Transcript The worm turns - James Cook University

The worm turns
Malcolm McDonald MBBS PhD FRACP FRCPA
Apunipima Cape York Health Council and James Cook University
The JCU Cairns Institute
Mandingalbay Yidindji people
Opening philosophical statements
“To do is to be.”
Réne Descartes [1596-1660] French philosopher
“To be is to do.”
GWF Hagel [1770-1831] German philosopher
“Do–be-do-be-do”
Frank Sinatra [1915-1998] American crooner
The wormier world of the
1950s
• worms: ‘love dirt’
• dirt: on the way out
• flush toilets: on the way in
• kids: got ‘wormed’ [nv]
• worms: in decline
• nowadays: few personal
worm stories in this room
Gut helminths: a spectrum
Disease [due to infection] α
dose X virulence
host resistance
Weak immune response  heavy worm burden  illness
Strong immune response  low worm burden  tolerance or even
immune-driven pathology
Strongyloides stercoralis
Greek: ‘strongylos’ = round ‘eidos’ = form
Latin: ‘stercora’ = dung, pus, general icky stuff
Percutiat te Dominus ulcere Aegypti et parte corporis per
quam stercora digeruntur scabie quoque et prurigine ita
ut curari nequea.
Deuteronomy 28.27
The LORD will smite thee with the boils of Egypt, with
the festering sores, the scabs and the itch, whereof thou
canst not be healed.
Deuteronomy 28.27
Strongyloides stercoralis life cycle
Autoinfection
Strongyloidiasis: clinical
• Infection/autoinfection  persistence,
often for decades. Mostly
asymptomatic. Eosinophilia common,
but not universal
• Skin: ground itch, later purpura
• Lung: cough, wheeze, pneumonitis
• GIT: abdominal pain, nausea, vomiting,
diarrhoea, malabsorption [rare]
• Buttocks: larva currens
Hyperinfection Syndrome [<10 cases/year]
• Autoinfection: rhabditiform larvae
transform to filariform larvae and penetrate the
gut wall  massive dissemination and sepsis
• Fever, cough, haemoptysis, wheeze,
GI symptoms, septic shock [enteric Gm –
ve]
• Eosinophilia typically absent
• Usually precipitated by impairment of
cell-mediated immunity: c’steroids
[>65%], chemotherapy, transplantation, severe
malnutrition, HTLV-1, etc
Letter: MJA 6th July 2015 – routine
serology in pregnancy?
Helminth immunomodulation
Worms need to live in our gut. Routinely
killing the host is not a cool strategy
Regulating the host’s immune response helps
worms to flourish and survive
T helper cell subsets: Th1, Th2, Th9, Th17
and Th22  each has an accompanying
response
• Th1: pro-inflammatory with TNF-α, IFN-γ, IL-12
and high levels of IgG2/3  Th1 anti-microbial
response; autoimmune diseases
• Th2: anti-inflammatory with IL-4, IL-5, IL-10, IL13 and higher levels of IgG4
• Th17: pro-inflammatory IL-17 and IL-22 [dual
roles]
Let’s dance
Helminths
• Switch the Th1 to Th2-type responses
[complex: partly through TLRs] and they
down-regulate Th17
• Have modulatory effects on both
regulatory T and B cells; and DCs
• Produce eosinophilia [through IL-5] and
a Th2 responses in adipose tissue 
AAM  accompanied by insulin sensitivity
• Also have a variable effect on the gut
microbiome  greater bacterial diversity
and reduced gut permeability  reduced
circulating pro-inflammatory markers
Th1 response
Th2 response
Lean
Adipocytes
Obese
IL-33
M2
M1
Insulin sensitivity
Insulin resistance
Th1 inflammation and type II diabetes mellitus
Raised inflammatory cytokines precede development of clinical manifestations, often for decades
Genetic & epigenetic factors
Dietary fat
Th1 inflammatory cytokines
Activation of
serine kinases
Phosphorylate insulin receptor
substrate proteins  insulin resistance
Hyper-insulinaemia
Adiponectin
Liver: gluconeogenesis
& fat deposition
Th1 inflamed adipose tissue
Islet cell ‘burnout’
IL-1β
IL-6
IFNα
Reduced pro-insulin conversion
Loss of glucose sensitivity
Th1 inflamed pancreatic islets
Increased amyloid polypeptide
Grossman V, et al. Diab Care 2015 [Apr]: ePub
Vaarala O, et al. Nature Rev 2012;8:323-5
Donath MY, et al. Nature Rev 2011:11:98-107
• Cross-sectional survey of 259 Aboriginal
adults in a remote WA community
• Prior S stercoralis infection determined by
ELISA
• Ninety two (36%) had prior infection and
131 (51%) had T2DM
• Those with prior S stercoralis infection
were 60% less likely to have T2DM than
those uninfected [adjusted for age, triglycerides, blood
pressure and BMI using propensity score: OR=0.39, 0.230.67, P=0.001]
• Strong ‘protective’ association but not
causation – certainly worth exploring with longitudinal
studies in populations at high risk of both conditions
Indonesian-Dutch
study published
June 2015
The homeostatic model
assessment for insulin
resistance (HOMAIR)
JCU study in a nearby community
• Cross sectional study using de-identified
data from the community’s annual Young
Persons Check [15-24yrs]
• Serology [ELISA test] to determine
past/current S stercoralis infection
• Identify who has the ‘metabolic syndrome’
[WHO criteria: based on glucose indicators, obesity,
lipid profile, BP and albuminuria]
• Aim: to determine if a positive ELISA is a
predictor of the metabolic syndrome, whilst
controlling for confounders [especially BMI]
• Study proposal has received JCU ethics
approval and is about to go ahead this month
Does exposure to ‘Old Friend’ organisms influence the
risk/progression of autoimmune diseases?
• There are many published mouse
studies
• Some have impressive results
• About 25 human trials completed/in
progress/registered
• Numbers are small; all phase I/II
• Inflammatory bowel disease,
rheumatoid arthritis, multiple
sclerosis, psoriasis, asthma, allergic
rhinitis
• Mixed results: as expected
Local champion
Hookworm vaccine
candidates
Relationship between
hookworm infection, IBD
and coeliac disease
Use of microarray
technology to explore the
activities of identified
helminth immunemodulating determinants
[ES proteins – AIP1 & AIP2]
Effect of helminth infection
on the gut microbiome
‘Autoimmune conditions’: Aboriginal Australians, Torres Strait
and Pacific Islanders  multiple factors [microbiome/worms?]
MM
PM
DB
Relatively common
Rare [a brave diagnosis]
• Systemic lupus erythematosus
• Crohn’s disease and ulcerative
colitis
• Psoriasis
• Reactive arthritis
• Myositis [also asymptomatic raised CK
with statins]
• Raised inflammatory markers: ESR,
CRP, ferritin [with ‘low’ Vit D]
• Raised gammaglobulins [polyclonal]
+ve RhF & ANA
• [Rheumatoid arthritis]
• Sarcoidosis
• Systemic sclerosis
• Ankylosing spondylitis [K]
• Type 1 diabetes mellitus
• Coeliac disease
• Pernicious anaemia
• Multiple sclerosis
• Eczema [scabies?]
What of the future?
Therapeutic possibilities
The immune modulatory potential of
gut helminths varies greatly.
• Potential benefits of helminth
infection in autoimmune and
metabolic disease
It depends on:
• the worm species
• the worm burden
• the gut microbiome
• the individual’s host response
• many other ‘knowns and unknowns’
• Further therapeutic trials of live
eggs/worms. Many ethical issues.
• Identification of immune
modulating determinants  clinical
trials
• Prospect of vaccines  protection
against helminth-related
disease……..and maybe even autoimmune and metabolic diseases
The future
"I would not say that the
future is necessarily less
predictable than the past.
I think the past was not
predictable when it started."
Donald Rumsfeld
Former US Secretary of Defence
“Today I saw a little worm
wriggling on its belly [rhabditiform?]
perhaps he’d like to come inside
and see what’s on the telly?”
“To whom do lions cast their gentle
looks?
Not to the beast that would usurp
their den.
The smallest worm will turn, being
trodden on,
And doves will peck in safeguard of
their brood.”
William Shakespeare: Henry VI, Part 3
Spike Milligan
The worm turns
Thanks for your attention