Malaria and the Sickle Cell Gene

What’s the connection?

Malaria

• Translates from Italian for “bad air “ (mal aria)• Once thought to be caused by breathing the

air in hot, humid areas around swamps• Now we know that it is transmitted by a

parasitic protozoa called Plasmodium that lives in both mosquitoes and humans and travels between both.

Causative agent: Plasmodium sp.

• Four Plasmodium species cause malaria:

• Plasmodium vivax, P. falciparum, P. malariae, P. ovale

• Falciparum is the most deadly

• Falciparum and vivax are the most common

A vector is any agent that carries and transmits an infectious pathogen to another living organism

Mosquitoes are the malaria vector• 350 species of mosquito; only 60 can transmit malaria. • Malaria-carrying mosquitoes primarily live in equatorial regions• Malaria eliminated in the the US in the 1950s, mainly by

eliminating most malaria-carrying mosquitoes • Only female mosquitoes bite humans and feed on blood; males

feed on plant nectar• The long lifespan and strong human-biting habit of the African

vector species is one reason why more than 90% of the world's malaria deaths are in Africa.

• Other possible vectors: dirty needles, blood transfusions, mother -> newborn (breastmilk, placenta)

Malaria Map:What is the pattern?

Parasitic behavior

• Plasmodium spend part of their life cycle living in human red blood cells

• Plasmodium digest human hemoglobin to complete their own protein synthesis

• Hemoglobin components called heme are toxic so the parasite crystallizes them into hemozoin (important detail for treatment…)

• Plasmodium reproduces inside a red blood cell and then the ruptures the cell, spreading to other red blood cells….

Symptoms• Paroxzyms- 24 hour interval fever and chills due to the periodic hemozoin release

• Hypoglycemia and lactic acidosis- low blood sugar, nausea and weakness because the parasite is able to digest blood glucose 70% faster than humans

• Hepatosplenomegaly- enlarged liver and spleen due to infection, spleen problems lead to increased infections…

• Hemogloburina- “black water fever” - due to the disposal of ruptured red blood cells in urine, turning urine brown or black

• Chronic anemia/ Respiratory distress- due to reduced oxygen transport

• Coma - (cerebral malaria) caused by P. falciparum, which has “knobs” and can enter the cerebral microvasculature (tiny blood vessels), by binding to endothelia cells in blood vessels. Here the parasite avoids disposal from our spleen and oxidative stress from red blood cells.

Treatment: Major Ones Come from Plants

• Chloroquine (originally quinone from the bark of the cinchona tree in Peru) – prevents the parasite from turning toxic heme into hemozoin and it dies.

• Most P. Falciparum resistant to chloroquine now - have developed membrane channels that transport heme out of their vacuole so it is not toxic

• Because of this resistance, WHO now recommends artemisinin (from Chinese wormwood tree) combined with chloroquine (Artemisinin Combination Therapy – ACT)

Statistics

• In 2010 the WHO estimates that there were 216 million cases of malaria (WHO)

• Most deaths are African children• In some countries, malaria is the leading cause of

death• Worldwide, it the 5th leading cause of infectious

disease death (WHO) • 1500 cases a year in US, only from returning

travelers (CDC)

Mortality • Previously thought 655,000 people died a year from malaria,

now think it 1.2 million. Mostly children. • COMPARE TO: US Mortality 2009 (CDC) , top 2 causes of death:

– Heart disease: 599,413 deaths– All Cancer: 567,628 deaths

• In the most severe cases of the disease, mortality rates can be over 20%, even with intensive care and treatment.

• In areas where malaria is common, treatment is often poor and the overall fatality rate for all cases of malaria can be as high as 10%

• Most deaths are of African children

Acquired Immunity

• After repeated exposure, individuals develop partial immunity to malaria

• Subsequent episodes are less severe in these people

• Older children and adults often semi-immune• Newborns often semi-immune due to

maternal antibodies transferred by placenta, but this immunity wears down

Major Risk Factors

• Older babies and toddlers - malaria huge cause of infant and young child mortality. Maternal immunity worn off, no acquired immunity yet….

• Pregnant Women – pregnancy reduces immunity. Pregnancy hormones suppress immune system so pregnant woman does not reject fetus.

• Malaria during pregnancy causes miscarriage, prematurity, and low birth weight and therefore contributes to overall infant mortality

Insecticide-treated Bed Nets Reduce Malaria Mortality

Protective Factors

• Some people have a genetic mutation that protects them from malaria infection.

• There are 2 protective mutations– Missing Duffy antigen - this is a receptor for the

parasite on the red blood cell. People who lack the Duffy receptor do not get vivax malaria, a very common malaria in Africa.

- Sickle Cell Trait……..

Sickle Cell Trait • Mutant Gene produces hemoglobin molecules that stick

to each other and cause the red blood cells they are in to “sickle” (elongate) and become rigid.

• *Plasmodium parasite cannot digest sickled hemoglobin• *Plasmodium causes sickled red blood cells to rupture

prematurely, before parasite can reproduce• Plasmodium dies before it can gain a foothold in the

bloodstream• In malaria areas, people with one copy of this mutant

gene have a survival advantage over people without it. • Gene common in malaria-prone parts of the world

Heterozygote Survival Advantage

• In malaria areas, people who carry one mutant allele have a survival advantage

• This is called a Heterozygote Advantage

• …….but what about people who are homozygous for the recessive sickling gene?

Homozygous Disadvantage: Sickle Cell Disease

• Carrying 2 mutant alleles causes Sickle Cell Disease. • People with the disease can only make defective hemoglobin,

and suffer from very painful symptoms and shortened life expectancy because of it. (more tomorrow on the disease)

• Normal blood cells live about 100-120 days, but sickled red cells die after about 10 to 20 days. Because they cannot be replaced fast enough, the blood is chronically short of red blood cells, a condition called anemia.

• What is the chance of 2 people with sickle cell trait having a child with Sickle Cell Disease? – Punnett Square!

Sickle Cell Punnett Square: Normal Hemoglobin A (A) and Sickled

Hemoglobin A (S) are codominant

Statistics

• Sickle Cell Disease was the first disease to be connected to a specific gene.

• 1 in 5,000 Americans are born the disease, but 1 in 500 African Americans are born with it. (CDC)

• In the US there is no malaria, so the sickle cell mutation has no advantage and natural selection works against its survival.

• Only .25% of American blacks have sickle cell disease, and this % is falling. (8% are carriers)

• In West Africa 4% of people have the disease.

Symptoms

• Suffer from vaso-occlusive crises: painful blockage in capillaries of the sickled blood cells that are extremely painful

• Prone to blood infections (from spleen damage)

• Delayed growth from lack of red blood cells• Fatigue, paleness, shortness of breath• Eye problems (poor blood nourishment of

retina)

Treatment

• Pain Relief from painful vaso-occlusive crises (painful blockages of small blood vessels)

• Folic acid to ensure adequate amounts for making new red blood cells (important to synthesizing, repairing and methylating DNA during cell division)

• Penicillin to prevent infections• Pneumococcal vaccine introduced in 2000 to

prevent pneumonia reduced sickle cell-related death among Black or African-American children younger than 4 years of age by 42%. (CDC)