Lecture 33

Question 1

1. What is Malaria?
2. How is it spread?
3. How much of the world is at risk?
4. How many cases in the U.S. are there per year?

Answer 1

1. A vector-borne disease caused by a protist.
2. A widespread, mosquito-borne infectious disease caused by Plasmodium (a protist in the apicomplexan group), occurs mainly in tropical and subtropical areas.
3. More than 40% of the world’s population is at risk. A major cause of illness and death in developing countries. 300-500 million cases of malaria occur each year. 1.5-3 million people dies of malaria each year, especially children and pregnant mothers.
4. In the U.S., about 1,200 cases of malaria each year; most cases in the U.S. are due to immigrants and travelers returning from malaria-risk areas. Because of its wide distribution and lethality, malaria has had a major influnce on human evolution.

Question 2

1. Who first described the disease?
2. What was a 17th century treatment for the disease?
3. Who is Alphonse Laverne?
4. Who is Camillo Golgi?
5. Who is Ronald Ross?

Answer 2

1. Hippocrates, Plato, and Aristotle.
2. Use of Cinchona Bark (source of quinine) for treatment.
3. French surgeon working in Algeria - discovered the plasmodium parasite in blood of a patient.
4. Roman physician - described Plasmodium vivax, malariae, and falciparum.
5. British military doctor working in India - discovered the role of mosquitoes in transmission of the disease in 1897. Received the Nobel Prize in 1902 and knighthood in 1911.

Question 3

1. What measures did the U.S. take during Vietnam?
   
   1. Why was there still incidence of malaria in the U.S. after Vietnam?
2. How many cases were there in 2011?

Answer 3

1. Soldiers were required to take one large blue pill of chloroquine each week.
   
   1. Not everyone did so or could do so, and many U.S. personnel contracted malaria, as reflected in the incidence of the disease in returning Vietnam veterans in the late 1960s to early 1970s.
2. 1,925 cases, 5 deaths. Most were aquired while travelling in Africa, especially West Africa, and India.

Question 4

1. When do symptoms usually start?
2. What are the symptoms?
3. Why do the chills occur?

Answer 4

1. Usually start 10 days to 4 weeks after being bitten by an infected mosquito (takes at least 7 to 9 days and in some cases can take up to one year after being bitten for symptoms to appear).
2. Fever of 40°C, shaking chills, headache, muscles aches, and tiredness, often with nausea, vomiting, and diarrhea.
3. The chills occur when a new generation of the parasite is released from erythrocytes. Because of the loss of red blood cells, malaria generally causes anemia and some enlargment of the spleen. If not promptly treated, the more serious kind of malaria can lead to kidney failure, spleen damage, seizure, coma, and death, especially in children.

Question 5

1. How many agents of malaria are there?
2. What is Plasmodium falciparum?
3. What is Plasmodium vivax?
4. What is Plasmodium ovale?
5. What is Plasmodium malariae?
6. What is Plasmodium knowlesi?
7. What do humans serve as?

Answer 5

1. Five species of Plasmodium can infect humans.
2. The most serious (highest fatality rate).
3. Most widespread, milder disease, generally not fatal. Most difficult to treat because schizont form can hide in liver for long periods of time.
4. Milder disease, generally not fatal.
5. Milder disease, generally not fatal.
6. Causes malaria in macaques, but can also infect humans.
7. Humans are a major mammalian reservoir for Plasmodium.

Question 6

1. Describe the life cycle of Plasmodium.
2. What happens when a female mosquito bites a human?

Answer 6

1. Life Cycle
   
   1. Transmission is human to mosquito (Anopheles) to human. The disease is associated with swampy, wet areas where mosquitoes breed.
   2. Animals - most are dead-end hosts (cannot serve as reservoirs).
   3. Humans - secondary host
   4. Mosquito - primary host (in which sexual reproduction of Plasmodium occurs).
2. Male and female mosquitos feed on plant juices.
   
   1. Females also bite humans; they need the blood as nutrients for development of their eggs, which are released onto the surface of water.
   2. If a female Anopheles bites a person infected with malaria, it can ingest, with its blood meal, male and female gametocytes of Plasmodium that are in that person’s blood. View pic to see what happens if the female becomes infected.

Question 7

1. What happens if the disease goes untreated?
2. What are quinine, quinacrine, or chloroquine effective against?
3. What is primaquine effective against?
4. Are there resistance to these drugs?

Answer 7

1. In the absence of treatment, malaria usually is self-limiting in adults and results in immunity for approximately one year. In children, however, the disease can progress rapidly and kills more commonly.
   
   1. Malaria kills one child every few minutes. Children in Africa under the age of 5 years old typically contract malaria 6 times a year.
2. Effective against the parasite within RBCs (merozoites).
3. Effective against stages of the parasite outside RBCs (sporozoites).
4. Yes, resistance to these drugs has developed in Plasmodium.

Question 8

1. How have we responded to Plasmodium treatment resistance?

Answer 8

1. Historically, applications of treatments have been through monotherapies, using one drug at a time.
2. However, through selective pressures, including continued use of a drug over time, drug counterfeiting, and incorrect drug regimens, Plasmodium species have become resistant to many of the drugs historically used.
3. Current treatments are therefore based on using a combination of drugs, two or more at a time, which reduces the chances that Plasmodium can develop resistance.

Question 9

1. What do drug treatments use today?
2. What is the treatment called?
3. Why is this treatment good?
4. Who discovered Artemisinin?

Answer 9

1. Current combination drug treatments use artemisinin, a fast-acting drug that attacks the parasite in red blood cells, in combination with other drugs (e.g. derivatives of chloroquine and primaquine) that persist longer in the body and attack the parasite inside and outside the RBCs.
2. Artemisinin Combination Therapies
3. Combintation of drugs decrease the chance that Plasmodium can develop resistance.
4. Youyou Tu
   
   1. Nobel Prize awarded “for her discoveries concerning a novel therapy against Malaria. Born in 1930 in Zhejiang Ningpo, China. Worked at the China Academy of Traditional Chinese Medicine.

Question 10

1. What project was Tu recruited to? What was its goal?
2. How did Tu discover Artemisinin?

Answer 10

1. Project “523”. The project, established by Mao Tse Tung, was tasked with finding a way of stopping Malaria.
2. From ancient text, The Manual of Clinical Practice and Emergency Remedies, by Ge Hong of the East Jin Dynasty. Tu found reference to the use of sweet wormwood to treat malaria.
   
   1. She extacted and identified an active compound from the plant that killed malaria-causing parasites in the blood.

Question 11

1. What methods can be used to diagnose the disease?

Answer 11

1. Methods:
   
   1. Microscopic examination of the blood, known as the the Gold Standard for identification and diagnosis.
   2. Rapid Diagnostic Test (antigen-antibody screening). also have been created to provide results in 2-15 minutes; however, the values RDTs is limited by their poor accuracy and variable results under field conditions; they are also expensive.
   3. PCR can be used to increase accuracy of RDTs. However, PCR has limited field use due to the expensive equipment and need for specialized training,

Question 12

1. What are some preventative measures we can take?
2. What happens dispite of these measures?

Answer 12

1. Prophylactic use of antimalarial drugs.
2. Avoidance of mosquitos.
   
   1. Insecticide treated nets - prevents mosquito bites while sleeping.
   2. Indoor spraying - prevents mosquitos from entering houses.
3. It is difficult to avoid being bitten by mosquitoes; travelers to countries where malaria is endemic may still become infected.

Question 13

1. How can we control the disease?
2. Why is DDT a dangerous control measure?

Answer 13

1. Elimination of the mosquito’s habitat by drainage of swamps and similar breeding areas. Elimination of the mosquito by insecticides (DDT). However, these ideas still present problems such as habitat loss and it can be harmful to other animals.
2. It’s an organic pollutant.
   
   1. It can remain in the environment for up to 12 years after application.
   2. It can enter food chain through crops and animal products.
   3. It is very harmful to wildlife
   4. There is some evidence that it may be a reproductive and endocrine disrupter in humans.

Question 14

1. How has malaria influnenced human evolution?
2. What hemoglobin has a lower affinity for oxygen?
   
   1. What happens to people who are heterozygous for this allele?

Answer 14

1. Sickle cell anemia and sickle cell trait. In people with sickle cell anemia and sickle cell trait, their RBCs have a mutant hemoglobin, hemoglobin S differs from normal hemoglobin (hemoglobin A) by having a single amino acid change, valine for glutamate, due to a random genetic change.
2. Hemoglobin S
   
   1. People who are homozygous for hemoglobin - sickle cell animea, often lethal. Heterozygous = sickle cell trait; less able to use oxygen effieciently, less able to survive at high altitudes, but not so much of a disadvantage in lowland tropical areas where oxygen levels are higher.

Question 15

1. What does being heterozygous for hemoglobin S confer?
   
   1. Why does it impact of the Plasmodium?
2. How many people living in sub-Saharan Africa are heterozygous?

Answer 15

1. Are more resistant to malaria.
   
   1. Growth of the Plasmodium in RBCs with hemoglobin S uses up the available oxygen and causes the cells to sickle more easily and to release potassium.
   2. The plasmodium has a highly aerobic metabolism and also needs high levels of potassium, so the sickle cell trait slows down progress of the disease by slowing down growth of the parasite.
   3. Also, when the deformed RBCs pass through the spleen, they are destroyed; this prevents the plasmodium from completing its life cycle, so it stops the progress of the disease.
2. Over 30%. The mutant form of the gene has been selected for by the disease; those who have it tend to survive better in areas with malaria, they reproduce and pass the mutant gene to their descendents. Descent with modification.

Question 16

1. What are some other examples of the role Malaria in human evolution?

Answer 16

1. Examples:
   
   1. West African groups - resistance to Plasmodium vivax correlates with the presence in RBCs of another mutat form of hemoglobin, hemoglobin E.
   2. Certain Mediterranean groups - resistance to plasmodium falciparium correlates with a deficiency in RBCs of the enzyme GPD due to a mutation; the mutated GPD allows higher levels of oxidants to build up in the cell, and these damage the membranes of the plasmodium.
   3. Certain Mediterranean groups - have genetic mutations that affect the production and efficiency of hemoglobin; these mutations, which result in an increase in oxidants in RBCs, confer some resistance to malaria.
   4. West African groups - have resistance to malaria comparable to that conferred by the hemoglobin S allele due to the presence of genes for certain MHC I and MHC II proteins, which activate a powerful immune response against Plasmodium; these specific gene variants are not found in other human groups.