Malaria Biology

Question 1

What is the impact that malaria has?

Answer 1

• Massive global impact
• Large- cases, small deaths in 2020 (Nigeria 2020: 151-275,000)
• 85 malaria endemic countries
• ~50% global population at risk
• ~241 million cases
• ~627,000 deaths
• 45-61 million DALYs (2017 data)
• 95% of malaria burden, 96% of deaths is in sub Saharan African - 80% of those deaths are children under 5. Also Pregnant women, patients with HIV/AIDS, non-immune migrants, mobile populations and travellers. 2016 ~1600 imported cased in UK.
• 5% increase in incidence between 2019-2020 due to service disruption during COVID pandemic
• 12% increase in malaria deaths between 2019-2020: 47,000 additional deaths due to service disruption during COVID pandemic – plus 22,000 through better data gathering

Question 2

Tell me the origins of the protists

Answer 2

Question 3

Origin of the protists

Answer 3

Question 4

What are Apicomplexa and give some examples?

Answer 4

a large phylum of parasitic alveolates. Most of them possess a unique form of organelle that comprises a type of non-photosynthetic plastid called an apicoplast, and an apical complex structure (this is involved in invasion)

All excepting one are obligate endoparasites of animals

Includes: Babesia, Plasmodium, Cryptosporidium, Toxoplasma.

Question 5

What does the tree of life only show about the genus plasmodium?

Answer 5

Tree only shows the best-known Plasmodium species - at least 164 other Plasmodium sp. named. Parasites of mammals, birds, reptiles, reportedly one in amphibia.

5 sp known human parasites, P. knowlesi - macaque monkey parasite in S. E Asia, but increasingly important as a human parasite.

Part of wider Apicomplexan order of blood parasites – the order haematosporida

Question 6

What is plasmodium part of?

Answer 6

Plasmodium is part of a wider Apicomplexan order of blood parasites – the malaria parasites / order Haemosporida.

Question 7

Why are the relationships within the Haemosporida historically difficult to understand?

Answer 7

Relationships within the Haemosporida historically difficult to understand due to limited sampling of species, absence of robust, multi locus sequence data and extreme nucleotide base composition bias in the group. P falciparum genome GC content 19%

Question 8

The evolutionary history of the malaria parasite is characterised by what?

Answer 8

A complex series of transitions in life-history strategies and host usage

Question 9

The malaria plasmodium is polyphyletic. What does this mean?

Answer 9

(of a group of organisms) derived from more than one common evolutionary ancestor or ancestral group and therefore not suitable for placing in the same taxon.

Question 10

Who won the nobel prize in 1902 for his work on the transmission of malaria (P. vivax) by mosquitos?

Tell me about his work

Answer 10

Ronald Ross

• Previously thought to be a (bacterial) gastro-intestinal disease
• He fed mosquitoes on infected soldiers and then dissected them
• Giovanni Grassi - the complete life cycle of P. falciparum, vivax, malariae (1898)
• Life cycle of Taenia nana
• Life cycle of Ascaris lumbricoides (by self-experimentation!)
• Grassi’s law: there is no malaria without Anopheles
• The term malaria (from the Italian mala “bad” and aria “air”) was used by the Italians to describe the cause of intermittent fevers associated with exposure to marsh air or miasma.
• The word was introduced to English by Horace Walpole, who wrote in 1740 about a “horrid thing called mal’aria, that comes to Rome every summer and kills one.”

Question 11

What are the stages of the malarial parasite life cycle?

Answer 11

1. At stage 1, an infected female mosquito injects sporozoites when taking a blood meal
2. Sporozoites migrate to the liver via the blood stream
3. Sporozoites mature in liver cells and turn into schizonts
4. Mature Schizonts divide (exo-erythrocytic schizogony) producing merozoites
5. The liver cells rupture and release the merozoites into the blood stream. (P. vivax & P. ovale also produce hypnozoites which lay dormant and can cause relapse months or even years later)
6. Merozoites penetrate the RBCs and divide asexually (erythrocytic schizogony). The RBCs rupture freeing the parasites to penetrate new RBCs. Rupture of the RBCs is synchronised every 24, 48 or 72 hrs, causing malarial fever & violent shaking.
7. Some differentiate into sexual erythrocytic stages (male microgametocytes and female macrogametocytes).
8. The gametocytes are ingested when a female mosquito bites and undergo a sporogonic cycle(other erythrocytic stages in the blood meal die)
9. Within 30 hrs of ingestion into the mosquito’s stomach, ♂ microgametocytes penetrate the ♀macrogametes to form zygotes.
10. The zygotes become motile and elongated and turn into ookinetes
11. The ookinetes penetrate the gut wall and form oocysts.
12. The oocysts grow, rupture and release sporozoites, which migrate to the salivary gland ready for injection into a new host

Question 12

The malaria life cycle in mosquitos vs humans

Answer 12

Question 13

What are the malaria parasites which infect humans?

Answer 13

P. falciparum - the cause of malignant tertian malaria

P. vivax - the most frequent cause of benign tertian malaria

P. ovale - the other, less frequent, cause of benign tertian malaria

P. malariae - the cause of benign quartan malaria

P. knowlesi - the cause of severe quotidian malaria in Southeast Asia since 1965

Plus a few other possible opportunist infections by other species identified by PCR.

Question 14

What do the following mean…

Tertian malaria

Quartan malaria

Quotidian malaria

Answer 14

Tertian malaria – fever every other day

Quartan malaria – fever every third day

Quotidian malaria – every day!

Question 15

What malaria paraistes account for nearly all human infections with plasmodium species?

Answer 15

P. falciparum, P. vivax, P. ovale, and P. malariae together account for nearly all human infections with Plasmodium species

Question 16

What malarial parasites account for the large number of malarial deaths?

Answer 16

P. falciparum accounts for the overwhelming majority of malaria deaths

Question 17

An increasing number of cases of severe malaria in SE Asia have been attributed to what malarial parasite?

Answer 17

P. knowlesi

Question 18

Tell me about Plasmodium falciparum

Answer 18

Found worldwide in tropical and subtropical areas, and especially in Africa where this species predominates.

Can cause severe malaria because it multiples rapidly in the blood, and can thus cause severe blood loss (anaemia).

The parasite- infected erythrocytes can clog small blood vessels. When this occurs in the brain, cerebral malaria results, a complication that is fatal without treatment.

Question 19

Tell me about Plasmodium vivax

Answer 19

Found mostly in Asia, Latin America, and in some parts of Africa

Because of the population densities especially in Asia it is probably the most prevalent human malaria parasite

Strict trophism for reticulocytes (reticulocyte-binding protein).

Historically believed to require duffy positive red blood cells

P. vivax (as well as P. ovale) has dormant liver stages (“hypnozoites”) that can activate and invade the blood (“relapse”) several months or years after the infecting mosquito bite

Duffy antigen on rbc surface historically thought to be required in P. vivax invasion, hence absence of this species from much of Africa.

Howes et al 2010 – global distribution of Duffy negative population frequency

But recent studies have identified P. vivax in duffy-negative individuals, so it isn’t the whole story, Gunalan et al 2018.

Question 20

Tell me about plasmodium ovale

Answer 20

Found mostly in Africa (especially West Africa) and the islands of the western Pacific.

It is biologically and morphologically very similar to P. vivax.

However, unlike P. vivax, it can infect individuals who are negative for the Duffy blood group (a non-specific chemokine receptor), which is the case for many residents of sub-Saharan Africa. This explains the greater prevalence of P. ovale (rather than P. vivax) in most of Africa.

Question 21

Tell me about plasmodium malariae

Answer 21

Found worldwide, is the only human malaria parasite species that has a quartan cycle (three-day cycle).

If untreated, P. malariae causes a long-lasting, chronic infection that in some cases can last a lifetime.

In some chronically infected patients P. malariae can cause serious complications such as nephrotic syndrome.

Question 22

Tell me about plasmodium knowlesi

Answer 22

Found throughout Southeast Asia as a natural pathogen of long-tailed and pig-tailed macaques

It has recently been shown to be a significant cause of zoonotic malaria in that region, particularly in Malaysia.

It has a 24-hour replication cycle and so can rapidly progress from an uncomplicated to a severe infection; fatal cases have been reported

Question 23

How is malaria diagnosed?

Answer 23

Microscopic examination of Giemsa-stained thick or thin blood (still preferred)

Antigen-based techniques:

• By detection of (host) antibodies to Plasmodium antigens (cannot distinguish between past & present infections)
• By direct detection of Plasmodium antigens (detects current infection)

PCR (not widely used due to cost and complexity but can detect low levels of parasites)

Question 24

When do the symptoms of malaria usually begin?

Answer 24

Typically begin 8–25 days following infection, or later in those who have taken antimalarial medications as prevention.

Question 25

What are the signs and symptoms of malaria in an individual?

Answer 25

Initial manifestations - common to all malaria species - are similar to flu-like symptoms. These can resemble other conditions (sepsis, gastroenteritis, and viral diseases). Symptoms may include headache, fever, shivering, joint pain, vomiting, haemolytic anaemia, jaundice, haemoglobin in the urine, retinal damage, and convulsions.

Question 26

What are the classic symptoms of malaria?

Answer 26

The classic symptom of malaria is **paroxysm** a cyclical occurrence of sudden coldness followed by shivering and then fever and sweating, occurring every one (quotidian – P. knowlesi), two (tertian fever – P. falciparum, vivax, ovale) or three days (quartan – P. malariae) for P. malariae. P. falciparum infection can cause recurrent fever every 36-48 hours, or a less pronounced and almost continuous fever.

Question 27

What parasite is severe malaria usually caused by and what are the symptoms?

Answer 27

Severe malaria is usually caused by **P. falciparum.** Symptoms of falciparum malaria arise 9–30 days after infection. Individuals with cerebral malaria frequently exhibit neurological symptoms, including abnormal posturing, nystagmus (“dancing eyes”), conjugate gaze palsy (failure of the eyes to turn together in the same direction), seizures, or coma. And death.

Question 28

What are the long term effects of malaria if not treated?

Answer 28

Malaria in pregnant women is an important cause of stillbirths, infant mortality, abortion and low birth weight -effects exacerbated by HIV infection Surviving infants susceptible to cardiovascular disease, diabetes, hypertension in later life Respiratory distress - up to 25% of adults and 40% of children with severe P. falciparum. Renal failure is a feature of blackwater fever, where haemoglobin from lysed red blood cells leaks into the urine. Enlarged spleen, enlarged liver or both of these. Complications may include spontaneous bleeding, coagulopathy, and shock. In malaria endemic areas, people may develop partial immunity, allowing asymptomatic infections to occur.

Question 29

Tell me about malaria induced anaemia

Answer 29

Malaria is a major cause of anaemia in tropical areas. Many malaria deaths result directly or indirectly from anaemia Direct lysis through schizont rupture (1-10% parasitaemia). Accelerated haemolysis of non-infected red cells (90% of red cell loss). bone marrow dyserythropoiesis – kidney medulla releases production-supressing mediators, red cell precursor apoptosis. P vivax – reticulocytes. Reduced red cell deformity – splenic destruction – reduced red cell life. Enlarged spleen – increased clearance capacity and lower threshold. Autoimmunity / Ig binding to red cells. Malaria infection causes haemolysis of infected and uninfected erythrocytes and which compromises rapid recovery from anaemia

Question 30

How may an individual have genetic resistance to malaria?

Answer 30

**Sickle cell disease:** disorder affecting haemoglobin causing severe anaemia. **Thalassemia (α & β)**: disorder resulting in the abnormal formation of haemoglobin causing mild to severe anaemia. **Glucose-6-phosphate dehydrogenase deficiency (X-linked):** Reduction of enzyme causes RBCs to break down prematurely (haemolytic anaemia). These are really common diseases, especially in areas with malaria – because in the heterozygous form they all confer some resistance to malaria.

Question 31

How was malaria used as a cure for syphilis?

Answer 31

Between 1917 and 1940, the treatment of last resort for patients with neurosyphilis, was to give them malaria! “Pyrotherapy” Based on the evidence that syphilis sufferers improved if they had prolonged high fever. Warm cabinets also used (41oC). Continued until the 1960s in the US & 1970s in the UK. Direct transfer of human blood infected with P. vivax! Then quinine cure. Made obsolete by penicillin.

Question 32

Malaria is a tale of two parasites, what are these two parasites?

Answer 32

Mosquito – Anopheles sp. – Ectoparasite Malaria – Endoparasite and Hyperparasite Only female Anopheles blood feed, male Anopheles don’t have mandibles and don’t blood feed – feed on nectar and other sugar sources. Females also nectar feed but require a blood meal to initiate egg maturation.

Question 33

Where do mosquitos breed? What is the speed of the life cycle dependent on?

Answer 33

Mosquitoes breed in standing water. Therefore, breeding increases dramatically in the rainy season when water Speed of life cycle temperature dependent

Question 34

How do mosquitos lay their eggs?

Answer 34

Eggs laid one at a time or in rafts. Most hatch in 48 hrs (some can withstand sub-zero temperatures before hatching)

Question 35

Where do mosquito larva live?

Answer 35

Larva lives in water and comes to the surface to breath – moults four times and then pupates

Question 36

When the adult mosquitos emerge what happens?

Answer 36

Adults emerge, mating and blood feeding two days later and (females) can live for a month

Question 37

Where does the name mosquito come from?

Answer 37

Mosquito comes from the Spanish or Portuguese meaning “little fly”.

Question 38

Where do all mosquito larvae need to live? What have mosquitos adapted to?

Answer 38

All mosquito larvae need to live in water. Well adapted to a very unstable, transient environments

Question 39

Tell me about the Anopheles spp.

Answer 39

Over 465 species 41 are malaria vectors to a significant level They all bite between dusk and dawn They lay eggs in water which hatch into larvae and emerge as adults Prefer shallow water (puddles, hoof prints) – subject to climate variations (i.e. humidity, rainy season) Malaria transmission is more intense if the mosquitoes live longer (parasites have time to complete their life cycle)

Question 40

What does the anopheles vector distribution depend on?

Answer 40

Depends on: **Abundance –** the species needs to exist in numbers high enough to ensure individuals encounter an infectious human to pick up the malaria parasite **Longevity –** individual mosquitoes need to survive long enough after feeding on infected blood to allow the parasite time to develop and travel to the mosquito’s salivary glands ready to infect the next person bitten **Capacity –** each mosquito needs to be able to carry enough malaria parasites in the salivary glands to ensure the parasite is transmitted to the next human **Contact with humans –** the species needs to prefer to feed on humans rather than other animals, and be able to survive and breed in places close to homes, and be able to find people (usually by entering their houses

Question 41

Malaria distribution

Answer 41

Question 42

What are some other diseases transmitted by mosquitoes?

Answer 42

* Malaria * Dengue * West Nile virus * Chikungunya * Yellow fever * Filariasis * Tularemia * Dirofilariasis * Japanese encephalitis * Saint Louis encephalitis * Western equine encephalitis * Eastern equine encephalitis * Venezuelan equine encephalitis * Ross River fever * Barmah Forest fever * La Crosse encephalitis * Zika fever

Question 43

How can one avoid getting malaria?

Answer 43

Visit the Foreign office website: https://www.gov.uk/foreign-travel-advice Take anti-malarials and **finish the course** Use insect repellents - DEET (50%) or citronella (roll-on or spray) Use bed (mosquito) nets Burn insect coils at night **Grassi’s law:** there is no malaria without Anopheles