Evolutionary Dynamics Of Infectious Disease II Flashcards
conserved determinants
- competition amoung strains for susceptible hosts
- immunological resistance to other strains
- evolve -> single strain pop structure (SIR)
- competitive exclusion: >R0 (optimal virulence)
variable determinate
- avoids competition through epitope variation (w/o function/fitness)
- multi-strain population model
- stratify pops @ single locus (Pneumococcus)
- independent co-circulation
- no decrease -> optimal virulence (maintained)
- different Ts
- discrete metabolic types (non-overlapping associations)
- vaccination unpredictable
T&V under variable determinants
- metabolite recruitment
- iron chelation
- receptor attachment
We need a more realistic model for antigenically variable pathogens
- many loci for highly diverse antigens
- multiple diverse antigens
- each epitope variable
Multi-locus models
- extend SIR into various dimensions
- assume γ = 0
Discordant subset
- self-organisation into a state where only one subset exists @ high frequency
- immune selection acting @ multi-locus level, resulting in competitive exclusion
- non-overlapping combinations emerge
- can be scaled up to many alleles/loci
Neisseria meningitidis
- gram -ve
- nasopharyngeal
- invasive infections: meningitis, sepsis
- capsule serotype defines serogroups: A, B, C, W135, Y…
- B, C, Y: endemic worldwide; European vaccines
- outbreaks in meningitis belt; SSA
- high mortality
- A, B, W135, Y = good vaccines
- C = bad vaccine
N. meningitidis serogroup C vaccine
- capsule too similar to certain host proteins
- we want to develop a protein-based vaccine
PorA
- outer-membrane protein
- barrel-like structure
- epitope variable regions 1 and 2 combinations are non-random and non-overlapping
Antigenic types associated specifically w metabolic types (defined by clonal complex)
- WG interrogation
- BASTs
- reaffirmed w longitudinal data from
Czech Republic
BASTS
Bexsero Antigen Sequence Types
γ
- the degree of immunological cross-protection conferred by exposure to any related antigenic type
- a measure of the strength of immune selection
- sufficiency of Abs to prevent further infection
Immunological interactions between strains can lead to stable or cyclical/chaotic dynamics
- no R0 assumptions: structure emerges regardless of fitness
- varying γ
γ = 1
- complete competitive exclusion
- co-circulation of strains that don’t share any alleles/variants
As γ = 0
- instability
- stochastic: determined by small differences in initial conditions
- frequency-dependent advantage
Relaxing selection
- relaxes intrinsic strain competition
- subsets can reverse/flip
The epidemic behaviour of influenza is primarily determined by
- immune responses acting upon antigenic determinants of limited variability (e.g. HA)
- can we exploit these re vaccine?
HIV
- SSA
- mortality is decreasing
- multi locus model
- various targets of both B and T cell immunity
HIV genome and virion structure
- envelope: CD4+ T cells (CCRX5 co-receptor)
- protein: head, stalk, epitopes; presented by MHC
- internal proteins also contain CD4+, CD8+ epitopes for immune escape
HIV process
1) peak; plasma visions
2) acute phase; viraemia
3) chronic; viral set point
4) CD8+ «_space;
5) memory
6) R mutants fast immune escape due to epitope change
7) CD4+ depletion
Why do CD8+ «
- short lifespan
- antigen stimulus removed
B cells
- slow acting
- not involved in initial crisis
- > 12 wks post-infection
- released against highly variable epitopes
Escape from CD8+?
- SIV model
- neither necessary nor sufficient for -> AIDS
- may lead to faster disease progression
CD8+ escape?
1) strong, broadly directed and high avidity γ-interferon + CD8+ persist
2) CD4+ cell count not correlated with anti-HIV CD8+ circulation or CD8+ mediated lysis
3) CD8+ function is not correlated with viraemia
4) no prognostic link between CD8+ functionality in early infection and AIDS survival time
Switch in tropism?
- ex vivo and animal models
- CXCR4 switch in late stages due to target cell depletion accelerates progression
Antigenic diversity threshold?
- epitopes differ in their degree of variability
- strain-specific responses to epitopes with high variability result in CD4+ differentiation
- primary determinant of each strain «_space;(SIR-type dynamic)
Modelling antigenic diversity threshold pre-requisites
- strain-specific responses: epitopes w high variability
- cross-reactive responses: shared invariant epitopes
Modelling antigenic diversity threshold
- seed model with 1 strain
- new strains w novel variable epitopes generated by mutation
- breakdown of control linked to how many antigenic types in system
- too many strains to support an equilibrium state
Immune response to HIV antigenic diversity
- neutralising Abs to high variability of B cell epitopes (depletion: chronic HIV viral load spike)
- CD8+ to low variability
- both affected by CD4+
Breakdown of HIV-I control is primarily linked to
- loss of Ab instruction
- increased B duration needs CD4+ for induction
- models replicate in-host dynamics
HIV antigenic determinant progress
1) sequential appearance of different variants, mediated by immune selection acting @ ML level
2) B and T cells maintain control
3) CD4+ decline; B decline; re-emergence
4) chronic (B; CD4+ aided)
5) CD4+ depletion leads to B breakdown; rapid growth
Elite controllers -
- create large variation in set point
