populate the concept map with terms from the lecture PowerPoint and draw/label any connections betwe

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Dr. Sean Murray

Mid-70s, Children in Lyme, CT

arthritis

Mid-70s, Children in Lyme, CT

arthritis

rash

Mid-70s, Children in Lyme, CT

arthritis

rash

conjunctivitis

Mid-70s, Children in Lyme, CT

arthritis

rash

conjunctivitis

fatigue/fever
headache
stiff neck

Mid-70s, Children in Lyme, CT

arthritis

rash

pain
numbness
weakness

conjunctivitis

fatigue/fever
headache
stiff neck

Mid-70s, Children in Lyme, CT

arthritis

facial
paralysis

rash

pain
numbness
weakness

conjunctivitis

fatigue/fever
headache
stiff neck

Mid-70s, Children in Lyme, CT

arthritis

facial
paralysis

rash

pain
numbness
weakness

conjunctivitis

fatigue/fever
headache
stiff neck

cardiac and/or neurological symptoms

What caused this illness?

Early 1980’s: the gram-negative
bacterium Borrelia burgdorferi

Identification of Borrelia as
causative agent of Lyme disease

• Isolate single colonies of Borrelia from ticks
• Grow up colonies, feed to ticks
• Let ticks bite rabbits
• See rash
• Isolate Borrelia from people with Lyme

disease

How were the children exposed to
this bacterium?

Dime

Photos by John VanDyk, Iowa State Univ.

How were the children exposed to
this bacterium?

Dime

Photos by John VanDyk, Iowa State Univ.

…via tick saliva (yuck!)

Tick after feeding….

Must feed for at least 24 hours to pass
on Borrelia burgdorferi bacteria to its host

How did ticks get infected with
Borrelia bergdorferi?

reservoirs

Life cycle of Borrelia burgdorferi in
the tick (Ixodes)

What we’ve discussed so far…

Lyme disease is NOT a new disease

• 1883 Lyme-related symptoms reported
in Germany

• 1909 Linked Lyme-related symptoms
with tick bites in Sweden

• ~1950 Treat symptoms with
antibiotics in Europe

• 1970 First tick-related rash reported in
USA

2002 Lyme Disease Cases by State as Reported to CDC
n=23,763

3989

37
219

261
18075535
852

4631
2349

194

D.C.
25

259

137

1112

1090

867

139

0 3

738

Ecological conditions in the northeast
maintain lyme disease

• Reforestation of northeast (after being previously
deforested for farmland); contiguous forested
area allows for mice, deer, birds, and ticks to
spread to new areas

• Residential development of reforested areas
(suburbs)

• Borrelia burgdorferi’s ability to infect multiple
species

How does Borrelia evade the immunity
of very different species?

reservoirs

Study Borrelia at the molecular level

Some Basic Immunology
• White blood cells recognize pathogen surface structures

(innate immunity)
• Pathogen is internalized and degraded to peptide

fragments

White Blood Cell Presents short
internalizes Pathogen degraded; peptides on surface
Pathogen peptides produced for Antibody production

Some Basic Immunology
• White blood cells recognize surface pathogen surface

structures (innate immunity)
• Pathogen is internalized and degraded to peptide

fragments

White Blood Cell Presents short
internalizes Pathogen degraded; peptides on surface
Pathogen peptides produced for Antibody production

Secretion molecules
to attract more WBCs;
inflammation

Some Basic Immunology
• White blood cells recognize surface pathogen surface

structures (innate immunity)
• Pathogen is internalized and degraded to peptide

fragments

White Blood Cell Presents short
internalizes Pathogen degraded; peptides on surface
Pathogen peptides produced for Antibody production

e.g. YVLEGTLTA
Secretion molecules
to attract more WBCs;
inflammation

Antibodies

• Bind to targets with
high affinity

• Trigger WBCs to
ingest pathogens and
destroy them

• Help complement
make holes in
pathogen membranes

Activated complement

Bacterial pathogens

bacterial
pathogen

intracellular

extracellular

Bacterial pathogens

bacterial
pathogen

intracellular

extracellular

Hide within host
cells, don’t worry
about hiding
surface protein

Avoid killing by
WBCs by living
inside them

Survival Strategies

Bacterial pathogens

bacterial
pathogen

intracellular

extracellular

Hide antigens to avoid immune response
Vary surface proteins by mutation

Survival Strategies

Hide in immune privileged sites

Hide within host
cells, don’t worry
about hiding
surface protein

Avoid killing by
WBCs by living
inside them

Bacterial pathogens

bacterial
pathogen

intracellular

extracellular

Hide antigens to avoid immune response
Vary surface proteins by mutation

Survival Strategies

Hide in immune privileged sites

Hide within host
cells, don’t worry
about hiding
surface protein

Avoid killing by
WBCs by living
inside host cells

Borrelia

Host-pathogen interactions

Tick saliva
inhibits immunity

Borrelia lacks or hides
common bacterial
surface structures

Bacterial cell envelopes
Gram-negative

Gram-positive

inner
membrane
(phospholipids)

peptidoglycan
(sugars)

lipopolysaccharide
asymmetric outer
membrane
phospholipids

lipids with chain of
sugars attached

endotoxin

Borrelia’s outer membrane has no
lipopolysaccharide endotoxin

Benefit: Borrelia doesn’t
trigger septic shock
in its hosts, which could kill
the host when Borrelia
travels though the host
bloodstream

outer membrane

inner membrane

periplasm

peptidoglycan

Borrelia’s flagella lie between the
inner and outer membranes

Benefit: Flagellar antigens hidden from the host immune system

Caulobacter

Tick saliva
inhibits immunity

Borrelia lacks or hides
common bacterial
surface structures

Borrelia prevents
attack by complement

Host-pathogen interactions

Complement evasion mediated by lipoproteins

outer
membrane

Borrelia is resistant to host-
complement

Borrelia has lipoproteins on its surface that recruit
a host protein that prevents pores from being
made in its membrane

Tick saliva
inhibits immunity

Borrelia lacks or hides
common bacterial
surface structures

Borrelia prevents
attack by complement

Borrelia adapts
to very different hosts

Host-pathogen interactions

Borrelia must adapt to its
environment

• Temperature
cold-blooded warm-blooded

Borrelia must adapt to its
environment

• Temperature

• pH

cold-blooded warm-blooded

Unfed tick
pH 7.4

Fed tick
pH 6.8

Borrelia must adapt to its
environment

• Temperature

• pH

• Cell density

cold-blooded warm-blooded

Unfed tick
pH 7.4

Fed tick
pH 6.8

Borrelia only expresses proteins
when needed

• OspA (Outer Surface Protein) lipoprotein is
adhesin used to bind to tick midgut – expressed
only in ticks

• OspC helps Borrelia migrate into salivary gland
• Feeding tick vs Unfed tick

OspA
OspC

How does Borrelia modulate OspA/
OspC?

• Temperature change regulates
topoisomerase enzymes, which control
supercoiling of DNA

• High Temp: decreased supercoiling
OspA OspC

• Low Temp: increased supercoiling
OspA OspC

DNA Supercoiling

Transcription factor binding promoter

OspA and OspC accumulation and ospA and ospC
transcription levels change in response to temperature

Alverson et al., Mol. Microbiol. 2003

Western blot
with anti-OpsA
or anti-OspC

RNA agarose gel

Plasmid supercoiling in Borrelia changes in
response to temperature

Alverson et al., Mol. Microbiol. 2003

Increased
supercoiling

Decreased
supercoiling

DNA agarose
gel of uncut
plasmid DNA

Plasmid supercoiling in Borrelia changes in
response to temperature

Alverson et al., Mol. Microbiol. 2003

supercoiling

ospA transcription

Plasmid supercoiling in Borrelia changes in
response to temperature

Alverson et al., Mol. Microbiol. 2003

supercoiling

ospC transcription

What happens to OspC if we change DNA
supercoiling with topoisomerase mutant?
• Gyrases increase DNA supercoiling
• gyrB mutants

– Reduced gyrase activity
– Decreased DNA supercoiling

OspC synthesis increases in gyrB mutant

Alverson et al., Mol. Microbiol. 2003

Wild type gyrB mutant

Western blot with anti-OspC

Tick saliva
inhibits immunity

Borrelia lacks or hides
common bacterial
surface structures

Borrelia prevents
attack by complement

Borrelia adapts
to very different hosts

Borrelia changes
its surface proteins
to stay one step ahead
of host antibodies

Host-pathogen interactions

Alter exposed antigens
Generate
antibodies
against specific
amino acid
sequences

Change amino acid sequence
of lipoproteins exposed on surface

original infection

original
Borrelia is now mixed population

Originals die
Variants 1 & 2 live
Cycle repeats

variant 1

variant 1 variant 2

When Borrelia faces a tough fight, it has
been proposed to hide…

• Immune privileged sites
– brain
– eye
– ovary/testis

• Immune system does not function in these
sites because inflammation there could
cause irreversible damage

• Borrelia may hide in these areas waiting to
surface again

Treatment
• antibiotics
• Chronic arthritis may develop after infection

clears………Why?

molecular mimicry

Molecular mimicry
• antibiotics
• Chronic arthritis may develop after infection

clears………Why?

White Blood Cell Presents short
internalizes Pathogen degraded; peptides on surface
Pathogen peptides produced for Antibody production

e.g. YVLEGTLTA

may resemble self-peptide

How can the immune system attack
itself?

Protein Sequence
OspA 165-173 YVLEGTLTA

Human Protein 332-340 YVIEGTSKQ

Associated with chronic arthritis

Prevention

• Don’t leave head or skin exposed in high-
risk areas

• Shower and inspect head or skin for ticks
afterwards and remove any ticks with
tweezers

• Get tested for Borrelia antibodies if you
have Lyme-disease-like symptoms

Lyme cycle: temperature, pH, cell density

ADAPT
OspA

#2#3

Lyme cycle: temperature, pH, cell density

ADAPT
OspA

ADAPT
OspC

OspA
#1

#2#3

Lyme cycle: temperature, pH, cell density

ADAPT
OspA

ADAPT
OspC

OspA

ADAPT

ADAPT
OspC

OspA

#2#3

Lyme cycle: temperature, pH, cell density

ADAPT
OspA

ADAPT
OspC

OspA

ADAPT

ADAPT
OspC

OspA

ADAPT AND FACE
IMMUNE ATTACK:
change antigens
hide in IP sites

More symptoms
#2

Lyme cycle: temperature, pH, cell density

ADAPT
OspA

ADAPT
OspC

OspA

ADAPT

ADAPT
OspC

OspA

IMMUNE ATTACK
AND ADAPTION:
change antigens
hide in IP sites

More symptoms

ADAPT AND FACE
IMMUNE ATTACK:
change antigens
hide in IP sites

More
symptoms

#2#3

Lyme cycle: temperature, pH, cell density

ADAPT
OspA

ADAPT
OspC

OspA

ADAPT

ADAPT
OspC

OspA

ADAPT AND FACE
IMMUNE ATTACK:
change antigens
hide in IP sites

More symptoms

ADAPT AND FACE
IMMUNE ATTACK:
change antigens
hide in IP sites

More
symptoms

#2#3

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