Download Host-Pathogen Interaction and Human Disease

Stanley Falkow, May 2007
HostHost-Pathogen Interaction and Human Disease
Stanley Falkow
Host-Pathogen Interaction and Human
Disease, Part 1
HostHost-Pathogen Interaction and Human Disease
Part 1. What is a Pathogen?
Stanford University
Trying to Understand Human
Biology by the Study of
Pathogenic Bacteria
Humans are Heir to a Veritable
Sea of Smaller Creatures
Humans are Heir to a Veritable
Sea of Smaller Creatures
Professor of Microbiology
Bacteria –the smallest freefree-living organisms
Humans are Heir to a Veritable
Sea of Smaller Creatures
Parasites like the Protozoa, Worms
and Flukes
The American Society for Cell Biology
Viruses –Obligate Intracellular Parasites
Humans are Heir to a Veritable
Sea of Smaller Creatures
And even insects that live in your
eyebrows, hair and elsewhere
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Stanley Falkow, May 2007
90% of the Cells Humans Carry are Microbes
1013 Human Cells
1014 microbial cells
Normal (Commensal) Flora
in Humans
1. The makeup of our flora
depends upon various
factors, including genetics,
age, sex, stress, nutrition,
and diet of the individual
Host-Pathogen Interaction and Human
Disease, Part 1
90% of the Cells Humans Carry are Microbes
1013 Human Cells
1014 microbial cells
Normal (Commensal) Flora
in Humans
3. The flora often reflects
specific anatomic sites
2. Our flora synthesize and
excrete vitamins that can be
absorbed as nutrients
by the host
Normal (Commensal) Flora
in Humans
Normal (Commensal) Flora
in Humans
4. The Normal Microbial
Flora contributes to the first
line of innate immune
defense against incursion
by ‘foreign’
microorganisms
The American Society for Cell Biology
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Stanley Falkow, May 2007
What is the Difference
Between a Pathogen and a
Commensal?
Pathogens can
establish themselves in
a niche usually devoid
of commensal microbial
populations
What is the Difference
Between a Pathogen and a
Commensal?
Host-Pathogen Interaction and Human
Disease, Part 1
What is the Difference
Between a Pathogen and a
Commensal?
Pathogens possess
the inherent ability to
cross anatomic
barriers or breach
other host defenses
that limit commensals.
The Pathogen –CommensalCommensal-Host Ecological Landscape
It’s in the Genes!
Three Phases of Host Defense
The American Society for Cell Biology
Phase 1 Non-induced Innate Immunity
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Stanley Falkow, May 2007
Host-Pathogen Interaction and Human
Disease, Part 1
Bacteria and Other Microbes Have Unique Structures
Bacteria and Other Microbes Have Unique Structures
Bacteria and Other Microbes Have Unique Structures
Phase 2 induced Innate Immunity
That form the basis for
how host’s detect
microbes who ‘go to far’
Phase 2 induced Innate Immunity
The American Society for Cell Biology
Phase 2 induced Innate Immunity
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Stanley Falkow, May 2007
Phase 3 Induced Adaptive Immunity
And, of Course the Type of Host Matters
Young
Host-Pathogen Interaction and Human
Disease, Part 1
Thus, A Significant Part of Human Evolution has
gone into Developing Ways to Thwart Microbial
Intrusion
Bacterial Pathogenicity – A “Lifestyle”
Old
Entry into Host
Entry into Host
Humans have nine
“Portals”
Portals” serve as a
point of entry for one
or more pathogenic
microbes.
The American Society for Cell Biology
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Stanley Falkow, May 2007
Colonize
Host-Pathogen Interaction and Human
Disease, Part 1
They may get there by swimming
Many bacterial pathogens
are motile
Attachment to a
unique host cellular
target usually
determines the
niche.
They may get there by swimming
Many bacterial pathogens
are motile
Colonize
To avoid physical
and immunological
removal, bacteria must
adhere near or to host
cells
Colonize
Attachment to a
unique host cellular
target usually
determines the
niche.
The American Society for Cell Biology
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Stanley Falkow, May 2007
PersistDespite Host
Defenses
AvoidAvoid- hide, mimic
PersistDespite Host
Defenses
Host-Pathogen Interaction and Human
Disease, Part 1
PersistDespite Host
Defenses
AvoidAvoid- hide, mimic
PersistDespite Host
Defenses
Circumvent the host
Enzymes and toxins
allow local tissue spread
and perturb immune
function
The Streptococcus Strategy to Circumvent
the host
PersistDespite Host
Defenses
HideMicrobial Invasion
The Streptococcus Strategy to Circumvent
the host
The American Society for Cell Biology
7
Stanley Falkow, May 2007
HideMicrobial Invasion
Host-Pathogen Interaction and Human
Disease, Part 1
HideMicrobial Invasion
•Why?
–escape immune
surveillance
–nutrients
–parasitize host
cell machinery
–transportation
HideMicrobial Invasion
What do you do once you’ve gotten in?
•How?
–tight adherence
–pick right receptor
(internalization)
–provoke a
“disturbance”
disturbance” at cell
surface
What do you do once you’ve gotten in?
Subvert the Host’s Defense
Bacterial Toxins
Break-out of the vacuole and even swim around
The American Society for Cell Biology
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Stanley Falkow, May 2007
Some Bacterial Components trigger inflammation
Host-Pathogen Interaction and Human
Disease, Part 1
Some Bacterial Components trigger inflammation
Bacterial Endotoxin
Gramnegative
cell
cytopl.
mem.
peptidoglycan
outer mem.
Lipopolysaccharide
(LPS)
Lipid A
Core
polysaccharide
O sidechain
The toxic part
Helps solubilise Lipid A
Some Bacterial Components trigger inflammation
Some Bacterial Components trigger inflammation
Somatic antigen
Some Bacterial Components trigger inflammation
Subvert the Host’s Defense
Bacterial Exotoxins
The ‘’Floppy’ Baby Syndrome – Infant Botulism
The American Society for Cell Biology
9
Stanley Falkow, May 2007
Host-Pathogen Interaction and Human
Disease, Part 1
Subvert the Host’s Defense
Bacterial Exotoxins
Are Among the Most Potent
Poisons Known
Yet, From a Biological
Viewpoint They Are
Extraordinary in Their Variety
and Mode of Action
All in All, Pathogens are Impressive Cell Biologists
All in All Pathogens are Impressive Cell Biologists
Pathogenic bacteria
Interfere or Manipulate
for Their Own Benefit
Normal Function(s) of
the Host Cell
Replicate
“Every
bacterium’s
dream is to be
bacteria”
The American Society for Cell Biology
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Stanley Falkow, May 2007
Exit the Host
Host-Pathogen Interaction and Human
Disease, Part 1
Exit the Host
Sooner or later you have
to find a new host
The Corollaries of Pathogenicity
Bacterial Pathogens Use
Elaborate Regulatory
Mechanisms to Key on
Biochemical “Cues”
Cues” From
Their Host
pH, temperature, O2
CO2, osmolarity etc.
The Corollaries of Pathogenicity
Pathogens Respond to a
Host’
Host’s Biological and
Social Behavior
The American Society for Cell Biology
The Corollaries of Pathogenicity
Some Diseases of Human
Progress
Legionnaire's Disease
Toxic Shock Syndrome
HIV/AIDS
Lyme Disease
E. coli Hemorrhagic Fever
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Stanley Falkow, May 2007
The Corollaries of Pathogenicity
Legionnaire's Disease
Host-Pathogen Interaction and Human
Disease, Part 1
The Corollaries of Pathogenicity
Legionnaire's Disease
Legionella Really Likes to Grow
in Fresh Water Protozoa
The Corollaries of Pathogenicity
Legionnaire's Disease
The Corollaries of Pathogenicity
We Changed Some of Our
Habits Over Time
Legionella Really Likes to Grow
in Fresh Water Protozoa
The Corollaries of Pathogenicity
And so Did Legionella
The Corollaries of Pathogenicity
Legionnaire's Disease
So a Human Alveolar
Macrophage
Looks Pretty Good Too!
The American Society for Cell Biology
12
Stanley Falkow, May 2007
The Corollaries of Pathogenicity
Some Diseases of Human
Progress
Host-Pathogen Interaction and Human
Disease, Part 1
The Corollaries of Pathogenicity
Toxic Shock Syndrome
Legionnaire's Disease
Toxic Shock Syndrome
HIV/AIDS
Lyme Disease
E. coli Hemorrhagic Fever
The Corollaries of Pathogenicity
Women Changed Their Habits
The Corollaries of Pathogenicity
The Corollaries of Pathogenicity
Toxic Shock Syndrome
Human – Microbe Interactions is Still a “Work in Progress”‘
And it provided Staphylococci
with a ‘new opportunity’
And Human Misery
The American Society for Cell Biology
13
Stanley Falkow, May 2007
Host-Pathogen Interaction and Human
Disease, Part 1
Evolve and Share The Experience
Evolve and Share
The Experience
Evolve and Share
The Experience
Horizontal GeneTtransfer
Bacterial Pathogenicity can
evolve in genetic quantum
leaps
A Single Genetic Event can Change a
Commensal into a Pathogen
A Single Genetic Event can Change a
Commensal into a Pathogen
E. coli that cause urinary tract
infection differ from those that are
commensal inhabitants of the
bowel because they inherited
several blocs of genes
The American Society for Cell Biology
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Stanley Falkow, May 2007
Host-Pathogen Interaction and Human
Disease, Part 1
Pathogenicity factors of the uropathogenic strain E. coli 536
Iron Uptake
Fe3+
3+
Fe
Enterobactin
Yersiniabactin
Hemin uptake
Iro-system
α-Hemolysins
3+
S-fimbrial adhesin I
(Sfa I)
Fe Fe3+
Serumresistance
P-related
fimbriae
(Prf)
PAI I
PAI V
PAI II
PAI IV
PAI III
Flagella
(H31)
O-antigen
(O6)
K-antigen
( K15)
Curli
(Fim)
Type I-fimbriae
key colonization
factor for the
urinary tract
The iceberg concept of infectious disease
poliomyelitis in a child
0.1-1% of infections are
clinically apparent
Asymptomatic Infection Rates
classical
clinical disease
less severe
disease
rubella
50% of infections are
clinically apparent
asymptomatic infection
Spectrum
of virulence
Overt Clinical
Disease Need
Not be the
Outcome of a
Host-Pathogen
Interaction
M. tuberculosis - 90%
Salmonella typhi – 80%
Helicobacter pylori - 80%
Disease is the more the
Exception than the Rule
rabies
100% of infections
are clinically apparent
Pathogenicity is the
reflection of ongoing
evolution between a
parasite and a particular
Host
The American Society for Cell Biology
When we study
pathogens
we learn as much
about ourselves
as we do about them
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