The role of immunity in host- pathogen co-evolution
Sunetra Gupta Department of Zoology University of Oxford Immune driven pathogen evolution
Dominant targets of immunity are conserved
eg. Bordetella pertussis
Dominant targets of immunity are variable
eg. Streptococcus pneumoniae
Mul ple variable targets of immunity
Populations of infectious agents will self-organise into non-overlapping combinations of antigenic variants as a consequence of immune selection. A"
C"
B" Severe malarial anemia
Cerebral malaria
O’Meara et al. 2008 Lancet PfEMP-1 mediates cytoadhesion of infected erythrocytes to host cells is associated with pathology
adapted from Miller, LH et al, 2002 Neisseria Outer membrane meningitidis proteins
CAPSULAR POLYSACCHARIDE
POR B POR A VR1 VR2
SUBCAPSULAR ANTIGENS PorA combinationsVR are non-random and non-overlapping Martin Maiden Maiden Martin 140" 120" Prevalence) 100" 80" 60" 40" 20" 0"
Variable)region)1)(VR1)) 5" 5#1" 5#2" 5#3" 7" 7#1"
VR1-VR2 combinations 1989-1991 1989-1991 combinations VR1-VR2 7#2" 7#11" 12#1" 18" 18#1" 18#7" 18#8" 19" 19#1" 19#8" 19#13" 21" 21#3" 22" 22#1"
2"
2#2"
3" Variable)region)2)(VR2)) 9" 10" 10#1" 13#1" 14#6" 15" 16" 16#8" 25" OMP variants are structured into discrete strains
Eleanor Watkins
Watkins,E.R. & Maiden,M.C.J. (2012) Persistence of Hyperinvasive Meningococcal Strain Types during Global Spread as Recorded in the PubMLST Database. PLoS One. 7: e45349. Figure 6. Longevity of the most frequent combinations of two and three antigen sub/variants.
Bambini S, Piet J, Muzzi A, Keijzers W, Comandi S, et al. (2013) An Analysis of the Sequence Variability of Meningococcal fHbp, NadA and NHBA over a 50-Year Period in the Netherlands. PLoS ONE 8(5): e65043. doi:10.1371/journal.pone.0065043 http://127.0.0.1:8081/plosone/article?id=info:doi/10.1371/journal.pone.0065043
Long term stability and persistence was observed also for several combinations of protein sub/variants. Antigen combinations showed a non-overlapping structure. Epitopes under strong immune selection will self-organise into non-overlapping combinations. FOR A GIVEN STRAIN, i: zax zay Proportion immune to strain i: zax dzi = λi (1− zi )− µi zi z z dt bx by
Proportion immune to strains sharing alleles with i: dw i 1 w w zax zay = ∑λ j ( − i )− µi i dt j~i wax Proportion infectious with strain i: zbx zby
dyi = λi ((1− wi )+ (1−γ )(wi − zi ))−σ i yi dt
Force of infection for strain i: zax zay y λi = β i wax - zax zbx zby Discrete Strain Structure No Strain Structure Cyclical Strain Structure
Increasing immune selection A multi-locus model for host and pathogen diversity
Infected Immune to pathogens with containing Bridget Penman ax or
Infected Immune to pathogens with containing ay AX/AX Infected with Immune to pathogens containing bx
Infected with
by
• Hosts can only become immune to epitopes they are capable of recognising.
• Hosts incapable of recognising any pathogen epitope risk dying from the infection.
Coevolutionary cycling
Propor on host genotype Propor on infected
0.25"
0.2" 0.005" 0.15" 0.004" 0.1" 0.003" 0.05" 0.002" 0" 0" 0.001" 250" 0" 500" 750" 1000" ax" bx" ay" by" Time (years) 1250" AY/BY" BX/BY" AX/AY" AX/BX" AY/BX" AX/BY" BY/BY" AY/AY" BX/BX" AX/AX" The model predicts that adaptive-immunity mediated pathogen selection on HLA loci should result in strong non-overlapping associations between HLA loci.
Propor on host 0.4% Propor on genotype infected 0.3% 0.0025% 0.2% 0.005"0.002% 0.004" 0.1% 0.0015% 0.003" 0% 0.001% 0.002" 0% 0.0005% 250% 0.001" 0% 500% 0" 750% 1000% Time%(years)% ax" bx" ay" by" 1250% AY/BY% BX/BY% AX/AY% AX/BX% AY/BX% AX/BY% BY/BY% AY/AY% BX/BX% AX/AX% (a) Proportion infected Pathogen selection and host haplotypes structuring in a 3 locus, 3 allele stochastic system 0.25
0.2
0.15
0.1
0.05
0 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000
(b) Host haplotype frequencies 0.6 111 211 311 0.5 121 221 321 131 231 331 0.4 112 212 312 0.3 122 222 322
0.2 132 232 332 113 213 313 0.1 Time (years) 123 223 323 0.3 0 133 233 333 0.25 0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000
0.2 Legend 0.15 amx bmx cmx anx bnx cnx aox 0.1 box cox amy bmy cmy any bny
0.05 cny aoy boy coy amz bmz cmz
0 anz bnz cnz anz bnz cnz 0 10000 Under pathogen selec on, the main ‘founder’ HLA haplotype is replaced sequen ally by sets of other, advantageous haplotypes :
0.6 Different colours represent different haplotypes (27 in total, in a 3 locus, 0.5 3 allele system)
0.4
0.3
0.2 HLA haplotype frequency HLA 0.1
0 0 1000 2000 3000 4000 5000 6000 7000 Time (years) Without pathogen selec on, the most frequent founder haplotype gradually declines in frequency over me - decaying through recombina on, or being replaced by other haplotypes through dri . 0.6
0.5
0.4
0.3
0.2 HLA haplotype frequency HLA 0.1
0 0 1000 2000 3000 4000 5000 6000 7000 Time (years) Non-overlapping HLA associations in the Burusho population in Pakistan
0.12% 0.12%
0.1% 0.1%
0.08% 0.08%
0.06% 0.06% frequency Haplotype frequency Haplotype 0.04% 0.04% B*08% B*58% B*08% B*52% B*58% 0.02% B*44% 0.02% B*52% B*44% B*35% B*35% B*13% 0% B*13% 0% B*37% B*37% B*41% B*41% B*51% A*01% B*51% A*02%% Cw*15% A*30% Cw*0701% Cw*17% A*24% Cw*04% A*03%% A*11% A*33% Cw*0602% Cw*05% Cw*1203% Cw*12% Cw*03% A*2601% Cw*0702% A-B associations B-C associations
Population-specific HLA haplotypes (i.e. non random associations between alleles at separate loci) have been identified in all human populations studied. Non-overlapping MHC associations in the Hutterite population One pathogen causes more mortality than the other: Immune selection within multi-locus systems
• can generate and maintain HLA associations, even in the presence of recombination
• can drive specifically non-overlapping associations between HLA alleles
possible implications for functional classification of HLA alleles
• can generate co-evolutionary dynamics matching allele system with adaptive immunity Acknowledgements
Bridget Penman Martin Maiden Caroline Buckee Keith Jolley Eleanor Watkins Ian Feavers Ben Ashby Paula Kriz
Neil Ferguson Chris Newbold Roy Anderson Bob Snow Robert May Kevin Marsh Karen Day Brian Greenwood