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GENOMICS OF DISEASE EMERGENCE/VIRULENCE - Coggle Diagram
GENOMICS OF DISEASE EMERGENCE/VIRULENCE
population genomics and the evolution of bacteria
methods are equally applicable across phenotypes
zoonotic - found in animals and humans, spread between the two
all are principally non-pathogenic
the big questions
what is the basis for pathogenicity? - what makes a pathogen pathogenic?
how do they cause disease? - epidemiology/transmission dynamics
where do pathogens come from (evolution)? - can we predict/detect early emerging pathogens?
often asked simultaneously
pathogenesis & disease emergence
compare genomes of pathogens with other genomes
ancestors
related non-pathogens
often already have a good idea of ancestors
can identify genomic changes resulting in pathogen
evolution...gene acquisition
very important
homologous recombination - bacterial genome acquires gene from another bacteria and that gene replaces the same gene
non-homologous recombination is the acquisition of a completely new gene
genomic islands - large chunks of DNA present in some strains but not others
how do we tell if they are adaptive ie. confer virulence?
functional homology: presence in pathogenic strains but absent in closely related non pathogenic strains eg. pathogenicity islands (PAI's)
PAIs
often differ from core GC content
laterally acquired DNA
often flanked by small direct repeats
recombination
often contain mobility genes
can lead to instability
mosaic structure
derive from multiple events
can be plasmid borne
plasmid derived:
Shigella, Y. pestis, B. anthracis
H. pylori
CagA PAI
Helicobacter pylori
history
in 1982 a culture of a spiral shaped bacterium from gastric biopsies of patients with gastritis was isolated
stomach was thought to be inhospitable because of acidic condition
epidemiology
discovery revolutionised diagnosis, treatment and prognosis of upper gastrointestinal diseases including gastric cancer (strong association)
infection occurs worldwide - up to 80% of some country's populations
prevalence depends on country and population groups
overall prevalence strongly correlates with socio-economic conditions
in middle aged adults in developing countries prevalence is 80%, in industrialised countries 20-50% (rate of acquisition decreasing)
acquisition
: oral ingestion of the bacterium
transmission
: within families in early childhood, not isolated from water etc.
pathogenesis
H. pylori genome
changes continuously
Vac A,
Vac
A Gene Variants, more severe disease
Can pathogenicity island, translocates CagA into host cell, phosphorylated, binds SHP-2 TP -> growth factor-like cellular responses and cytokine production by host cell
Bab A adhesion, Binds fucosylated Lewis B, Blood group antigen
Hop proteins, adhesins
Ure 1
, pH Gated urea channel
by looking at the genome we can see that there are explainable observable functions relating to enhanced virulence/pathogenicity
A GWAS on
Helicobacter pylori
strains points to genetic variants associated with gastric cancer risk
Cag PAI
CagA (cytotoxin-associated gene A) on the 40kb Can PAI is found in ~60% of strains isolated in Western countries and almost all from East Asia
also encodes for a type 4 secretion system used to "inject" CagA into a target host cell. after translocation, CagA localises to the inner surface of the cell membrane and undergoes tyrosine phosphorylation by Src family kinases
Role in Cancer
CagA is thought to be involved in cancer development
phosphorylated CagA is able to interact with the SHP-2 tyrosine phosphatase, rendering it functionally active, triggering a host cell morphological change to a more motile phenotype known as the "hummingbird phenotype". this phenotype may participate in various aspects of cancer, including metastasis
the proteins encoded by these genes assemble to form a complex type IV secretion apparatus capable of delivering CagA from the bacterium into host cells
translocation of CagA into gastric epithelial cells
phosphorylation of CagA by host cell kinases
c
-Src and Lyn
1 more item...
E. coli
LEE (locus for enterocyte effacement, enterohemorrhagic
e. coli
EHEC
salmonella
PAIs
phage derived: shiva toxin, cholera toxin
provide strong clues to basis for pathogenicity of the bacterium
PAIs in
Bodatella pertussis
a component of the lipopolysaccharide (LPS), O-antigen is an important Gram-negative factor
protects against innate immunity
blocks antibody binding
provides protection against environmental stresses eg. antibiotics
this genomic region has low GC content suggesting HGT
convergent evolution (homoplasy)
genomics of pathogen emergence
where do pathogens come from? (evolution)
can we predict/detect early emerging pathogens?
pathogenic `
S.aureus
causes a variety of diseases in poultry and other avian species
plasmic mediated virulence has been implicated
hock burn
foot lesions
systemic infections
poultry associated - unlike the CagPIA the genomic elements of disease association are not known
Recombination-Mediated Host Adaptation by Avian
Staphylococcus aureus
population structure
some isolates from chickens, some from humans
association vs. adaptation
look for acquisition of genes
has acquired variation en route to pathogenicity
how do we know which of these acquisition events actually caused disease?
which are neutral/adaptive/actually cause disease?
majority of poultry-association in the core and accessory genome is colocalized in three chromosomal regions which are labeled
PAIs
transposon-related genes
hypothetical proteins
phage-related genes
HOMOPLASY - THE INDEPENDENT EMERGENCE OF THE SAME FEATURE IN SEPARATE LINEAGES