Concept map creation on extracellular pathogens

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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