Evolutionary Dynamics of Infectious Disease Flashcards
SIR
- measles, mumps, rubella
- childhood diseases
- we can vaccinate (durable protection)
SI
- HIV
- potential vaccination; don’t want to replicate natural immunity (because of stable dynamic)
- logistic growth that reaches equilibrium
- evades immune clearance
SIRS
- flu, SARS-CoV-2
- clearance and re-infection
- antigenic diversity
- model expansion (strains, behavioural differences [sequential dominance, e.g flu])
- potential for short term vaccines against circulating strains (partial prevention)
Antigenic diversity
- changes antigens through which we recognise and mount immunity
- R host becomes S
Dominant targets of immunity
Determinant epitopes
Invariant epitopes
SIR
Measles vs flu
- Constrained -> variable continuum
- multi-locus entities @ level of antigenic sites
- similar viruses: HA
HA
- surfaces to facilitate viral attachment
- RBS to engage relevant receptor
Measles
- epitope central of RBS (Arg333, Asp505)
- under v. strong immune selection
- escape = difficult due to high structural constraint
Flu RBS
- protected in crater by overhanging crags of HA loop epitopes
- binds to sialic acid residues in host cell membrane
- released from structural constrains = change!
You can categorise an array of genes by specific functions
- Regulatory
- Metabolic
- Structural
Functions must separately encode
1) transmission
2) virulence
3) antigenic determinants
SIR models assume
- conservation of dominant epitopes
- same virulence
What if there is a different in transmissibility under SIR
- creates different “I” compartments
- higher transmissibility leads to higher R0 (R0 = BD)
- competitive exclusion
What is the strains are equally transmissible, but vary in virulence?
- α (pathogen-induced mortality, from I compartment) has an inverse relationship with D
- virulence reduced competitiveness
Variability in virulence: D =
1 / (σ + α); where σ = I->R
T/V Tradeoff
- factors can affect both (e.g. viral load)
- B α V
- D α -V
- R0 may be maximised at intermediate virulence
European rabbit in Australia
- 1859: 24x rabbits introduced
- 1866: 14,253 rabbits shot
- 1950: Myxoma release as vertebrate biocontrol
Grade I myxoma
- fully virulent
- mortality: 10-15 days
- 12% fleas infective
Grade 3
- intermediate virulence
- mortality: 17-44 days
- 42% fleas infective
Grade 5
- attenuated
- no mortality
- 8% fleas
1952-1955 myxoma distribution
- 1: 12%
- 3: 52%
1975-1981 myxoma distribution
- 1: 1%
- 3: 68%
Can imperfect vaccines increase virulence?
- protect against severe outcomes (still good!)
- don’t necessarily stop infection; decouples intrinsic virulence + effect on host
Vaccinating a fraction of the population…
- alters effect on host, but not transmission
- point of optimal virulence is higher, since prolonging lifespans «_space;α
- removes evolutionary pressure
- severe strains higher frequency
- need total vaccination
- accessibility
Marek’s disease
- highly contagious lymphoproliferative disease of poultry
- caused by MDV
- chronic
- annual loss > $1bill
- overcome vaccines
- independent virulence paths in Eurasia and NA
Marek’s disease live vaccine
- in ovo: 18 day old embryo
- hatchlings
- hard to prove > R arises from vaccination advent
MDV
oncogenic herpesvirus
Absence of competition
- promotes co-existence
- cross-immunity = γ
When γ = 0,
Strains function independently
To what extent can you get coexistence, depending on the level of immunological interference?
- range!
- total coexistence -> total competitive exclusion
- region of coexistence broadens as γ -> 0
- niche differentiation along axes hypervolume
- partitioning and segregation
Escaping γ
- How can human-associated B. parapertussis and B. pertussis coexist when vaccinating against B. pert protects you against B. para?
- How could B. para invade when B. pert was endemic?
Bordetellae
- came from B. bronchiseptica in pigs (persistent commensal)
- O antigen, outer core, inner core, Lipid A
B. pert
- 5-10,000ya
- Neolithic revolution
B. para
- acute immunising respiratory pathogens
- genomic rearrangement and reduction
- more recently emerged (500ya)
- evolutionarily independent lineage (re. phylogeny)
O- antigen
- part of LPS
- structural preservation and membrane transport
- rough/smooth: P/A
- protects B. para from γ in Mus
- crucial for establishment; facilitated coexistence and co-circulation
O antigen phylogeny
- B. pertussis: no
- B. para: retained
- B. broncho: retained
Deleting O antigen from B. para
- naive mice: no change
- B. pertussis immunised mice: no colonisation (makes it immune-susceptible)
B. para vaccine
- prevent severe disease
- not lifelong
Streptococcus pneumoniae
- Gram +ve
- nasopharyngeal
- invasive infections: pneumonia, meningitis, sepsis
- > 800,000 deaths < 5yo (esp. SSA)
- > 100 capsule types (minimises γ: differentiation of antigenic targets)
- ~15 pathogenic
- natural immunity: no R, prevents α
Pneumococcal conjugate vaccines:
- polysaccharide: protein
- PCV7
- PCV13
“From the POV of the adaptive immune system,
each S. pneumoniae serotype represents a distinct organism”
cps locus
- polysaccharide biosynthetic enzymes
- associated w virulence
- targeted by vaccines
Serum therapy?
- anti-capsular horse serum
- type-specific vaccines
- little evidence from natural immunity
Differentiation of cps locus:
- high
- flippase assembly system
- v high diversity permits coexistence
Kilifi, Kenya methodology
- 2840 children (3-59m): nasopharyngeal swabs
- 1868 (66%) +ve @ baseline
- reswabbed: 1, 2, 4, 8, 16, 30, 60, 90 days
- until two consecutive swabs found -ve for baseline serotype (no pneu/ a different type
Kilifi, Kenya measuring
- R0 (B, D)
- weak competition and widespread coexistence
- no optimisation of single strain; standing diversity
Salmonella typhimurium
- direct interactions mediate competition; classical ecology
- recruits immune system to alter competitive landscape via sophisticated strategy
- respires ethanolamine (abundant simple substrate carbon source released by host tissues but useless to competitors)
- growth advantage
- requires tetrathionate (respiratory EA)
Salmonella typhimurium pathology
- invasion: T3SS
- epithelium -> macrophages -> inflammation!
- neutrophils: secrete ROS; thiosulphate oxidation -> tetrathionate
Lineage structure in bacterial pops
sequence clusters associate w antigenic serotype
Resource competition
Discrete metabolic types, drives diversification
Metabolic analysis of pneumococcal genomes
- 616 from Massachusetts
- 890 loci (+ transport)
- allelic diversity: Genome Comparator
- discrete, distinct barcodes constitute metabolic loci, and associate w a particular serotype
PCVs can alter the genome profile of non-vaccine serotypes
- vaccinating against particular serotypes in a modular pop
- immune selection on capsule
- increased T and V?
- ## 40% increase in Pilus Type II in 19A since PCV7; elements rearrange to find optimal structure
Modular reorganisation investigation
- machine learning analysis
- immune selection on groEL HSP
- elicits Ab
1) identify which serotype each isolate belongs to, via barcode
2) rank genotype informativeness of isolates by serotype
3) score = gene predictivity
groEL
- operation is critical in protein folding
- epistatic
- potential vaccine candidate?
