Malaria

Question 1

What phyla are within the kingdom Protozoa?

Answer 1

Sporozoa, includes Plasmodium and Babesia

Flagellates, includes Giardia (bever fever) and Trichomonas (STD)

Amboebozoa

Question 2

Kingdom Protozoa

Answer 2

Single-celled, eukaryotic organisms

2-100 microns in size

Classified by how they move: flagellates by flagella, amoebas by pseudopods, sporozoa don’t move much but penetrate cell, ciliates by cilia

Most similar to bacteria (in terms of pathogenesis and immune response)

Question 3

Malaria Vector

Answer 3

Anopheles mosquito

Only females transmit Malaria

Feed at dawn and dusk

Transmission does not occur at elevations over 2000 meters or temps under 60 degrees

Question 4

What is Malaria?

Answer 4

Febrile illness caused by protozoan parasite transmitted by Anopheles mosquito

Can also be transmitted by blood transfusion, organ transplantation, or sharing of needles

Mainly in Sub-Saharan African, mainly 5 year olds

Question 5

Malaria Parasites

Answer 5

Plasmodium species causes illness, parasite infects red blood cells

5 different species cause disease in humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium knowlesi

Question 6

What are some of the ways we have developed protections against malaria?

Answer 6

Malaria infects red blood cells, which carry hemoglobulin. Because of this, those with hemoglobulin mutations have protections.

Sickle cell disease: People who are heterozygous for sickle cell are less susceptible to the malaria. Being homozygous (Hemoglobulin S) causes sickle cell, but being heterozygous is beneficial. African descent

Thalassemia for those of Mediterranean descent (alpha and beta thalassemia)

Question 7

Plasmodium falciparum

Answer 7

Most severe infection, most death

More than one parasite infect single red blood cell –> high parasitemia

Particularly Sub-Saharan Africa, children 2 -10

Highest levels of drug resistance

Question 8

Plasmodium vivax

Answer 8

Second most common cause of malaria

Primarily South America and Southeast Asia

Requires Duffy antigen for entry into host cells

Can stay dormant in liver and then cause relapsing disease months or years later

Prefers to infect young red blood cells (reticulocytes)

Question 9

How does Plasmodium vivax gain entry into host cells? What group benefits from this?

Answer 9

Plasmodium vivax requires Duffy antigen for entry into host cells

Duffy antigen: glycoprotein found on surface of red blood cells

Those in Sub-Saharan Africa are Duffy-negative, so they are unable to get Plasmodium vivax - why it is rare in Africa and predominate in Asia

Question 10

Malaria Life Cycle

Answer 10

1. Mosquito bites you and injects sporozoites (haploid, infectious)
2. Sporozoites travel to liver where they reproduce asexually (schizogony) - In P. vivax and ovale, parasite establishes hypnozoites (dormant, can relapse infection later)
3. Infected liver cell ruptures and releases merozoites into bloodstream where they invade red blood cells
4. Parasite reproduces asexually within the red blood cell and eventually bursts open, releasing more merozoites into the bloodstream, which then go on to infect more RBCs
5. Sometimes parasite develops into male or female gametocyte within the RBC - if mosquito ingests one of each type, they then combine to form zygote (diploid) in gut of mosquito (sexual reproduction)
6. Zygote develops into ookinete, and then an oocyst, which migrates out of gut. Divides by meiosis to produce many (haploid) sporozoites that migrate to mosquito salivary glands, where they are ready to infect next person

Question 11

Phases of asexual reproduction of malaria parasite within RBC

Answer 11

Ring –> Trophozoite –> Schizont

Question 12

Plasmodium falciparum can infect…..

Plasmodium vivax can infect…..

Answer 12

Plasmodium falciparum can infect erythrocytes at any moment, and multiple parasites can infect single cell

Plasmodium vivax has preference for young erythrocytes and in general only one found in a given RBC

Question 13

Hypnozoites

Answer 13

Only Plasmodium vivax and Plasmodium ovale

When sporozoites travel to liver where they reproduce asexually, hypnozoites are also produced

Dormant stage

Question 14

Malaria Clinical Disease

Answer 14

Plasmodium falciparum: Onset 8-25 days after bite - Delay due to parasite replicating in liver, Asymptomatic

Non-P. falciparum: Time corresponds to cycle of RBC rupture (24/48/72 hour cycles); Cycling fever and chills

Anemia, splenomegaly (enlarged spleen)

Severe cases: Cerebral malaria, renal failure, hypoglycemia, lactic acidosis

Question 15

Cerebral malaria

Answer 15

Usually caused by Plasmodium falciparum, kids in Sub-Saharan

Presents as abnormal behavior, impaired consciousness, seizures, coma

Fatal if not treated

Question 16

Renal failure

Answer 16

AKA blackwater failure

All the detritus from ruptured RBCs (hemolysis) overwhelms kidney’s filtration system

*Can get dark urine without renal failure

Question 17

Adaptive immune response to Plasmodium falciparum

Answer 17

Immune response to malaria involves both humoral (antibody) and cell (CD8+ cytotoxic T cells) mediated components

Antibodies to sporozoites and merozoites –> Cytotoxic CD8+ T cells kill infected hepatocytes –> Infected erythrocytes removed by spleen

Question 18

Innate immune response to Plasmodium falciparum

Answer 18

Innate immune system can also respond to malaria

Dendritic cells engulf merozoites or infected erythrocytes, and macrophages eat infected erythrocytes

Splenic macrophages are the main way that malaria is cleared from bloodstream - also release inflammatory cytokines, contributing to fever

Question 19

Who is affected by malaria and why?

Answer 19

Mainly children and travelers most affected - not protected by antibodies

Also people returning to endemic area after long absence - acquired immunity has waned

But people who live in endemic areas have developed antibodies so they don’t get as sick

Question 20

Thin blood smears

Answer 20

Drop of blood put on microscope slide and second slide used to smear blood across slide

Film is fixed with methanol - cells stay intact during staining

Stained with Giemsa staining - Red blood cells look pink, parasites blue

Better for determining which species is present; Necessary for counting how many erythrocytes are infected (parasitemia)

Question 21

Thick blood smear

Answer 21

Drop of blood spread in small circle with corner of microscope

Not fixed

Stained with Giemsa staining - RBCs will lyse so all that is left are parasites which will be blue

More sensitive for detection

Question 22

Rapid diagnostic tests

Answer 22

Distinguish Plasmodium falciparum from Plasmodium vivax

Enzyme immunoassays that detect malaria antigens in blood

Results within minutes

Don’t require expert

Question 23

Malaria Prevention

Answer 23

Don’t get bitten

DDT

Prophylaxis for travelers (chloroquine, atovoquone-proguanil, dox, mefloquine)

Question 24

Quinine

Answer 24

From bark of cinchona tree

Lead to chloroquine

Question 25

Chloroquine

Answer 25

Target heme metabolism

Cheap

Minimal side effects: GI upset, itching

Resistance widespread - not understood, mutations thatconfer chloroquine resistance prevent acculumation of drug (maybe effluc pump, or something similar)

Question 26

Mefloquine

Answer 26

Psychiatric side effects

Weekly dosing

Drug of choice for prophylaxis in pregnancy

Question 27

Sulfadoxine-pyrimethamine

Answer 27

Cheap

Almost no side effects

Targets folate metabolism

Resistance widespread in Asia and Africa

Question 28

Artemisia annua

Answer 28

New option malaria drug

Used in Chinese herbal medicine

Became preferred treatment in early 2000s - resistance emerging

Question 29

Artemisinin Combination Therapy

Answer 29

Artemisinin compound combined with second anti-malarial drug (Artemether-lumefantrine; Artesunate-amodiaquine; etc)

Meant to prevent artemisinin resistance - emerged in Asia

Artemisinin monotherapy discouraged - kills parasites quickly so parasite load quickly drops off but has short half life

Question 30

Malaria Vaccine

Answer 30

RTS,S vaccine recently approved

Requires 4 doses

Not great efficacy but better than nothing - reccommended for kids in areas with high Plasmodium falciparum infections