17. Persistent bacterial infection Flashcards
How does a persistent infection differ from an acute infection?
some bacteria remain and resist the immune system
immune status quo established
what 7 things drive persistence?
- Colonisation of specific site
- Modification of intracellular environment
- Host mimicry
- Resistance to immune effector mechanisms
- Anti-phagocyte defence
- Selective gene inactivation
- Antigenic variation
what is Lyme disease?
first described in 1977 while investigating juvenile arthritis
most prevalent tick-borne illness in US, Europe and Asia
skin, nervous system, heart and joints
bimodal age distribution
transmitted by Ixodes tick when feeding
what causes Lyme disease?
Borrelia burgdorferi (main one)
Borrelia garinii
Borrelia afzelii
what is Borrelia burgdorferi?
is a spirochaete
motile
spiral structure flagella enclosed between the membranes
distinct morphology
What is the Ixodes tick life cycle?
2 year life cycle
4 development forms
eggs laid in spring and hatch in summer
larva becomes infected when it feeds from infected organism
Nymph takes blood meal through the next spring
adults feed and mate during next summer and autumn
then lay eggs
What are the 4 developmental forms of the Ixodes Tick?
Eggs, Larva, Nymph, Adults
What form of the Ixodes Tick is primarily responsible for transmission to humans?
The Nymph
due to human mostly being outside in the spring and summer
need to feed for 36-48 hours to transmit infection
What is the early stage of Lyme disease?
localised infection
expanding rash from bite - erythema migrans
lasts 3-4 weeks
what is the dissemination stage of Lyme disease?
in the weeks following initial infection
spread haematogenously to body tissues
multiple rashes
fatigue, chills, headache, fever, joint pain, swollen lymph nodes
can persist for 3 months
what is post-treatment Lyme disease syndrome (PTLDS)?
Disabling symptoms lasting more the 6 months
joint pain, cognitive issues, fatigue
no evidence of active infection so a question of if its actually caused by Lyme disease
What is the pathogenesis of B. burgdorferi?
lipoproteins interact with host immune system (no toxins or LPS)
OspA and OspB stimulate cytokine release and trigger inflammation
disruption of tight junctions
induce break down of ECM
pass between cell endothelial linings into the blood and outrun phagocytes
what persistence mechanism does B. burgdorferi have?
OspC lipoprotein binds tick protein SALP15 impairs phagocytosis
BbCRASP binds factor H to inhibit complement activation
Antigenic variation of lipoproteins and surface proteins
What is chlamydiaceae?
gram negative
obligate intracellular pathogens
what are the relevant 3 species of Chlamydiaceae?
C. trachomatis
C. pneumonia
C. psittaci
what disease does C. trachomatis cause?
STI - most common in humans
Trachoma (blindness) - endemic in Africa and Asia
what disease does C. psittaci cause?
psittacosis from parrots, pigeons and ducks
flu-like
what disease does C. pneumoniae cause?
Pneumonia and respiratory tract infections
why is chlamydia an obligate intracellular pathogen?
it cannot make ATP itself
What are the 3 developmental forms of chlamydia?
elementary body - non replicating and infectious
reticulate body - replicating and non infectious
Persistent body
what is the normal C. trachomatis lifecycle in the cell?
- elementary body binding to the cell and taken into the endosome
- elementary body turns into the reticulate and uses ATP from the cell
- undergoes 8-12 rounds of replication
- randomly, asynchronously goes back to the elementary body
- exit the cell via cell lysis or extrusion of the inclusion
how is the chlamydia persistent body infection different?
structurally and genetically distinct
survives for many months waiting to reactivate
infected cells constantly producing inflammatory cytokines
what are the 2 chlamydia pathogenesis hypotheses?
we don’t actually know what causing the disease pathogenesis
cellular hypothesis
immunological hypothesis
what is the chlamydia cellular hypothesis?
chronic proinflammatory cytokines release drives the tissue damage
What is the chlamydia immunlogical hypothesis?
the tissue damage is resulted from the host response to the chlamydia proteins
what are chlamydia mechanisms of persistence?
enhanced survival inside host cells as it limits exposure to Ig, phagocytes and T and B cells
persistent bodies cannot be treated with Ig
Type 3 secretion systems
inhibit host cell apoptosis
diverse surface proteins
Ig doesn’t prevent reinfection
what is Clostridioides difficile?
gram positive
Anaerobic
rod shaped
spore former so it can survive in the environment
C.diff infection
a spectrum of disease: mild diarrhoea to pseudomembranous colitis
hospital acquired
increases when treated with broad-spectrum antibiotics
what are the 3 infection outcomes of C. diff?
Asymptomatically colonised by non toxic C. diff
Asymptomatically colonised by toxic C. diff and an IgG response present
Symptomatic colonised by toxic C. diff and patient cannot mount an immune response
what is C. diff toxin induced colitis?
colonisation of the mucus layer
TcdA and TcdB encoded by pathogenicity island
TcdA binds the apical layer of the epithelium
causes glycosylates RhoGTPase
disrupts the tight junctions between cells
TcdB binds the basolateral side
causes neutrophil, epithelial breakdown and pseudomembrane formation
what makes up a pseudomembrane?
Immune cells
mucus
dead epithelium cells
what percentage of patients will have reinfection?
20-30% within 2 months
what causes the reinfection of C.diff?
relapse
a minority due to exogenous infection with spores
Antibiotic treatment cannot eliminate C. diff spores
what is helicobacter pylori?
a rod bacteria
acquired in childhood
half the world is infected
disease often doesn’t develop until adulthood
what does helicobacter pylori cause?
gastritis, peptic ulcer disease, gastric cancer
what is the only bacteria classed as a class 1 carcinogen?
helicobacter pylori
H. pylori pathogenesis: flagella
allows movement through mucus
H. pylori pathogenesis: surface adhesins
bind to gastric epithelium
BabA
BabB
H. pylori pathogenesis: secreted enzymes
urease makes ammonia to neutralise stomach pH
breakdown of musins so acid comes into contact with the epithelium
H. pylori pathogenesis: toxins CagA
Delivered by type 4 secretion system
disrupts tight junctions
stimulate pro inflammatory cytokines
H. pylori pathogenesis: toxins VacA
induces uptake into cells
vacuolation
apoptosis
what is vacuolation?
formation of large vesicles in epithelial cells
increase permeability of the epithelial cells
disrupts mitochondria and cause apoptosis
how does H. pylori persist?
environmental niche - the stomach
most immune cells cannot access the stomach due to the harsh environment
impairs phagocytic killing
evades PRR with not very biologically active LPS
VacA blocks antigen dependant T cell proliferation
promotes Treg cells
how is H. pylori’s genetic diversity good for persistence?
adapts constantly changing bodies and antigens
naturally competent cells that can take up DNA from other bacteria easily
