. 2008 Mol. Micro.

36. Selection for diversity (expressed rarely, in older hosts, cause mild disease?) Strong immune selection (optimized for functionality, expressed early, expressed “commonly” in young hosts, cause severe disease?) NON-OVERLAPPING?

37. Relating sequence and serology to epidemiology…

38. Frank & Bush (2007) BMC Evol Bio. Analogous to trade-offs among viruses between transmissibility and immune evasion? Trade-offs balanced at the individual genome level. Definition of strain?

39. 1 2 1 2 Can we infer anything from serology (phenotype)? acute convalescent Symmetrical Response

40. Agglutination? Agglutination assay ACUTE CONVALESCENT

41. Variable expression? Discrete genotypes? Frequency of strains Frequency of vars/exp

42. Hosts infected with the same parasite should show correlated d scores (increasing Ab titres)… Structuring by immune selection - relies on the hosts seeing both antigenic determinants during infection Variable exposure to repertoires?

43. ACUTE CONVALESCENT Bull et al. 1999

44. ACUTE RESPONSE Buckee et al. (2008)

45. Parasite isolate Parasite isolate d h Host 1 Host 2 Parasite var repertoire: i f h i a b c d e f g h a b c d e g Host antibodyrepertoire: Time (infection length) Time (infection length)

46. Discrete strains Random repertoires Intermediate structure?

47. RANDOM DISCRETE INTERMEDIATE

48. What is a strain? • Potential vs realized repertoire of vars ? • Strain depends on host context ? • Parts of repertoires highly structured ? • Flexible phenotype and partitioned genome allows for balancing of evolutionary trade-offs on different levels.

49. Acknowledgements KEMRI Pete Bull Kevin Marsh George Warimwe Oxford Sunetra Gupta Mario Recker Oliver Pybus