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B3.0 > Evolutionary Dynamics Of Infectious Disease II > Flashcards

Evolutionary Dynamics Of Infectious Disease II Flashcards

1
Q

conserved determinants

A
  • competition amoung strains for susceptible hosts
  • immunological resistance to other strains
  • evolve -> single strain pop structure (SIR)
  • competitive exclusion: >R0 (optimal virulence)
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2
Q

variable determinate

A
  • 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
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3
Q

T&V under variable determinants

A
  • metabolite recruitment
  • iron chelation
  • receptor attachment
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4
Q

We need a more realistic model for antigenically variable pathogens

A
  • many loci for highly diverse antigens
  • multiple diverse antigens
  • each epitope variable
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5
Q

Multi-locus models

A
  • extend SIR into various dimensions
  • assume γ = 0
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6
Q

Discordant subset

A
  • 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
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7
Q

Neisseria meningitidis

A
  • 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
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8
Q

N. meningitidis serogroup C vaccine

A
  • capsule too similar to certain host proteins
  • we want to develop a protein-based vaccine
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9
Q

PorA

A
  • outer-membrane protein
  • barrel-like structure
  • epitope variable regions 1 and 2 combinations are non-random and non-overlapping
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10
Q

Antigenic types associated specifically w metabolic types (defined by clonal complex)

A
  • WG interrogation
  • BASTs
  • reaffirmed w longitudinal data from
    Czech Republic
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11
Q

BASTS

A

Bexsero Antigen Sequence Types

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12
Q

γ

A
  • 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
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13
Q

Immunological interactions between strains can lead to stable or cyclical/chaotic dynamics

A
  • no R0 assumptions: structure emerges regardless of fitness
  • varying γ
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14
Q

γ = 1

A
  • complete competitive exclusion
  • co-circulation of strains that don’t share any alleles/variants
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15
Q

As γ = 0

A
  • instability
  • stochastic: determined by small differences in initial conditions
  • frequency-dependent advantage
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16
Q

Relaxing selection

A
  • relaxes intrinsic strain competition
  • subsets can reverse/flip
17
Q

The epidemic behaviour of influenza is primarily determined by

A
  • immune responses acting upon antigenic determinants of limited variability (e.g. HA)
  • can we exploit these re vaccine?
18
Q

HIV

A
  • SSA
  • mortality is decreasing
  • multi locus model
  • various targets of both B and T cell immunity
19
Q

HIV genome and virion structure

A
  • envelope: CD4+ T cells (CCRX5 co-receptor)
  • protein: head, stalk, epitopes; presented by MHC
  • internal proteins also contain CD4+, CD8+ epitopes for immune escape
20
Q

HIV process

A

1) peak; plasma visions
2) acute phase; viraemia
3) chronic; viral set point
4) CD8+ &laquo_space;
5) memory
6) R mutants fast immune escape due to epitope change
7) CD4+ depletion

21
Q

Why do CD8+ «

A
  • short lifespan
  • antigen stimulus removed
22
Q

B cells

A
  • slow acting
  • not involved in initial crisis
  • > 12 wks post-infection
  • released against highly variable epitopes
23
Q

Escape from CD8+?

A
  • SIV model
  • neither necessary nor sufficient for -> AIDS
  • may lead to faster disease progression
24
Q

CD8+ escape?

A

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

25
Q

Switch in tropism?

A
  • ex vivo and animal models
  • CXCR4 switch in late stages due to target cell depletion accelerates progression
26
Q

Antigenic diversity threshold?

A
  • epitopes differ in their degree of variability
  • strain-specific responses to epitopes with high variability result in CD4+ differentiation
  • primary determinant of each strain &laquo_space;(SIR-type dynamic)
27
Q

Modelling antigenic diversity threshold pre-requisites

A
  • strain-specific responses: epitopes w high variability
  • cross-reactive responses: shared invariant epitopes
28
Q

Modelling antigenic diversity threshold

A
  • 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
29
Q

Immune response to HIV antigenic diversity

A
  • neutralising Abs to high variability of B cell epitopes (depletion: chronic HIV viral load spike)
  • CD8+ to low variability
  • both affected by CD4+
30
Q

Breakdown of HIV-I control is primarily linked to

A
  • loss of Ab instruction
  • increased B duration needs CD4+ for induction
  • models replicate in-host dynamics
31
Q

HIV antigenic determinant progress

A

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

32
Q

Elite controllers -

A
  • create large variation in set point

B3.0 (26 decks)

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