Parasitology

Question 1

What is a parasite

Answer 1

An organism that lives and feeds on or in an organism of a different species and causes harm to its host

Question 2

What are the only types of parasite we learn about

Answer 2

eukaryotic endo-parasite groups classified as protozoa and helminths.

Question 3

What are indirect parasite life cycles

Answer 3

direct, involving a single definitive host
(sexual cycle)

indirect, involving both definitive and intermediate hosts

some lifecycles rely on an invertebrate vector host

Question 4

How does pathology of parasites differ from most pathogens

Answer 4

Like most pathogens, parasites can cause acute disease, but unlike most pathogens, almost all parasites will cause chronic disease as well.

disease will be caused by direct damage from the parasite, and indirect damage caused by immunopathological response to infection.

Question 5

How was the evolution of parasites driven

Answer 5

by natural selection for optimizing replication within a host and transmission between hosts.

Selection will determine the spectrum, intensity, geographic range and persistence of disease.

Question 6

How can helminths be divided

Answer 6

into flatworms and roundworms

Question 7

What is the most common route of parasite infection

why

Answer 7

oral-faecal route

most endo-parasites will have been originally derived
from consumption of free-living organisms by one of the hosts

Question 8

What is the host, transmission and life cycle of whip worm

how common is it

where is it mostly distributed

Answer 8

Human parasite, direct life cycle, oral-faecal transmission

3rd most common nematode infection worldwide, an estimated 1 billion people carry an infection.

Mostly tropical and subtropical geographic distribution

Question 9

Describe the pathology of whip worm

Answer 9

Pathology ranges from asymptomatic to severe (possibly leading to rectal prolapse, or anaemia in children)

Infection may persist for years

Hygiene and sanitation key to control

Question 10

What is Trichuris trichuria

What is its lifespan

Answer 10

whipworm

1 year

Question 11

How is trichuris treated

Answer 11

with helminth microtubule inhibitor albendazole

Question 12

Describe in detail the life cycle of whipworm (5)

Answer 12

unembryonated eggs are passed with the stool
In the soil, the eggs develop into a 2-cell stage T
an advanced cleavage stage and then they embryonate
eggs become infective in 15 to 30 days.
After ingestion (soil-contaminated hands or food), the eggs hatch in the small intestine, and release larvae that mature and establish themselves as adults in the colon
adult worms (approximately 4 cm in length) live in the cecum and ascending colon

Question 13

What is the proper name for pinworm

Answer 13

Enterobius vermicularis

Question 14

What is the most common worm infection in the UK

What is interesting about its behaviour

Answer 14

pinworm

crawls out of the rectum to the peri-anal region to lay eggs at night. The eggs are then spread by scratching and touching bed clothes, furniture, doors etc.

Question 15

Give an exmaple of a large roundworm

How do they tend to cause damage

Answer 15

the giant round worm Ascaris lumbricoides

can be very large and cause disease by simple mechanical blockage of the intestine.

Question 16

Describe the pathology of toxocara canis

what is it an example of

Answer 16

a helminth parasite with the dog as definitive host, causes human toxocariasis when the eggs are ingested. The larval worms do not develop, but migrate to the eye and brain causing inflammation which may result in blindness and epilepsy respectively

Oral-fecal routes of infection between definitive and intermediate hosts can have severe pathologies as sometimes the worm does not develop properly in the intermediate host

Question 17

What is tanenia solium and what is its definitive host

What are the larvae called

Answer 17

the pork tapeworm

human is the definitive host with pig as a common intermediate host.

cystercerci

Question 18

How can a human develop taeniasis

Answer 18

When humans ingest the larval stage of tanenia solium (cystercerci) from infected meat, a cystercircus may develop into a
hermaphroditic adult worm intestinal infection

Question 19

What are some of the effects of having a pork tape worm

Why is this surprising

Answer 19

generally asyptomatic but in severe cases anaemia and emaciation may occur

surprising considering they can be several meters long

Question 20

How does pork tape worm pass from humans to pigs

what do they do once they enter the intermediate host

Answer 20

The adult worm sheds gravid proglottids (containing up to 50,000 embryolated eggs) that are excreted by the human host. The proglottid/eggs are ingested by the intermediate host (pig) where the the eggs hatch and larval worms migrate to a variety of tissues including muscle and brain to settle as cystercerci

Question 21

When does severe disease occur in the tanaenia solium life cycle

How does pathology differ between humans and livestock

Answer 21

when the eggs are ingested and cystercerci grow causing cysticercosis.
Further, since the large cystercerci are fluid filled bladders containing worm proteins, they may cause a fatal massive inflammatory response upon accidental rupture.

Most livestock do not live long enough to suffer serious disease, but in humans some cystercerci may grow into an intermediate form that can be very large (20 cm) and obstruct organ function

Question 22

What happens if a pork tape worm reaches the brain

Where is this a real problem

Answer 22

epilepsy, seizures and blindness.

In regions with poor sanitation, cysticercosis is thought to be a major cause of epilepsy.

Question 23

What are the 3 primary classes of anti-helminth drug

Briefly describe the modes of action

Answer 23

ivermectin - NT inhibitor

albendazole/ mebendazole - microtubule assembly inhibitor

praziquantel - permeability of membranes to Ca2+

Question 24

What are the drug targets for antihelminth drugs

Answer 24

ivermectin - glutamate gated chloride channels

albendazole - colchicine

praziquantel - unknown

Question 25

Describe schistosomiasis

Answer 25

an ancient tropical/subtropical disease first described by
the Egyptians noting symtoms including skin rash, chills, fever, abdominal
pain, enlarged liver and spleen, blood in stool or urine.

caused by Schistosoma spp (flatworm, trematode)

Question 26

Why is Bilharzia

Answer 26

another name for schistosomiasis

Theodor Bilharz in
the mid-1850s made the connection between the worm and disease

Question 27

Where is most of the disease burden of schistosomiasis focussed?

Answer 27

sub-Saharan Africa
harbors 80-90% of global disease burden.

Worldwide, 600 million are at risk from schistosomiasis, 260 million infected and an estimated 200,000 deaths annually

Question 28

What is the socio-economic impact of schistosomiasis?

Answer 28

Morbidity due to infection may be a greater socio-economic burden than mortality as severe disease leading to mortality is about 5-10% of cases.

Question 29

How can schistosomiasis be divided

What does severe disease in these categories lead to

Answer 29

into intestinal and bladder disease.

Severe intestinal disease includes hepato-splenomegaly, varicies, fibrosis and calcification of the liver.

Bladder disease includes bladder fibrosis, calcification
and cancer, with urogenital “sandy patches on the cervix

Question 30

What is the lifecycle of schistosoma spp (7)

Answer 30

S. mansoni cercaria in the water will come in contact with swimmers or waders.

After penetration of the skin and loss of tail, the larval schistosomula undergo development into the adult worm.

The adult male and female pair will migrate and attach in the mesenteric venules living 5- 10 years.

They will deposit 300-3000 eggs/day depending upon species.

Egg size and shape are diagnostic for each species.

The eggs hatch in the water releasing
miracidia that invade the snail
host.

Sporocysts in the snail will release the motile cercaria into the water

Question 31

What is diagnostic of the different types of schistosoma spp.

Answer 31

Egg size and shape are diagnostic for each species

Question 32

What are the organ preferences for two of the different species of schistosoma

Answer 32

S. japonicum is more frequently found in the superior mesenteric veins draining the small intestine image

S. mansoni occurs more often in the inferior mesenteric veins draining the large intestine image

However, both species can occupy either location and are capable of moving between sites.

Question 33

What causes morbidity in schistosomiasis

Answer 33

egg deposition

Most of the eggs will transit the gut wall into the intestinal lumen and shed with faeces.
However, a fraction will reflux with blood flow back into the liver causing granuloma formation. Severe disease will include fibrosis and calcification

Question 34

How will schistosoma eggs try to transit the gut wall

Answer 34

via the induction of some of the tissue repair pathways, particularly fibrin coating and then plasmin fibrinolysis.

Along with wound healing mechanisms, the eggs may form granulomas.

Question 35

Why does a heavy worm load lead to more severe disease

Answer 35

After reflux
to the liver, granuloma formation dominates and in severe disease, the wound healing
cytokine milieu persists leading to fibrosis and calcification of the liver. A heavy worm
burden, hence egg burden and granulomas will contribute to severe disease.

Question 36

What is required from the body to avoid severe schistosomiasis

Answer 36

a balanced immune response involving a range of cell types

Question 37

How does the immune response to schistosoma eggs begin (5)

Answer 37

Egg antigens will be picked up by dendritic cells and processed to present antigen and activate Th2 cells that in turn will produce a Th2 cytokine profile.

Basophils will also be activated by egg antigen and reinforce the Th2 cytokine profile.

Alternatively activated macrophages and eosinophils will support wound-healing mechanisms including collagen
deposition.

B-cells responding to egg antigens produce igE and IgG antibodies that may aid in destruction of eggs in granulomas.

However, egg antigens will participate in Treg formation that, with the alternatively activated macrophages, produce IL-10 to limit granuloma size and liver tissue wound healing response.

Question 38

How does the immune response to schistoma change over time

What can go wrong

Answer 38

After an initial Th1 inflammatory response to cercaria penetration and larval worm migration, egg deposition initiates a switch to Th2 response that peaks about 9 weeks p.i. Treg cells are formed and IL-10 production starts a modified Th2 response.

A continued strong Th2 response may lead to severe disease, fibrosis and calcification.

Question 39

Define parastitic protozoa

Answer 39

Unicellular eukaryotic organisms that are endoparasites and cause harm to their hosts.

Question 40

What does natural selection act to improve in parasite fitness

Answer 40

1) Replication within a host

2) Transmission between hosts.

Question 41

Why does leishmania not really have a definitive host

Answer 41

conventional meiosis is not part of its life cycle

Question 42

What acts as a definitive host for toxoplasma

Answer 42

the cat family

Question 43

What are the intermediate hosts for leishmania

Answer 43

range of intermediate hosts for leishmania (that infect humans) appears to be fairly wide, but is probably limited by what the vector will feed on.
The sand fly vector will specialize in both host preference and location

Question 44

What is the invertebrate vector used by toxoplasma

Answer 44

does not use one because transmission is via contaminated vegetables or carnivory.

Question 45

What are the potential intermediate hosts for toxoplasma

Answer 45

Virtually all warm-blooded animals

Question 46

Give a surprising animal we have found to be infected with toxoplasma

Answer 46

Even marine mammals like sea otters that never come in contact with cats or land-based prey can be infected.

Question 47

Where does natural selection toxoplasma and leishmania act for parasites

Answer 47

within the host immune system and regional ecosystems.

Question 48

How old is leishmaniasis

How has it been found throughout history

Answer 48

an ancient disease and has been depicted in clay figures found in Mexico dating back to 400 AD

In Africa during the 1700’s the disease was named Kala Azar, but the parasite was only described in the early 1900s by William Leishman, a Glaswegian army doctor based in India

Question 49

Where does leishmaniasis occur

Answer 49

The disease is
primarily tropical and subtropical but occurs in temperate environments from
Spain to the Middle East through northern China/southern Mongolia.

Question 50

Where is the distribution of leishmania restricted to

Answer 50

The distribution is probably limited by where the sand fly vector occurs.

Question 51

Which organisms does the leishmania species life cycle involve

Which stages of the lifecycle are associated with each host

Answer 51

alternates between the mammalian host and the sand fly vector

flagellated promastigote forms are associated with growth in the sand fly midgut

the ovoid non-flagellate amasitgote form occupies macrophage host cells within the mammalian host.

Question 52

Describe the structure of promastigotes in the leishmania life cycle

Answer 52

have a single flagellum connected with the axoneme and basal body.
Directly adjacent to the basal body is the kinetoplast

Question 53

What is a kinetoplast

Answer 53

a DNA-containing structure that is held within the single

mitochondrion

Question 54

Which parts of the promastigotes can be easily seen in a LM

Answer 54

The kinetoplast and nucleus are easily seen under light microscopy when appropriately stained

Question 55

Where are leishmania amastigotes found

Answer 55

the ovoid form seen within macrophages in the mammalian host in areas of tissue damage.

Question 56

How do amastigotes enter the sandfly

What happens next

Answer 56

ingested by the sandfly and held within the peritrophic matrix while the host cell is broken down

parasite transforms into a promastigote, replicates and the flagellum attaches to the sand fly midgut

Question 57

Why does the new promastigote attach to the wall of the sand fly’s midgut

Answer 57

to prevent loss via defaecation

Question 58

What happens to the promastigote after it has attached to the sand fly’s midgut wall

Answer 58

replicates and then further transforms into an infective promastigote, detaching from the midgut and migrating to just behind the mouthparts and can be injected into the mammalian host on the next blood meal

Question 59

How do promastigotes enter a mammal

Answer 59

injected into the
mammalian skin tissue and taken up by
macrophages (Mϕ) and dendritic cells (DC)

Question 60

Why is the promastigote not destroyed as soon as it is injected into the mammal

Answer 60

the Mϕ does not respond to is as it isn’t activated - this allows replication of the amastigote

Question 61

What happens to DC cells after they are infected with a promastigote

What is the next sequence of events

Why is this sequence of events important in the parasite’s lifecycle

Answer 61

migrates to a local
lymph node, presents antigen to a Th1 cell activating the Th1 cell to secrete IFN-γ, activating Mϕ.

Nitric oxide bursts kill the parasites but some will escape to re-infect new Mϕ.

Inflammation and Mϕ death produces localized tissue damage, attracting more Mϕ host cells

this is the major amplification of the parasite

Question 62

How does the Leishmania parasite protect its self from loss and attach in mammals and sandflies

Answer 62

The outer surface of the parasite (including flagellum) are coated with the carbohydrate lipophosphoglycan (LPG).
LPG maintains the parasite in the sand fly midgut and protects the parasite from immune attack in the mammalian host.

Question 63

How does Leishmania LPG act in the sand fly

Answer 63

In the sand fly midgut, LPG initially binds a midgut galactin to anchor it from loss via defecation

As the parasite divides and develops, the LPG
changes length and side chains, releasing it from attachment, allowing it to be injected into the mammalian host.

LPG helps the parasite resist complement attack and during transformation into the amastigote, LPG gets longer and more decorated helping it resist oxidative bursts within the macrophage

Question 64

What are the 2 key Leishmania species

Compare the pathologies of each

Answer 64

Old world (Europe and Asia) and New
world (Americas) species

in both cause human pathologies ranging from a simple selfhealing cutaneous lesion, to severe facial tissue destruction, to a serious and
fatal (if untreated) visceral disease

Question 65

What has the recent evolution of New and Old world Leishmania species been due to

Answer 65

recent evolution of these parasites and concomitant disease pathologies has been largely due to human activity.

Question 66

What is the origin of leishmania

Answer 66

Visceral leishmaniasis was not recorded in the Americas before the European explorers, so the origin of L. chagasi has been a question. Recent data suggests that L. chagasi is likely to have been brought to Brazil by the early Portuguese explorers, specifically their dogs as reservoir host

Question 67

Which other Leishmania species is most closely related to L. chagasi

Answer 67

L. infantum from Portugal

Question 68

What can L. braziliensis cause

What is the natural host

Answer 68

both a simple cutaneous lesion and severe mucocutaenous disease.

two-toed sloth, an animal that spends the vast majority of its life in the upper canopy of the rainforest and has little contact with humans

Question 69

Why is it initially surprising L. braziliensis affects humans

Answer 69

transmission cycle for L. braziliensis is in an ecological niche that doesn’t include humans.

However with rainforest destruction for roads and agriculture, the sloth, L. braziliensis and the sand fly vector came in close contact with humans and their companion animals.

Question 70

What is the peri-urban life cycle of L. braziliensis

Answer 70

human occupation of towns that are surrounded by rainforest have developed a peri-urban transmission cycle that includes other intermediate hosts like rodents and horses.

L. braziliensis has adapted to use different sand fly vectors so the parasite is now a common human parasite.

Question 71

What is the pathology of L. braziliensis an example of

Answer 71

severe pathologies that occur when parasites infect a non-natural host like
humans (although severe disease does only develop in a minority of cases)

Question 72

L. major

what pathology does it cause?
where is it found?
what is interesting about its disease pattern?

Answer 72

causes simple cutaneous disease and is a common species from southern Europe to India and China.

The disease pattern mirrors the distribution of the primary L. major sandfly vector, Phlebotomus papatasi.

Question 73

What are the different vectors for L. major

Answer 73

primary vector = P. papatasi (restrictive vector)

also, P. arabicus (permissive host and transmits a variety of Leishmania species)

Question 74

Compare the vector hosts of L. major

Answer 74

By using the restrictive P. papatasi as the primary vector but also using P. arabicus as a permissive vector, L. major can avoid competition for the most part, but can also expand into other ecological
niches

Question 75

Compare the distributions of L. major vectors

Answer 75

P. papatasi has greater global geographic range than P. arabicus.

Where the sand fly species overlap locally like in the Sinai, P. arabicus tends to live at higher elevations than P. papatasi .

L. major can use both vectors.

Question 76

What makes P papatasi a restrictive vector

Answer 76

because no other leishmania species is known to grow in it

Question 77

How does L major settle in the P. papatasi vector

Answer 77

P. papatasi has the lectin galactin on the midgut villi that binds L. major – specific LPG so the parasite can reproduce.

Question 78

Why is P. arabicus considered permissive

Answer 78

is thought to have

a common mechanism that allows a variety of Leishmania species to bind in its midgut.

Question 79

What is the most common protozoan on earth

Answer 79

Toxoplasma gondii

Question 80

Describe toxoplasma gondii as a protozoan

Answer 80

obligate intracellular protozoan parasite that infects any nucleated cell in virtually all warm-blooded animals

apicomplexan

Question 81

What is the definite host for toxoplasma gondii where the sexual cycle takes place

Answer 81

cat family

Question 82

What is toxoplasma classified as

What is it related to

Answer 82

As a gut-infective parasite, toxoplasma is classified as a coccidian

related to
other important livestock pathogens like Eimeria species (e.g. avian coccidiosis) and Neospora caninum (cattle neosporosis)

Question 83

How does a cat get an acute infection of toxoplasma

Answer 83

The cat can eat a tissue cyst (bradyzoites) or oocyst (sporozoites) and the parasite will transform into an actively dividing tachyzoite resulting in an acute infection

Question 84

What happens after the acute infection of toxoplasma in cats

Answer 84

cat immune system will clear the tachzoites but many will have transformed into micro and macro gametocytes that fuse to form an oocyst that is shed in feces. The oocyst will go through meiosis in the environment and produce an octet of
sporozoites

tachyzoite will also transform into the bradyzoite form and reside in a tissue cyst, thousands of parasites in a single cell. Bradyzoites are generally quiescent but may re-activate upon immune suppression and cause acute disease

Question 85

Can you become immune to toxoplasma

Answer 85

Healthy individuals are immune from further

infection after the first exposure to the parasite.

Question 86

What does acute toxoplasmosis look like

what about in pregnancy

Answer 86

mild flu-like symptoms in healthy individuals, but with immunosuppression, can result in a fatal encephalitis and chorioretinitis (blindness).

If the parasite crosses the placenta during pregnancy, birth defects and spontaneous
abortion may occur.

Question 87

What is surprising about the population structure of toxoplasma

Answer 87

Although toxoplasma is a global parasite that has a sexual cycle and therefore recombination, the population structure is remarkably clonal, particularly in North America and Europe, where the population is dominated by 3 clonal lineages, called types I, II and III.

Question 88

How similar are the 3 clonal lineages of toxoplasma

What do we think caused this

Answer 88

90-95% similarity.

An analysis of the type strains suggest that in NA and Europe, the parasite went through a population bottleneck about 6-10,000 years ago.

Question 89

How does diversity of toxoplasma strains change across the world

why is this

Answer 89

Asian isolates show somewhat greater diversity but mostly variation within a basic type strain and recombination between the three type strains.

South American isolates show considerably more diversity. Although the NA and European type strains are present, there are more clonal lineages.

thought to be due to the comparatively high number of cat species in SA and
therefore ecological niches

Question 90

Why was there a bottle neck for toxoplasma 10,000 years ago

Answer 90

Agriculture was developing at this time in the Fertile Crescent, with previously unseen stores of grain with the associated high numbers of rodent pests and domesticated cats

new transmission route - parasite escaped the definitive host and could pass directly between intermediate hosts via carnivory

Question 91

What is probably responsible for the massive expansion of toxoplasma and its global distribution

Answer 91

its unique transmission between intermediate hosts:

its is able to transmit within definitive hosts, transmit from definitive to intermediate host and between intermediate hosts

Question 92

What is the defining feature of apicomplexan parasites

Answer 92

the apical complex - the structural feature at which the parasites can control motility and host cell invasion

Question 93

How do apicomplexans control motility and invasion

what are the key organelles

Answer 93

hrough an evolved set of secretory organelles that allow the parasites to store and then secrete proteins and membrane precisely when required.

the micronemes, rhoptries and dense granule

Question 94

Describe the structure of toxoplasma

Answer 94

has an inner membrane complex consisting of a corset of microtubules and microfilaments that radiate from the apical complex, where the organelles secrete proteins and membrane

Question 95

What do micronemes secrete in apicomplexans

Answer 95

proteins that make transient attachments to the host cell surface and bridge attachment to the actin-myosin motor that drives gliding motility.

The parasite propels itself by a kind of ‘rowing’ action.

Question 96

How do apicomplexans access the host cell

Answer 96

glides through microneme secretion on the host cell surface, finds an appropriate attachment site and blows a transient hole in the host cell PM,
rhoptries then secrete protein and membrane
These migrate back to the host cell PM and fuse creating a ring through which the parasite pushes host cell membrane to form a PV that includes parasite proteins and membrane

Question 97

How do apicomplexans differ from viruses, bacteria and other protozoans

Answer 97

can actively invade host cells without using any host cell functions , e.g. cytoskeletal rearrangements

Question 98

What can the apicomplexans do once the parasitophorous vacuole is formed (4)

Answer 98

parasite membrane and protein secreted by the rhoptries form a ring though which the parasite moves through.

The ring excludes many host cell transmembrane proteins, including those that normally promote vacuole acidification and fusion with lysosomes.

The PV also retains rhoptry proteins that will be useful in protecting the PV.

Dense granules
secrete proteins that decorate the membrane network within the PV and process host cell molecules for uptake by the parasite.

Question 99

What is ROP18

whhat is its purpose

Answer 99

s a kinase that will phosphorylate IRGs and other host proteins

inactivate IRGs, protecting the PV from membrane attack

Question 100

What is the mouse LD100 so different for type 1 apicomplexans compared to II and III

Answer 100

Type I parasites have ROP18 whereas Type II and III parasites do not

the LD100 is massively lower for type 1 parasites

Question 101

What are IRGs

Answer 101

Immune Related GTPases (IRGs), some of which attack vacuolar membranes allowing other intracellular mechanisms to kill pathogens

Question 102

Why do most toxoplasma strains have a very high LD100

Answer 102

they can be killed by IRG mechanisms

Question 103

How does immune resistance to toxoplasma differ between species

Answer 103

Humans do not have the same number or function of IRGs, and it is likely that the variation in immune systems across warm-blooded animals will require different levels of specific IRG protection. Hence, polymorphism for
different immune-modulating mechanisms including ROP18 will be selected for overall.

Question 104

How can toxoplasma adjust its resistance to the immune system of the current host

Answer 104

Combinations of different immune modulators can “tune” the response for specific hosts.

Toxoplasma can take advantage of both clonal growth via
transmission between intermediate hosts and sexual recombination via the cat.

Question 105

What is the causative agent of malaria and when was this established

Answer 105

plasmodium

was not
until the late 19th century that plasmodium species were shown to be the
causative agents of malaria and the link with mosquitos as vectors established

Question 106

Which species of mosquito transmits malaria

Answer 106

Anopheles

Question 107

How prevalent is malaria

Answer 107

is the world’s most prevalent vector-borne disease, endemic in about 91 tropical and subtropical countries

About 41% of the world’s population is at risk, with 3-500 million clinical cases of malaria annually,
where over 90% are in sub-Saharan Africa. Of the approximately 2 million deaths each year, half are in children 5 years old and under.

Question 108

What is the brief history of how malaria has evolved with humanity

Answer 108

plasmodium species that cause human malaria have co-evolved with humans for about 100,000 years, with a rapid expansion about 10,000 years ago around the time that agriculture developed. Since malaria has its greatest impact in pre-reproductive mortality, natural selection for resistance to the disease has left a lasting impact on the human genome.

Question 109

What are the 4 main plasmodium species

Which is the most important

Answer 109

P. falciparum, P. vivax, P. malariae and P. ovale

P. falciparum is by far the most important malarial species on the basis of proportion of cases and ultimately disease burden

Question 110

What is important to remember when diagnosing which type of malaria a patient has

Answer 110

Notably, a high proportion of infections are not

diagnosed at the species level and some are mixed infections.

Question 111

where is there a low incidence of P. viviax

Why?

How does P. falciparum compare?

Answer 111

conspicuously absent or in low frequency across sub-Saharan Africa.

Human resistance has been selected for in this region

P. falciparum dominates sub-Saharan Africa and is therefore responsible for most of the malarial disease.

Question 112

Describe the heat map for P. vivax

Answer 112

peak at just over 7%
infection rate across all age groups in peak transmission
season.
The primary foci are in Brazil and Indonesia

Question 113

Describe the heat map of P. falciparum

Answer 113

has a peak at just over 70% infection rate in just the 2-10 year old age group in peak transmission season. This
is an order of magnitude higher than for P. vivax.

The foci are in West Africa and Mozambique but most of sub-Saharan Africa is high and given the comparative rate of
infection, is high in the Amazon basin and Southeast Asia.

Question 114

Describe the first stage of the P. falciparum life cycle in the human

Answer 114

the liver stage

infection by the mosquito borne sporozoites is a relatively cryptic injection of 10-100 parasites that travel to the liver and invade hepatocytes. The amplification of the parasite is massive during liver stage merogony

Merozites are released into the circulation to infect RBCs (moves into 2nd stage of lifecycle in humans)

Question 115

What happens in merogony in the P falciparum human life cycle

Answer 115

the growing parasite is no longer a single entity but a mass of dividing nuclei and other organelles that re-form into single merozoite parasites.

A single liver hepatocyte cell can contain about 10,000 merozoite
parasites in a schizont

Question 116

What does schizont refer to

Answer 116

the group of parasites that represent a single original parasite PV

Question 117

What is a problem with functional sporozoites vaccines

Answer 117

even if the vaccine kills all but one of the parasites, the infection will still have amplified by 4 orders of magnitude

Question 118

What happens in the 2nd stage of the P falciparum lifecycle in humans

Answer 118

parasites replicate at a rate 3 orders of magnitude lower than in the hepatocyte

free merozoites invade a new RBC and transform into a “ring form” trophozoite. Trophozoite growth is the beginning of merogony in the RBC resulting in only tens of parasites being generated in a single schizont.

During trophozoite growth, the RBC surface is decorated with parasite-derived proteins that will assist the infected RBC (hence parasites) from destruction in the spleen. Other merozoites are pre-committed to become sexual cells and the ring form will develop into either a microgametocyte (male) or macrogametocyte (female). These if taken up together in a mosquito blood meal, they will fuse to carry out the sexual cycle within the mosquito

Question 119

How does P falciparum enter the human

what happens once the parasite has entered the human

Answer 119

sporozoites may be injected into the human host by the mosquito during a blood meal.

The sporozoites invade liver hepatocytes

Question 120

What happens to the P falciparum sporozoites once they have entered the hepatocyte

what happens next

Answer 120

transform and initiate a single round of merogony where the parasite amplifies

The released parasites infect RBCs, transform into ring form trophozoites and then growing
trophozoites to initiate a new round of merogony. Merozoites are released to re-infect new RBCs. Some of the merozoites transform into a single crescent-shaped microgametocyte or a single macrogametocyte.

Question 121

What happens to the micro- and macrogametocytes after the mosquito has been infected with P falciparum

Answer 121

After ingestion the micro- and macrogametocytes exflagellate and fuse to form an ookinete.

The diploid ookinete traverses the gut wall and becomes an oocyst that attaches to the outside of the stomach

Question 122

What happens to diploid ookinete after it reaches the outside of the mosquito during the P falciparum life cycle

Answer 122

parasite within goes through meiosis and replication, culminating in the release of sporozoites that travel to the salivary glands for injection into the human host upon next blood
meal.

Question 123

What are the stages of the mosquito phase of the P falciparum lifecycle begin

Answer 123

with the ingestion of about 100 each
of micro- and macrogametocytes that exflagellate and pairs of micro and
macrogametocytes fuse to form an ookinete that traverses the stomach wall and develops into an oocyst that attaches to the outside of the stomach where
meiosis, transformation into sporozoites and parasite replication occur

Question 124

How many sporozoites are released from each oocyst

Why is this an estimate

Answer 124

1000-5000

Since the maturation of the oocysts is not synchronized, estimating the number of sporozoites per oocyst is difficult. Evidence suggests that about 20% will get to the salivary glands for injection and only 10-100 will actually make it into the human host during a single feeding event.

Question 125

Why do the symptoms of P falciparum vary so much (5)

Answer 125

because of factors including the current infection level, immunological experience, age, nutritional status and co-infections.

the most important correlate with severe disease is age.

Question 126

What are the symptoms assocaited with the different phases of the P falciparum life cycle

Answer 126

Commonly the liver phase of infection is close to asymptomatic, but with the initiation of the RBC phase, common symptoms
include muscle ache/pain, nausea & vomiting and high fever.

Severe disease includes anemia, respiratory distress, renal failure and cerebral inflammation

Question 127

What does immunity look like in areas where P falciparum is endemic

Answer 127

adults may be clinically immune and infants are protected by maternal care, which limits exposure and also often contributes maternal antibodies for immune protection

Question 128

When do the symptoms of P falciparum begin

Answer 128

10-15 days post-exposure and sporozoites infection

Question 129

How do symptoms of P falciparum vary with age in endemic areas

Answer 129

the reduction in symptoms generally correlates with age. Maternal protection of infants is lost, but over time into adulthood, the symptoms may cease altogether.

However, this appearance of clinical immunity does not mean that the individual is free of parasites.

Question 130

When is the age of greatest danger of severe disease and mortality from P falciparum

Why

Answer 130

ages 1- 5

Maternal protection is lost and exposure to the parasite is limited, so both parasitemia and immunopathology are not very well modulated, resulting in a high frequency of respiratory distress, renal failure, anemia and cerebral inflammation.

Question 131

What is the most important part of the P falciparum lifecycle

Answer 131

Initiation of the RBC cycle is critical for disease. The ability of the parasite to
firmly attach to the RBC is critical for invasion.

Question 132

Describe the process of RBC invasion of Plasmodium species

How does it compare to that of toxoplasma

Answer 132

The plasmodium merozoite will move along the RBC using microneme secretion and then re-orient to have the apical end irreversibly attach to the RBC plasma membrane. RBC surface receptors and the cognate receptors at the apical end of the merozoite interact to achieve this.
Secretion by the
rhoptries is similar to toxoplasma and
the initiation of the PV begins.

The process of invasion is similar to toxoplasma, except that Plasmodium species’ selection of host cell receptors for binding is much more specialized.

Question 133

What is the sole or major RBC receptor used by P vivax

Answer 133

The Duffy Antigen Receptor for Chemokines (DARC)

Question 134

Why do we think P vivax was important for human evolution in West Africa

Answer 134

The virtual lack of P. vivax in sub-Saharan Africa suggests that P. vivax was historically a very important selective factor in West Africa as there is
a high frequency of DARC negative alleles in the population

Question 135

Can you become resistant to P falciparum by evolving DARC negative RBCs

Answer 135

no: P. falciparum uses a variety of receptor interactions to achieve RBC binding. The ubiquitous presence of P. falciparum globally with intense foci in sub-Saharan Africa suggests that selection for human resistance to this species does not operate via a mechanism like DARC negative RBCs.

Question 136

What is the reason P falciparum has a much higher rate of infection and parasitemia than P. vivax

Answer 136

P falciparum uses multiple receptors

Question 137

What do we need to know about the immune response to P falciparum

Answer 137

very complex and beyond the scope of this lecture series. However, it is useful to illustrate how, like other pathogens with highly variable pathologies, infection can lead to variation in cytokine production and hence immunopathology in severe disease

Question 138

What is the problem with the immune response to P falciparum for young children

What can this lead to

Answer 138

An imbalance of cytokines may occur and this will be particularly problematic in 1-5 year olds with little or no previous immunological experience with P. falciparum because many immunomodulatory mechanisms haven’t been developed.

over-production of either (or both) pro- and antiinflammatory cytokines such that the cytokine profile may inappropriately activate a variety of cells and tissues that conspire to generate the range of severe disease pathologies.

Question 139

What has P falciparum had to evolve in the RBC phase of its lifecycle

Answer 139

Selection for the parasite to replicate includes destruction of its host cell. RBCs are exquisitely metabolically balanced to maintain the ability to carry oxygen and therefore ultrastructure/shape. Infection will disturb this balance to the extent that infected RBCs can be cleared in the spleen

evolved to avoid clearance by cytoadherence to uninfected RBCs and vascular endothelium

Question 140

How does P falciparum affect the structure of the RBC

Answer 140

growing trophozoites will produce
and secrete proteins (eg PfEMPs) that will decorate the RBC plasma membrane and also cause the RBC to acquire “knobs” on the surface

these mediate cytoadherence for rosetting

Question 141

What is rosetting in the P falciparum life cycle

Answer 141

adherence of infected RBCs to uninfected RBCs

Question 142

What is a problem with local inflammation during a P falciparum infection

can this become systemic

Answer 142

consequence of cytokine imbalance such as excess IFN-γ and TNF-α is the activation and upregulation of adhesive molecules on the vascular endothelium as normally seen in local inflammation and neutrophil recruitment

yes - this can become systemic including brain vasculature, leading to cytoadherence of infected RBCs to the vascular endothelium

Question 143

What does PfEMP interact with

Answer 143

CR-1 on RBCs
and
iCAM-1 on activated vascular endothelium

Question 144

What happens when the P falciparum infected RBCs get sequestered in systemic infection

Answer 144

they are sequestered and kept from clearance in the spleen, so the parasites can mature into merozoites and be released for new infection. The sequestration probably exacerbates the brain swelling due to inflammation

Question 145

What is a key feature of P falciparum infection from a diagnosis standpoint

Answer 145

the rarity of late trophozoites and schizonts in peripheral blood smears as a consequence of sequestration.

Question 146

What are PfEMPs composed of

Which genes encode them

Where are the genes located

Answer 146

mixed set of adhesive domains

var gene family

at the subtelomeric regions of the majority of the 14 chromosomes

Question 147

Why may a given P falciparum have a unique set of var genes

Why is this a problem for the immune system

Answer 147

The var genes undergo substantial intra-gene somatic recombination leading to a high variation

makes it difficult for the immune system to keep up with the antigenic variation in any given infection.

Question 148

it has been hypothesized that for PfEMP variation is selected for in immunologically experienced individuals with clinical immunity to P falciparum. Why is this important?

Answer 148

for maintaining continuity in the parasite’s life cycle between high transmission seasons, where it may be months in between wet seasons and expansion of the mosquito vector - mosquito population goes down in dry season so have to survive until the next wet season so it varies its antigens to persist in the host

Question 149

How does natural resistance to malaria appear

Answer 149

as selection for haemoglobinopathies in malaria endemic regions such as the haemoglobin sickle cell anaemia allelem(HbS), α and β thalassemias

Question 150

What are the potential mechanisms for protection against malaria in a heterozygotic Sickle cell patient (4)

Answer 150

Impairment of P. falciparum RBC invasion and growth under low oxygen tension
• Enhanced removal of parasite-infected HbAS RBCs
• Reduced pathogenicity of P. falciparum infected RBCs via reduced PfEMP expression
• Improved acquisition of malaria-specific immunity

Question 151

What are the mechanisms of protection against malaria provided by α thalassemia (3)

Answer 151

Protection against malaria-induced anemia
• Reduced pathogenicity of P. falciparum infected RBCs
via reduced rosetting & sequestration
• Immunological cross protection between species

Question 152

What are the mechanisms of protection against malaria provided by β thalassemia (3)

Answer 152

• Enhanced removal of parasite infected RBCs
• Reduced invasion and growth of P. falciparum
• Reduced pathogenicity of P. falciparum infected RBCs
via reduced rosetting & sequestration

Question 153

What is a potential protection mechanism provided by G6DP deficiency against malaria

Answer 153

• Loss of reducing power, free radicals hostile to parasite

Question 154

What protection against malaria do most haemoglobinopathies provide

Answer 154

impairment of the parasite to replicate within the affected RBC:

Haemoglobin disorders affect critical balances in things like water potential and solute concentration, particularly in low oxygen tension. In turn parasite growth is impaired so the parasitemia is lower and the expression of critical adhesive proteins like PfEMPs are lower so severe disease is less likely

Question 155

Give a notable example of where each of the following were once endemic:
US
Japan

Answer 155

Malaria was once endemic to the eastern US and

schistosomiasis in Japan (now both locally extinct)

Question 156

Why were polio and smallpox easy targets for complete eradication

How does control differ for schistosomiasis and malaria

Answer 156

Protection of the individual and herd immunity via mass vaccination worked because the viruses were sufficiently conserved that vaccination programmes could break the transmission cycle

vector control via improved water, drainage and hygiene were critical infrastructure measures,
but mosquito control tipped the balance for malaria in the US

Question 157

Which drug is known as the ‘wonder drug’

why

Answer 157

Ivermectin

its spectrum of use ranges from worm parasites to arthropod ectoparasites

Question 158

How was Ivermectin discovered

Answer 158

1970s
Streptomyces avermitilis
contained a Macrocyclic lactone that binds to glutamate gated
chloride channels and kills parasitic worms and some arthropods

Question 159

What is the difference between avermectin and ivermectin

Answer 159

the original active compound named avermectin was further developed for better activity and safety into ivermectin, classified by itself as an “endectocide”.

Question 160

What is Onchocerciasis

Answer 160

African River Blindness caused by the round worm Onchocerca volvulous

Question 161

Was ivermectin given to treat human onchoceriasis immediately

Answer 161

no originally seen to be effective against the microfilariae of onchocerca cervicalis in horses

Question 162

How is onchocerca volvulus transmitted

Answer 162

The black fly will pick up microfilaria upon a blood meal from an infected human.

In the black fly, the microfilaria will undergo a transformation into an infective larval worm.

In a subsequent blood meal, the larval worm will enter the human tissue and develop into an adult worm.

Question 163

What is the vector for the transmission of onchocerca volvulus

Answer 163

the black fly insect vector (Simulium spp.)

Question 164

Where do adult onchocerca volvulus worms reside

what do they do

Answer 164

in subcutaneous nodules

produce microfilaria that will travel in blood and lymphatics to distal tissue

Question 165

How long do adult O. volvulus adults live for

microfilaria ?

What causes disease?

Answer 165

Adults may live as long as 15 years

microfilaria live about 2 years

inflammatory response to the microfilaria - this can lead to blindness if in the eye

Question 166

Where is onchocerciasis focussed

Answer 166

in sub-Saharan Africa but occurs sporadically in South America

Question 167

How is global control of River lindness going

Answer 167

eliminated in Colombia, Ecuador, Mexico and Guatemala

• 100 million people treated in 2013

delivery/coverage
and some drug resistance has hampered some of the efforts in sub-Saharan Africa.

Nevertheless, ivermectin use has at least locally eliminated river blindness

Question 168

Why is control/ treatment of malaria so important

Answer 168

40% of the world’s population is at risk

Question 169

How long have treatments for malaria been around

why is this surprising

Answer 169

Although it has only been 130 years since Plasmodium spp. were identified as the causative agent of malaria and the life cycle confirmed, treatments for malaria have been around for millennia

Question 170

How do Native South Americans treat malarial fever

Answer 170

with a preparation from the bark of the quina quina or Cinchona tree

Jesuit priests brought this back to Europe in the 1600s

Question 171

What is the active ingredient in the quina quina preparation to treat malarial fever?

For how long was it the treatment of choice for malaria

Answer 171

Quinine (an alkaloid)

for the next 100 years until synthetic drugs like chloroquine

Question 172

What is the first line drug against malaria

Answer 172

Despite drug resistance in P. falciparum, chloroquine is still the first line drug for P. vivax and P. ovale infections.

Question 173

Which remedy for malarial symptoms has been used for 2000 years in Asia

How was it used in the 20th century

Answer 173

qinghoa

fractionated to find an extract that was 100% effective against P. berghi in mice and P cynomolgi in monkeys

was even effective against P falciparum (which is resistant to chloroquine)

Question 174

What is the active ingredient in a qinghoa preparation

what has been further developed from it

Answer 174

a sesquiterpene lactone, named qinghaosu, now known as artemisinin

dihydroartemisinin (better activity)

Question 175

What forms the basis for synthesising artesunate and artemether

Answer 175

dihydroartemisinin

Question 176

What are the 2 proposed hypotheses for the MOA of artemisinin and its derivatives

Answer 176

The endoperoxide bridge breaks and creates a free radical which puts a lot of oxidative and metabolic stress on the parasite

• PfATP6 inhibition leading to intracellular accumulation of calcium and subsequent cell death.

Question 177

What is ACT

What is it important for

Answer 177

Artemisinin-based Combination Therapies

reducing the development of drug resistance

Question 178

What is the first line of therapy for uncomplicated P falciparum infections

What are the possibilities to take in one tablet (2)

Answer 178

ACT

Artemether/lumefantrine
• Artesunate/amodiaquine

Question 179

Name 6 companion drugs for ACT

Answer 179

lumefantrine, 
mefloquine, 
amodiaquine, sulfadoxine/pyrimethamine,
piperaquine 
chloroproguanil/dapsone.

Question 180

Why is cultivating Artemisia annua difficult

what does this mean

Answer 180

it is a weed so is not reliable in terms of biomass and yield of artemisinin.

Importantly, the market is unstable so prices and shortages will fluctuate accordingly.

Question 181

How have we tried to stabilise the market for A. annua

Answer 181

genetically modify microorganisms to produce artemisinin

yeast designed to produce artemisinic acid as a precursor for SSA

Question 182

What made malaria elimination possible in the US

Answer 182

water and drainage control,

but mosquito control probably tipped the balance towards elimination

Question 183

Describe the steps involved in eradication of malaria in the US

Answer 183

The project commenced in 1947

• By end of 1949, 0ver 4.6 million houses sprayed with DDT
• In 1950 the US was declared free of malaria

• Drainage and aircraft spraying in
areas of recent cases

• In 1951 the CDC ceased to actively participate
• In 1952 the CDC went to surveillance only

Question 184

What happened to the Global Malaria Eradication Programme in the late 1950s

Answer 184

The success in the US provided inertia

The campaign succeeded in eliminating malaria from Europe, most of North America, parts of Central and South America, the Caribbean and parts of Asia but failed is sub-Saharan Africa where the bulk of malaria cases are today.

Question 185

What are the major emphases of the Roll Back Malaria initiative (beginning 1998)

Answer 185

Long Lasting Insecticidal Nets (LLINs) and Indoor Residual Spraying (IRS)

Question 186

Give 5 facts about Long Lasting Insecticidal Nets

Answer 186

LLINs contain pyrethroid insecticides only
• LLIN minimum lifespan of 20 washes or 3 years use in field conditions
• 2000-2015 over a billion LLINs were delivered to endemic countries
• 29% households could protect all family members
• Coverage of children under 5 years in sub-Saharan Africa
– <2% in 2000
– ~68% in 2015

Question 187

Give 2 facts about Indoor Residue Spraying coverage

Answer 187

DDT is used for IRS as it lasts ~6 months

• 16 million people protected in 2014 (4% at-risk)

Question 188

Where are the remaining hotspots for P falciparum infection

Answer 188

areas of recent civil war/ unrest

Question 189

5 things WHO and UNICEF have managed to do since 2000

Answer 189

• 60% reduction in malaria deaths, focused in sub-Saharan Africa
• Under 5 malaria death rate decreased by 65%
• Caucuses and Central Asia fastest decreases reported zero cases in 2014
• Six countries reported fewer that 10 cases
• 13 countries reported zero cases

Question 190

What vector control effective for control of malaria

Answer 190

local elimination

Question 191

What have Oxitec done in the fight against malaria

Answer 191

engineered a 2nd generation Anopheles mosquito that carries a female lethal gene that is active only when inherited in
non-laboratory settings.

The process is self-limiting so unlike gene drives is not designed to drive populations to extinction but rather simply knock down local populations for several generations.

Question 192

How do gene drives differ from the Oxitec method

Answer 192

Gene drives based on CRISPR/Cas 9 genome editing tools, new twist on the sterile male mosquito control has the potential to knock down mosquito populations locally and even to extinction. Clearly there are ethical and environmental concerns to be addressed