L6: (Mine) African and American Trypanosomiasis

Vocabulary-style flashcards covering the pathology, life cycles, diagnosis, and treatment of African and American Trypanosomiasis as presented in the lecture.

T. brucei gambiensie

Causes West African sleeping sickness (trypanosomiasis)

Found in West + Central Africa

Causes 95% of cases of HAT

Chronic: slow disease causing death in $1-3$ years

Anthroponosis

T. brucei rhodiensie

East Africa

5% of cases of HAT

Zoonosis

Acute form of sleeping sickness: death often after ~ 1 year

T. brucei brucei

Only infects animals (Ngana), ie cattle

The vector responsible for transmitting African trypanosomiasis between latitudes $20^{\circ}N$ and $20^{\circ}S$.

Tsetse fly (Glossina spp.)

What are the three Trypanosoma Brucei subspecies + where are they mainly found

– T. brucei gambiense (West Africa)

– T. brucei rhodesiense (East Africa)

– T. brucei brucei (animals only eg cattle)

The specific group of tsetse flies responsible for transmitting T. brucei gambiense.

Glossina palpalis group

The specific group of tsetse flies responsible for transmitting T. brucei rhodesiense.

Glossina morsitans group

A component found in the serum of humans and some other primates that lyses T. b. brucei.

Trypanolytic factor (TLF)

The gene expressed by T. b. rhodesiense that provides resistance to lysis by human serum component (TLF)

SRA gene

Metacyclic trypomastigotes

The infective stage of T. brucei that is injected into the human host during a tsetse fly blood meal.

Procyclic trypomastigotes

The stage of T. brucei that multiplies by binary fission in the tsetse fly's midgut after being ingested.

Epimastigotes

The stage of T. brucei that multiplies in the tsetse fly's salivary gland before transforming into metacyclic trypomastigotes.

Larviparous

A reproductive trait of female tsetse flies where they give birth to fully mature larvae.

Primary chancre

1st stage of HAT occurring at the site of the tsetse bite - local parasite multiplication,

-occurs in~ half of T. b. rhodesiense infections (acute)

-rare in T. b. gambiense infections

• Normally self-heals in 3-4 weeks

Haemolymphatic stage

What is it

Symptoms

2nd stage of HAT

Parasites spread to draining lymph nodes + bloodstream

Malaise, headache, and fever

Cervical lymphadenopathy (Winterbottom’s sign) frequent in T. b. gambiense infections

Winterbottom’s sign

Swelling of lymph nodes frequent in T. b. gambiense infections during the haemolymphatic stage.

Meningoencephalitic stage

What happens in this stage?

Clinical features?

Third stage of HAT

Parasites invade internal organs incl. CNS

Headache, sleep disturbances, weight loss — progresses to coma, and death

Pathology of HAT (3)

• Infiltration of lymphocytes and plasma cells around cerebral vessels (perivascular cuffing)

• IgM levels very high

• Foamy plasma cells (morular cells of Mott) present

How does the parasite survive so long?

Antigenic Variation:

Variant surface glycoprotein (VSG) covers trypanosome body

> 1000 VSG genes & can sequentially express >100 of them

• Each antigenic variant is ultimately destroyed by host antibody – but then changes again

• Leads to the very high IgM levels found and to immunopathology

3 stages of Human African Trypanosomiasis clinical disease

–Primary chancre

–Haemolymphatic

–Meningoencephalitic

Diagnosis of T. b. gambiense HAT

Microscopy: Trypanosomes in blood, lymph, gland aspirates or CSF (concentrate blood samples as low sensitivity)

Antibody detection: IFAT, ELISA, CATT (card agglutination trypanosomiasis test)

Rapid diagnostic test (RDT) - very cheap 50c each

PCR, molecular amplification tests

Confirmation of CNS Involvement: Examine CSF for

• Parasites (diagnostic)

• IgM (an early & specific marker)

• Morula cells

• lymphocytes (normally > 5 per µl)

Ways to concentrate organisms for blood film for T. b. gambiense HAT

Mini anion exchange column – most sensitive (about 100 orgs/ml)

Micro-haematocrit

Quantitative buffy coat

Which species is harder to find in blood films and requires concentration of blood

T. b. gambiense

Diagnosis of T. b. rhodesiense infections

Diagnosis by stained blood films is easier as parasitaemia is higher

• Seroconversion occurs after the onset of clinical symptoms and thus is of very limited use

• Coagulation tests may also be used (non-specific)

• PCR/ molecular amplification tests

Molecular amplification tests for T. b. gambiense & T. b. rhodesiense

– PCR mostly– More specific and sensitive than traditional methods

• Sensitivity and specificity depend on target sequence

• microsatellites (sub-genus specific) high sensitivity (~99%) but slightly lower specificity (~ 91%) than assays that target species specific genes.

• Application in endemic countries difficult

– detection by Oligochromatography simple and rapid dipstick format for detection of amplified PCR products. These are

visualized by hybridization with a gold-conjugated probe – 5’

– isothermal amplification methods

Human African Trypanosomiasis is also called

HAT; Sleeping Sickness

Human African Trypanosomiasis Treatment: Early stages (before CNS involvement)

– Pentamidine (T. b. gambiense)

– Suramin (T. b. rhodesiense)

Human African Trypanosomiasis Treatment: Late Stage (CNS

– Melarsoprol (but 2-12% die from drug toxicity; efficacy decreasing)

– Eflornithine (T. b. gambiense only; requires 56 i.v. Infusions over 14 days) Miracle drug

– Adding nifurtimox to both eflorinithine & melarsoprol (NECT)

Eflornithine

A drug used for late-stage T. b. gambiense HAT, which requires $56$ i.v. infusions over $14$ days.

Works very well

NECT

A combination therapy adding nifurtimox to eflornithine or melarsoprol for treating HAT.

Melarsoprol

Late stage drug for HAT (but 2-12% die from drug toxicity; efficacy decreasing)

Trypanosoma cruzi

The kinetoplastid protozoan that causes American Trypanosomiasis, also known as Chagas disease.

Triatomine bugs

Commonly known as "kissing bugs," these are the vectors that transmit T. cruzi through their faeces.

Amastigotes

The morphological form of T. cruzi that replicates inside nucleated mammalian cells.

Metacyclic trypomastigotes (T. cruzi)

The form of T. cruzi excreted in bug feces that enters the human host through a bite wound or mucous membrane.

Epimastigotes (T. cruzi)

The form of T. cruzi that replicates in the midgut of the triatomine bug vector.

Chagoma

Local inflammation and swelling occurring at the site of a T. cruzi infection during the acute stage.

Romaña’s sign

A hallmark of acute Chagas disease characterized by swelling on the eyelid.

Indeterminate stage

The asymptomatic chronic phase of Chagas disease that occurs in $60-70\%$ of infected individuals.

Cardiomegaly

Relentless destruction of myocardial cells in $30\%$ of chronic Chagas patients, leading to an enlarged heart and arrhythmias.

Megaoesophagus

Destruction of autonomic ganglia in the digestive tract walls of Chagas patients, causing abnormal enlargement of the esophagus.

Megacolon

Destruction of autonomic ganglia in the digestive tract walls in $10\%$ of chronic Chagas patients, leading to severe constipation and colon enlargement.

Sylvatic transmission

A transmission cycle involving wild mammals rather than domestic animals or humans.

Xenodiagnosis

A traditional diagnosis method where uninfected triatomine bugs are allowed to feed on a patient to see if they become infected with T. cruzi.

Benznidazole

The primary drug of choice for treating the acute phase of Chagas disease.

Nifurtimox

An alternative drug used to treat Chagas disease, although it was briefly withdrawn from production by Bayer in the 1990s.

T. infestans

The principal vector of Chagas disease whose transmission was successfully stopped in Chile, Uruguay, and Brazil.

DALYs

Disability Adjusted Life Years; HAT results in approximately $1.5$ million DALYs lost per year.

When does Meningoencephalitic stage of HAT occur for T. b. rhodesiense and T. b.gambiense

Within weeks with T. b. rhodesiense, months to years

and maybe never? with T. b. gambiense

What leads to the very high IgM levels found and to immunopathology

Variant surface glycoprotein (VSG) covers body

• > 1000 VSG genes & can sequentially express >100 of them

• Each antigenic variant is ultimately destroyed by host antibody – but then the next one grows up

Which trypanosoma brucei subspecies causes the most cases of HAT (+ %)

T. brucei gambiense 95% of cases

(West & Central Africa)

Which T. brucei subspecies is a anthroponosis and which is a zoonosis

T. brucei gambiense - anthroponosis

T. brucei rhodesiense - zoonosis

Is T. brucei gambiense anthroponosis or zoonosis

anthroponosis

Is T. brucei rhodesiense anthroponosis or zoonosis

Zoonosis