Transcript Bacterial Interactions with Host

Bacterial Interactions
with Host
Medical Microbiology
SBM 2044

When describing the interaction between
host and microbes, analogies to war are
common, as in references to a microbial
“attack” or “invasion” repelled by host
“defense systems.”
 In reality what drives microbes is not
aggression but survival and
reproduction. To succeed, many
microbes have evolved the ability to
persist in the body, only incidentally
causing disease…
Pathogenesis
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The pathogenesis of bacterial infection
includes initiation of the infectious process
and the mechanisms that lead to the
development of signs and symptoms of
disease.
Infectious process
– Once in the body, bacteria must attach or adhere
to host cells, usually epithelial cells
– After establishment, the bacteria multiply and
spread directly through tissues or via the
lymphatic system to the bloodstream.

E.g. S. pneumoniae
Microbial survival

To survive, microbes must do the
following:
– Avoid being washed away (colonize the
surfaces of host cells)
– Find a nutritionally compatible niche
– Survive the constitutive and induced
defenses
– Transfer to a new host
MCQ: True or False?
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Microorganisms are the worst pathogens if
they produce asymptomatic infection, rather
than death of the host. (T/F ?)
Why?
False. Because pathogens that normally live
in people enhance the possibility of
transmission from one person to another.
Surface colonization

Once the bacteria enter the body of the
host, they must adhere to cells or a tissue
surface
–
–

avoid being wash away
compete with resident flora for adherence sites
Complex interactions
– net surface charge
– surface hydrophobicity
– binding molecules on bacteria (ligands,
adhesins) and host cell receptors
Overview of interactions with host surfaces
 Nonspecific adhesion
• overall, surface interactions
• entrapment in mucin
> 50 nm
10 – 20 nm
 Specific
adhesion
Weak
long-range
attractive
Weak attractive
Electrostatic
repulsion
Van der Walls
< 2 nm
Repulsion reduced by:
(a) high ionic strength
(b) small diameter
Hydrophobic
interactions
< 1.0 nm
Specific
interactions
adhesin
receptor
easily
disrupted
Very strong
irreversible
Nonspecific adhesion
 Weakly adhering bacteria - easily removed by
physical shear forces or washing
 May allow colonisation of surfaces not subject to
strong physical/washing forces (e.g. skin, vagina)
 Not sufficient to colonise e.g. urinary tract, small
intestine, etc
Specific adhesion
EPEC adhering to an
intestinal epithelial cells
Bordetella pertussis on
to ciliated tracheal cell
Specific adhesion
The adhesin
specific molecule
on bacterial cell
surface
The receptor
specific molecule
on host surface
Usually: A surface protein Carbohydrate part of a
glycolipid or glycoprotein
(often lectins)
Others: e.g. LTA in Gram +
 Specificity analogous to enzyme-substrate specificity
Types of bacterial adhesins
 Individual protein molecules protruding from OM of
Gram-neg. bacteria, or cell-wall of Gram-pos. bact.
• protrude for distances ranging from < 10 - 20 nm,
up to ca.100nm (some Gram-pos. fibrillar adhesins)
Example:
Streptococcus pyogenes
M proteins
 Physical reasons why locating adhesins further away
from bacterial cell-surface – facilitate contacts with
receptors on mammalian cells
Bacterial Fimbriae
 Specialized, multimeric, adhesive ‘appendages’
protruding several microns - much further than
individual surface proteins.
• Adhesin often a minor subunit at tip
• many 100’s of copies of major
structural subunit
• Assembly apparatus in OM
OM
IM
AFIMBRIAL
adhesin
Fimbriae on surface of a human ETEC strain
 Strains may express > 1 distinct type of fimbriae,
with different receptor specificities
CS3 – thin, flexible
CS1
Adhesin-Receptor specificity
 First noted in late 1950s:
• A particular soluble sugar, but not others, inhibited
adhesion of E. coli to cells (rbc adhesion model )
Specific
adhesin
Specific
receptor
• By mimicking critical part of the specific receptor,
inhibitor blocked receptor-binding site of adhesin
 Type I pili: First E. coli adhesin identified
• MSHA: mannose-sensitive haemagglutination
Other bacterial species
 Wide variety of adhesins – both fimbrial & afimbrial
(e.g. invasin that recognises integrins)
 Some incorporate information on receptor-specificity
in name:
• Staphylococcus aureus: Fibronectin-binding proteins
Sialoprotein-binding protein
• Streptococcus pyogenes: Fibronectin-binding proteins
Collagen-binding protein
 Others first named for various reasons & only
later discovered to act (also) as adhesins.
• Streptococcus pyogenes: M proteins
• Neisseria gonorrhoeae: Opa proteins
Consequences of adhesion
1. Organism colonizes surface – e.g. normal flora
2. Pathogen colonizes surface and secretes toxins
Examples:
Vibrio cholerae
Enterotoxigenic E. coli (ETEC)
Small intestine
 Damage due mainly to action of secreted toxins
 Damage often localized (e.g. cholera), but if toxin
absorbed efficiently (e.g. diphtheria), may be
systemic (i.e. throughout body)
Consequences of adhesion
3. Colonize surface and form a biofilm
 In contrast to localised ‘colonies’, some pathogens
can form a spreading surface layer – a ‘BIOFILM’
• bacteria encased in a polysaccharide slime that aids
attachment and protects bacteria.
 ‘Simple’ biofilm: comprises a single species
• Staphylococcus epidermidis
biofilm on a catheters
‘Complex’ Biofilms:
 Comprise multiple species
 Bacterial ‘co-aggregation’
 Some species produce polysaccharides, ‘trapping’ others
Example: Dental plaque
Finding a Compatible Niche
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Nutritious plasma contains sugars, vitamins and
minerals…
– but bacteria grow sparsely on fresh plasma in a test
tube
– plasma lack free iron
Bacteria adapt by:
– use polymeric form of iron
– siderophores which are specific for ferric iron
– scavenging intracellular iron i.e. haemolysing
Specific nutrients only in certain body tissues
– streptococci use sucrose in the mouth
Evading the Consitutive/Induced
Defenses
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The host possess
– First line defense
– Second line defense

How do microbial agents overcome
these defenses?
Defending against complement
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1.
2.
3.
4.
5.
Microbes must prevent complement activation
Masking surface components (i.e. LPS, teichoic
acids) that activate alternative pathway 
secreting capsules to cover up
Incorporate sialic acid into their capsular
polysaccharides e.g. gonococci
Coating with circulating IgA – meningococci
Binding of C3b with viral envelope glycoprotein
such as in herpes simplex virus
Prevent access of MAC to its target, the bacterial
outer membrane – Salmonella and E. coli with
long O-antigen polysaccharide chain
Avoiding phagocytosis
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Many bacterial pathogens are rapidly
killed once they are ingested by
polymorphs or macrophages
But some pathogens are able to
multiply within host cells, by shielding
with normal host components on their
surfaces
Avoiding phagocytosis
1.
Inhibiting phagocyte recruitment and
function
•
•
Bordetella pertussis inhibit neutrophil
motility and chemotaxis – toxin
production
Group A streptococci produce C5a
peptidase – inactivates the chemotactic
products
Avoiding phagocytosis
2.
Microbial killing of phagocytes
•
•
3.
Leukocidins kill neutrophils and
macrophages – pseudomonads,
staphylococci, group A streptococci,
clostridia
shigellae kills phagocytic cells
Escaping ingestion
•
•
capsules
reduce opsonization e.g. staphylococci
protein A binds to IgG by the wrong end,
the Fc region
How microbes survive
inside phagocytes?
1.
2.
Inhibition of lysosome fusion with
phagosomes
Escapes into the cytoplasm
– shigellae, Listeria monocytogenes and
the rickettsiae cross the membrane of
the phagocytic vesicle and the
phagosome to enter cytoplasm, hence
protected from lysozymes
– L. monocytogenes secretes a poreforming toxin, listeriolysin
How microbes survive
inside phagocytes?
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Resistance to lysosomal enzymes
– Leishmania have resistant cell surfaces and
can withstand acidic environment
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Inhibition of the phagocytes ‘oxidative
pathway’
– Legionella inhibit the hexose-monophosphate
shunt and oxygen consumption in neutrophils,
thus reducing the free radicals respiratory
burst
– staphylococci produce catalase that breaks
down the H2O2
Intracellular life
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Obligatory for viruses, but not
bacteria.
Advantages? Protected from
antibodies, and from some
antimicrobial drugs
Intracellular microorganisms must be
able to:
– Penetrate
– Survive host cell defenses
– Transmit to other cells
1.
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Penetration
Easy with phagocytes
For non-phagocytic cells, penetration must be
induced by microbial activities –
–
2.
3.
bind to specific receptors and send signals
Surviving host cell defenses
Transmission to other cells
–
upon lysis of the host cells, transmission through
blood or body fluids
– viruses spread by cell fusing with uninfected
adjacent cells  formation of syncytia and
multinucleated giant cells
– use of host cytoskeleton to spread e.g. Shigella, L.
monocytogenes induce polymerization of actin at
one of their ends
Subverting the immune
responses
1.
Immunosuppression
–
infectious agents may suppress the host’s immune
responses. HIV infects the CD4+ T-helper
lymphocytes which lead to the collapse of the
immune system.
– tuberculosis was more common during the measles
outbreak
2.
Diversion of lymphocyte function:
superantigens
–
excessive stimulation of immune cells in a
nonproductive way e.g. toxins secreted by
streptococci are superantigens that cause
misdirection of the immune response
Subverting the immune
responses
3.
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Masquerading by changing antigenic coats
Trypanosomes
–
–
–
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covered with thick protein coat called variable surface
glycoprotein
have several hundred genes that encode various
antigens, but only ONE is expressed at a time
Gonococci
–
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Trypanosoma brucei cause sleeping sickness
periodic changes in pilin, protein of its pili
Influenza viruses
–
antigenic changes emerge gradually in a population of
viruses over an epidemic season
Subverting the immune
responses
4.
Proteolysis of antibodies
–
–
5.
extracellular proteases inactivate secretory IgA e.g.
in gonococci, meningococci and Haemophilus
influenzae
staphylokinase cleaves host plasminogen into
plasmin at the bacterial cell surface
Viral latency
– Herpes infection
– herpes virus pass from one cell to another through
cytoplasmic bridges
– viruses do not proliferate within cells
– other pathogens, Helicobacter pylori which causes
gastric ulcers and Mycobacterium tuberculosis also
maintain chronic associations with the host
Transmission of infection
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Infectious agents are carried into a new
host through food, aerosols, sexual contact,
wound or soil
Many microbes differentiate into a transit
form, to survive the environment
– Chlamydiae – elementary body
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Clinical manifestation of disease by
microorganisms often promote transmission
e.g.
– Vibrio cholerae, E. coli and Shigella cause
diarrhoea – intestinal contents secretion;
– M. tuberculosis induce coughing –dispersal via
aerosols