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’ [nv]

• worms: in decline

• nowadays: few personal worm stories in this room

Gut helminths: a spectrum

Disease [due to infection] α dose X virulencehost 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, IL-

13 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

Insulin sensitivity Insulin resistance

M2 M1

AdipocytesLean Obese

IL-33

Th1 inflammation and type II diabetes mellitusRaised inflammatory cytokines precede development of clinical manifestations, often for decades

Genetic & epigenetic factors Dietary fatTh1 inflammatory cytokines

Th1 inflamed adipose tissue

Activation of serine kinases

Phosphorylate insulin receptor substrate proteins insulin resistance

Hyper-insulinaemia

Th1 inflamed pancreatic isletsIncreased amyloid polypeptide

IL-1βIL-6IFNα

Islet cell ‘burnout’

Grossman V, et al. Diab Care 2015 [Apr]: ePubVaarala O, et al. Nature Rev 2012;8:323-5Donath MY, et al. Nature Rev 2011:11:98-107

AdiponectinLiver: gluconeogenesis & fat deposition

Reduced pro-insulin conversionLoss of glucose sensitivity

• 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, 0.23-

0.67, 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?

• 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

• There are many published mouse studies

• Some have impressive results

Local championHookworm vaccine candidates

Relationship between hookworm infection, IBD and coeliac disease

Use of microarray technology to explore the activities of identified helminth immune-modulating 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?]

Relatively common

• Systemic lupus erythematosus

• 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]

Rare [a brave diagnosis]

• Crohn’s disease and ulcerative colitis

• Sarcoidosis

• Systemic sclerosis

• Ankylosing spondylitis [K]

• Type 1 diabetes mellitus

• Coeliac disease

• Pernicious anaemia

• Multiple sclerosis

• Eczema [scabies?]

MMPMDB

What of the future? The immune modulatory potential of gut helminths varies greatly.

It depends on:

• the worm species

• the worm burden

• the gut microbiome

• the individual’s host response

• many other ‘knowns and unknowns’

Therapeutic possibilities

• Potential benefits of helminth infection in autoimmune and metabolic disease

• 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 auto-immune 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?”

Spike Milligan

“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

The worm turns

Thanks for your attention