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TRYPANOSOMES AND AFRICAN SLEEPING SICKNESS Flashcards

1
Q

WHAT IS TRYPANOSOMA BRUCEI AND HOW IS IT TRANSMITTED?

A
  • A UNICELLULAR AND EXTRACELLULAR EUKARYOTIC PARASITES

- TRANSMITTED VIA TSETSE FLIES

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2
Q

WHICH DISEASE DOES TRYPANOSOMA BRUCEI CAUSE IN HUMANS AND WHICH IN ANIMALS? WHAT ARE THE CONSEQUENCES?

A

HUMANS: SLEEPING SICKNESS (FATAL DISEASE, NO VACCINE, TREATMENS CAN BE HIGHLY TOXIC)

ANIMALS, MOSTLY WILD ANIMALS AND CATTLE: NAGANA (MAJOR CONTRIBUTOR TO POVERTY, ECONOMIC IMPACT OF 4.5 BIL $ PER YEAR IN AFRICA)

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3
Q

HOW MANY CASES OF AFRICAN SLEEPING SICKNESS ARE THERE EACH YEAR?

A

CCA 1000

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4
Q

OTHER NAME FOR AFRICAN SLEEPING SICKNESS?

A
  • HUMAN AFRICAN TRYPANOSOMIASIS (HAT)
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5
Q

WHERE DOES AFRICAN SLEEPING SICKNESS (HAT) OCCUR?

A
  • IN THE 36 SUB SAHARAN COUNTRIES WHERE THERE ARE TSETSE (SPREAD HIGHLY RELATED TO THE PRESENCE OF THE FLY; VECTOR DEFINES THE DISEASE DISTRIBUTION)
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6
Q

WHICH PEOPLE ARE MOST EXPOSED TO TSETSE FLIES?

A

PEOPLE LIVING IN RURAL POPULATIONS DEPENDENT ON AGRICULTURE, FISHING, ANIMAL HUSBANDRY OR HUNTING

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7
Q

WHAT ARE THE ‘FOCI’ OF INFECTION?

A

the places where the key elements necessary for transmission of a disease are present: vectors and reservoirs

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8
Q

WHICH COUNTRY IS THE MAJOR DISEASE FOCI FOR AFRICAN SLEEPING SICKNESS?

A

DEMOCRATIC REPUBLIC OF THE CONGO

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9
Q

HOW MANY SUB SPECIES OF AFRICAN TRYPANOSOME CAUSING HAT ARE THERE? WHAT ARE THEY AND HOW PREVALENT ARE THEY?

A

T.B. RHODESIENSE (SEVERE, <10% OF THE CASES)
T.B.B. GAMBIENSE (VHRONIC, 90% OF THE CASES)
—-> HAVE DISTINCT GEOGRAPHIC PROFILES, T.B.G. MORE CENTRAL AND WESTER AREAS, T.B.R. MOR EASTER AREAS

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10
Q

ANIMAL TRYPANOSOMIASIS? NAMA+MEANING

A

IN CATTLE, THE DISEASE IS CALLED NAGANA, WHICH IS A ZULU WORD MEANING ‘TO BE DEPRESSED’

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11
Q

IMPACT OF NAGANA (ANIMAL TRYPANOSOMIASIS) ON THE ANIMALS AND THE ECONOMY?

A
  • IN ANIMALS, CAUSES LETHARGY, MASSIVE WEIGHT LOSS AND LOSS OF PRODUCTIVITY
  • MAJOR OBSTACLE FOR ECONOMIC DEVELOPMENT OF THE AFFECTED RURAL AREAS
  • DOMESTIC AND WILD ANIMALS ARE AN IMPORTANT PARASITE ‘RESERVOIR’ FOR HUMAN INFECTIVE PARASITES
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12
Q

EPIDEMIOLOGY OF AFRICAN SLEEPING SICKNESS IN THE HISTORY?

A
  • EPIDEMIC 1896-1906, KILLING 300,000-500,000 PEOPLE (MOSTLY UGANDA AND CONGO)
  • EPIDEMIC IN 1920
  • DISEASE ALMOST WIPED OUT IN THE 1960s, BUT RELAXING CONTROL MEASURES CAUSED A RESURGENCE IN THE 1970s
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13
Q

CONTROL STRATEGIES FOR AFRICAN SLEEPING SICKNESS?

A

TARGET PARASITE RESERVOIR IN THE HOST: SCREENING AND TREATMENT PROGRAMS FOR HUMANS, TREATMENT OF DOMESTIC CATTLE, ELIMINATING THE WILD ANIMAL RESERVOIR, BETTER HEALTH OF THE POPULATION

TARGET THE VECTOR: SPRAYING OF INSECTICIDES, INSECTICIDE TREATED FLY TRAPS, INSECTICIDE TREATED BED NETS

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14
Q

AFTER RESURGANCE IN SLEEPING SICKNESS IN 1970s, CONTROL PROGRAMS WERE RE-IMPLEMENTED, WHEN?

A

1990s

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15
Q

EXAMPLE OF VECTOR CONTROL FOR AFRICAN SLEEPING SICKNESS - NETS

A
  • BLUE FLY TRAPS; NET THAT HAS A PIECE OF BLUE FABRIC NEXT TO IT, FLIE ATTRACTED TO THE COLOUR, FLY AROUND THE NET AND GET INTO IT
  • COST IS CCA250$ PER SQUARE MILE
  • MUST BE REPLACED EVERY 5 MONTHS
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16
Q

TSETSE FLY BITE: WHAT HAPPENS FIRST IN THE PATHOLOGY OF HAT?

A
  • TRYPANOSOMES MULTIPLY IN THE TISSUE AROUND THE INITIAL BITE SITE
  • THIS OFTEN RESULTS IN A CHARACTERISTIC LOCAL INFLAMMATION TERMED ‘TRYPANOSOME CHANCRE’
  • MOR COMMON IN EUROPEANS; AFRICAN PATIENTS OFTEN EXHIBIT NO PATHOLOGY AT THIS STAGE
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17
Q

PATHOLOGY OF AFRICAN SLEEPING SICKNESS?

A

1) TRYPANOSOMES MULTIPLY AT THE SITE OF THE BITE, PATCH OF INFLAMMATION FORMS (MORE COMMON IN EUROPEAN THAN AFRICAN PATIENTS)
2) EARLY STAGE=HAEMOLYMPHATIC STAGE: FROM THE INITIAL BITE SITE, PARASITES ENTER THE BLOOD, LYMPHATIC SYSTEM AND BODY TISSUES WHICH CAUSES REGULAR BOUTS OF FEVER AND FLU LIKE SYMPTOMS + MAY CAUSE SWELLING OF THE LYMPH NODES (WINTERBOTTOM’S SIGN) —> SYMPTOMS AT THIS STAGE ARE QUITE MILD IN THE GAMBIENSE SPECIES BUT CAN BE SEVERE IN THE RHODESIENSE WITH OFTEN A FATAL OUTCOME
3) LATE STAGE=ENCEPHALITIC STAGE: TRYPANOSOMES CROSS THE ‘BLOOD-BRAIN’ BARRIER AND ENTER THE CNS LEADING TO SYMPTOMS LIKE ENCEPHALITIS, HEADACHES, SLEEPING DISORDER, ABNORMAL BEHAVIOUR (AGRESSION IRATIONALITY, LEADING TO LOSS OF CONSCIOUSNESS AND COMA
- –> OFTEN FATAL IF UNTREATED
- —> ACUTE FORM LASTS A FEW WEEKS, CHRONIC FROM LASTS MONTHS TO YEARS

18
Q

UNTIL 2010, THE MOST WIDELY USED TREATMENT FOR SLEEPING SICKNESS WAS?

A

MELARSOPROL, AN ARSENIC DERIVATIVE, THAT KILLED 1 IN 20 PATIENTS

19
Q

HOW MANY STAGES DOES AFRICAN SLEEPING SICKNESS HAVE?

A

3, AND THE 3RD ONE IS TRYPANOSOMES CROSSING THE BLOOD-BRAIN BARRIER TO KILL THE PATIENT

20
Q

WINTERBOTTOM’S SIGN?

A

SWELLING IN THE LYMPH NODES ASSOCIATED WITH THE 2ND STAGE OF THE AFRICAN SLEEPING SICKNESS

21
Q

PARASITAEMIA RELATED TO TRYPANOSOMES IS MUCH HIGEHER IN RODENTS OR COWNS AND HUMAN?

A

RODENTS

22
Q

STUDIES IN 2016 REVEALED THAT WHICH ORGANS ARE MAJOR RESERVOIRS OF TRYPANOSOMES? HOW DID THAT INFLUENCE UNDERSTANDING OF THE DISEASE, HAT?

A

SKIN (MAKES SENSE BECAUSE THE PATHOGEN IS INTRIDUCED BY THE TSETSE FLY BITING THE SKIN) & ADIPOSE TISSUE
—> BEFORE THAT, PRESENCE OF TRYPANOSOMES IN THE SKIN WAS OVERLOOKED AND HAT WAS CONSIDERED TO BE A ‘HAEMOLYMPHATIC DISESE’

23
Q

ARGUMENTS FOR AND AGAINST ADIPOSE TISSUE BEING A FUNCTIONALLY SIGNIFICANT AREA FOR TRYPANOSOMES TO INHABIT?

A

FOR:

  • TRYPANOSOMES APPEAR TO ADAPT TO THIS NICHE BY UPREGULATING FAT METABOLIC ENZYMES
  • MAY EXPLAIN THE WASTING DISEASE PATHOLOGY

AGAINST:

  • LARGELY HIDDEN FROM BITING TSETSE
  • AFRICAN COWS HAVE LITTLE FAT ANYWAY
24
Q

SOME UNANSWERED QUESTIONS ABOUT BLOODSTREAM TRYPANOSOME HABITAT?

A
  • ARE PARASITES IN THE FAT, SKIN AND THE BLOOD FUNCTIONALLY IDENTICAL
  • ARE FAT AND SKIN PARASITES ‘PROTECTED’ FROM DRUG TREATMENT
  • CAN PARASITES FROM THE FAT, SKIN AND BLOOD REPOPULATE EACH OTHER
  • ARE PARASITES FROM THE FAT, SKIN AND BLOOD EQUALLY TRANSMISSIBLE
  • ARE PARASITES FROM THE FAT, SKIN AND BLOOD EQUALLY PATHOGENIC (WHICH POPULATION KILLS PEOPLE???)
25
Q

WHAT ARE THE 2 DISTINCT PARASITE STAGES IN THE LIFECYCLE OF THE TRYPANOSOMES?, DESCRIBE THEM

A
  • SLENDER (LONGER AND SLENDER, PROLIFERATIVE, SPECIALISED FOR GLUCOSE METABOLISM VIA GLYCOLYSIS, DIFFERENTIATES INTO STUMPY FORM IN RESPONSE TO SECRETED QUORUM SENSING FACTORS, NON TRANSMISSIBLE)
  • STUMPY (SHORT AND STUMPY, CELL CYLE ARRESTED; NON-PROLIFERATIVE, PREADAPTED TO SURVIVAL IN THE INSECT MIDGUT (METABOLIC, PROTEASE RESISTANT, EXPRESS SENSORY PROTEIN…)
26
Q

WHICH STAGE OF THE TRYPANOSOMES LIFE CYCLE IS THE PROLIFERATIVE STAGE?

A

SLENDER STAGE

27
Q

WHICH STAGE OF THE TRYPANOSOMES LIFE CYCLE IS ADAPTED TO SURVIVAL IN THE INSECT MIDGUT? HOW?

A
  • STUMPY STAGE
  • ADAPTED BECAUSE IT IS: METABOLIC (MITOCHONDRIAL ACTIVATION), PROTEASE RESISTANT, EXPRESSES SENSORY PROTEINS, RAPIDLY DIFFERENTIATES TO THE INSECT PROCYCLIC FORM IN THE MIDGUT
28
Q

LIFE CYCLE OF TRYPANOSOMES IN THE HOST AND IN THE TSETSE FLY?

A

HOST:

1) SLENDER FORMS PROLIFERATE
2) AT HIGH PARASITAEMIA, THEY DIFFERENTIATE TO STUMPY FORMS (THIS IS ‘QUORUM SENSING’, AND IS DUE TO SECRETED PARASITE FACTORS
3) THIS LIMITS THE PARASITAEMIA AND PRESERVES THE LIFE OF THE HOST, ENHANCING PARASITE TRANSMISSION
4) STUMPY FORMS ARE THEN TRANSMITTED VIA THE TSETSE BITE

  • –> PARASITES TRAVERSE THE TSETSE ANATOMY: HAVE TO MOVE FROM THE CROP (WHERE THE BLOOD MEAL IS TAKEN DURING FFEDING) TO THE MIDGUT (WHERE THE DIGESTION OCCURS) THEN TRAVEL TO PROVENTRICULUS (ACTS AS A 3-WAY ‘VALVE’ BETWEEN THE CROP, MIDGUT AND PROBOSCIS) AND END UP IN THE SALIVA GLANDS
  • —> IN THE MIDGUT, THE SLENDER FORMS ARE KILLED BY PROTEASES, STUMPY FORMS DIFFERENTIATE TO PROCYCLIC FORMS
  • —> WHEN THE PATHOGEN REACHES SALIVARY GLANDS, IT IS IN THE ‘EPIMASTIGOTE’ FORM
  • —-> AFTER REACHING THE SALIVARY GLANDS, EPIMASTIGOTES ADHERE TO THE SALIVARY GLANDS VIA THEIR FLAGELLUM, REPRODUCE AND DIFFERENTIATE TO METACYCLIC CELLS
  • —–> METACYCLICS ARE PREADAPTED FOR SURVIVAL IN THE HOST AND GET INJECTED BACK INTO THE HOST WHEN THE TSETSE BITES
  • WHEN TSETSE BITE AN INFECTED HOSTS, TRYPANOSOMES ARE TAKEN INTO THE INSECT MIDGUT AND TRAVEL TO THE SALIVARY GLANDS AGAIN AND THE CYCLE CONTINUES
29
Q

4 MAIN FORMS O TRYPANOSOMES?

A

1) SLENDER (PROLIFERATIVE IN THE HOST, E.G. HUMANS)
2) STUMPY (NON-PROLIFERATIVE, TRANSMISSIBLE FORM THAT IS PREADAPTED FOR TSETSE)
3) PROCYCLIC (ESTABLISHES TSETSE MIDGUT INFECTION)
4) METACYCLIC (NON-PROLIFERATIVE FORM THAT DEVELOPS IN INSECT SALIVARY GLANDS THAT INOCULATE A NEW HOST)

30
Q

WHICH FORM ARE TRYPANOSOMES IN WHEN THEY REACH THE TSETSE SALIVARY GLANDS? WHICH STRUCTURE DO THEY USE TO ADHERE TO THE GLANDS?

A

EPIMASTIGOTE FORM, USE FLAGELLUM

31
Q

WHICH AREAS/ORGANS DO TRYPANOSOMES INHABIT IN THE HOST?

A
  • BLOOD
  • SKIN
  • ADIPOSE TISSUE
  • CNS (ONLY IN LATE, I.E. 3RD, STAGE OF THE DISEASE)
32
Q

TRYPANOSOMES ARE EXTRACELLULAR PARASITES; WHAT DOES THAT MEAN IN REGARDS TO THEIR EXPOSURE TO THE HOST IMMUNE SYSTEM?

A
  • THEY ARE FULLY EXPOSED TO HOST IMMUNE FACTORS, E.G. ANTIBODIES (IMMUNE MOLECULES THAT BIND TO PATHOGENS AND MARK THEM FOR DESTRUCTION BY THE IMMUNE CELLS), COMPLEMENT (IMMUNE MOLECULES THAT ‘PUNCTURE’ PATHOGENS), IMMUNE CELLS (E.G. MACROPHAGES)
  • REGARDLESS OF THAT, TRYPANOSOMES ARE ABLE TO SURVIVE IN THE SAME HOST FOR YEARS
33
Q

TRYPANOSOMES VARIANT SURFACE GLYCOPROTEIN (VSG)?

A
  • ONE OF THE KEY CONTRIBUTORS TO TRYPANOSOME IMMUNE RESPONSE EVASION
  • VSG PROTECTS THE PARASITE CELLS FROM THE HOST IMMUNE SYSTEM BY MAKING A PHYSICAL BARRIER: 1x10^7 DENSLEY PACKED VSG PER CELL (CCA 10% OF TOTAL CELLULAR PROTEIN) —-> PROTECTS THE UNDERLYING PROTEINS FROM ANTIBODY RECOGNITION, PROTECT THE MEMBRANE FROM COMPLEMENTS
34
Q

TRYPANOSOMES HYDRODYNAMIC FLOW?

A
  • ONE OF THE KEY MECHANISMS OF TRYPANOSOME IMMUNE EVASION
    VSG (ANOTHER FACTOR CONTRIBUTING TO IMMUNO EVSAION) IS HIGHLY IMMUNOGENIC —-> TRYPANOSOMES ESCAPE THE INCOMING ANTIBODIES BY ‘EATING’ THEM:
  • AS THE PARASITE SWIMS, THE VSG::ANTIBODY COMPLEX IS ‘SWEPT’ TO THE POSTERIOR OF THE CELL
  • THE COMPLEX THEN ENTERS THE FLAGELLAR POCKET (PART OF THE CELL SPECIALISED FOR ENDOCYTOSIS)
  • THE COMPLEX IS THEN INTERNALISED BY ENDOCYTOSIS AT THAT SITES
  • IF ANTIBODY LEVELS ARE HIGH, CLEARANCE BECOMES LESS EFFECTIVE AND THE CELL IS LYSED
35
Q

DESCRIBE THE ROLE AND MECHANISM OF TRYPANOSOME IMMUNE EVASION VIA ANTIGENIC VARIATION?

A
  • AFTER ENTERING THE HOST, TRYPANOSOMES ARE IN SLENDER FORM AND THEY PROLIFERATE, REACHING A ‘PEAK’ AND CHANGING FORM FROM SLENDER TO STUMPY
  • STUMPY FORM CAN EITER BE TRANSMITTED BY A TSETSE BITE OR CLEARED BY THE IMMUNE SYSTEM
  • VSG AND HYDRODYNAMIC FLOW ARE STRATEGIES TRYPANOSOMES USED TO ESCAPE THE IMMUNE SYSTEM, BUT VSG IS HIGHLY IMMUNOGENIC AND THE AMOUNT OF ANTIBODIES OFTEN OVERWHELMS HYDRODYNAMIC FLOW KILLING THE CELL, AND THERE IS A LARGE DROP IN OVERALL PARASITEMIA
  • BUT, AFTER SUCH DROP, THERE IS SOON ANOTHER RISE (SLENDER PROLIFERATION) AND THE CYCLE CONTINUES
  • THIS IS POSSIBLE BECAUSE OF ‘ANTIGENIC VARIATION’
  • TRYPANOSOMES HAVE 20 DIFFERENT VSG LOCI, I.E. EXPRESSION SITES, LOCATED AT CHROMOSOME TELOMERE, AND EACH SITE CONTAINS A DIFFERENT VSG ISOTYPE
  • ONLY THE ACTIV EXPRESSION SITE IS EXPRESSED (MONOALLELIC EXPRESION), SO TRYPANOSOMES CAN ‘SWITCH’ TO A DIFFERENT EXPRESSION SITE CONTAINING A DIFFERENT VSG ISOTYPE FOR WHICH ANTIBODY HASN’T YET BEEN PRODUCED (BUT THIS MIGHT NOT BE A VERY LONG TERM SOUTION)
  • TRYPANOSOMES HAVE CCA 1000 VSG GENES ELSEWHERE IN THE GENOME (10% OF ALL GENES); LOCATED IN SEVERAL LARGE ‘SUB-TELOMERIC ARRAYS’ AND NOT EXPRESSED
  • THESE VSGs CAN BE SWAPPED INTO VSG EXPRESSION SITES BY HOMOLOGOUS RECOMBINATION, WHICH GIVES THEM A REPERTOIRE OF CCA 100 VSGs
  • SUBTELOMERIC VSGs CAN RECOMBINE WITH THE EXPRESSION SITE VSG, MAKING ENTIRELY NEW VSG ‘MOSAICS’ —–> LEADS TO UNLIMITED CSG REPERTOIRE
  • THIS ALLOWS TRYPANOSOMES TO SURVIVE AS EXTRACELLULAR PARASITES FOR YEAR, DESPITE BEING HEAVILY ATTACKED BY THE HOST IMMUNE SYSTEM (EVERYTIME THERE IS A DROP IN PARASITEMIA, NEW VSG IS EXPRESSED AND THE SLENDER PROLIFERATION OCCURS AGAIN)
36
Q

HOW MANY VSG ISOTYPES DO TRYPANOSOMES HAVE? WHY IS THAT USEFUL?

A

CCA 20 VSG ISOTYPES

  • ONLY ONE VSG SITE IS EXPRESSED/ACTIVE AT A TIME (‘MONOALLELIC EXPRESSION’)
  • AFTER ANTIBODY RESPONSE HAS BEEN PRODUCED BY THE HOST TO ONE SITE, TRYPANOSOMES CAN SWITCH TO ANOTHER VSG ISOTYPE AND CONTINUE EVOLVING
  • BUT ANTIGENIC VARIATION ALLOWS FOR OTHER UNEXPRESSED VSG GENES IN THE GENOME (THERE IS CCA 1000) TO BECOME EXPRESSED WHEN THE INITIAL ONES ARE EXHAUSTED
  • ADITIONALLY, THE VSGs CAN MIX LEADING TO MOSAIC VERSIONS OF VSGs AND UNLIMITED REPERTOIRE
37
Q

MAIN TRYPANOSOME IMMUNE EVASION MECHANISMS?

A
  • VSG
  • HYDRODYNAMIC FLOW
  • ATIGENIC VARIATION
38
Q

% OF TRYPANOSOME GENES WHICH ARE VSG GENES?

A

10%

39
Q

WHAT ARE THE 3 WAYS ANTIGENIC VARIATION ALLOWS THE CELL TO CHANGE THE VSG ISOTYPE THAT IS EXPRESSED BY TRYPANOSOMES TO ACHIEVE IMMUNE EVASION?

A
  • EXPRESSION SITE SWITCHING (SWITCHING BETWEEN THE 20 VSG ISOTYPES)
  • INSERTING DIFFERENT VSG INTO THE EXPRESSION SITE (FROM THE 1000 VSG GENES)
  • MAKING ENTIRELY NEW, MOSAIC VSGs (UNLIMITED NUMBER OF POSSIBLE COMBINATIONS OF THE 20 ISOTYPES AND REMAINING VSG GENES)
40
Q

THE REASON WHY VACCINE AGAINST TRYPANSOSOMES IS UNLIKELY?

A

BECAUSE OF ANTIGENIC VARIATION

41
Q

THE ‘WAVES OF PARASITAEMIA’ IS A CHARACTERISTIC OF WHICH DISEASE/PATHOGEN? WHAT CAUSES THE WAVES?

A

CHRONIC INFECTION BY TRYPANOSOMES (AFRICAN SLEEPING SICKNESS)
WAVES EXPLAINED BY THE FOLLOWING PATTERN IN THE PARASITE’S BIOLOGY:
1) SLENDER FORM PROLIFERATION (RISE)
2) SLENDER TO STUMPY DIFFERENTIATION (PEAK)
3) PARASITE DEATH CAUSED BY ANTI-VSG ANTIBODIES (WHEN HYDRODYNAMIC FLOW IS OVER-WHELMED) (DECLINE)
4) ANTIGEN VARIATION (LEADS TO ANOTHER RISE)

INF (40 decks)

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