Clearing the Bad Air: Let's Talk About Malaria!

It occurred to me today that I have yet to post about one of the most famous and infamous parasitic diseases: Malaria.  The name of this disease literally translates to "Bad Air" because early conquistadors believed you could get it from breathing in...well...bad air.  This misconception came along as the Spanish pushed into the tropical regions of the New World and lost many lives to this strange new (to them) tropical disease.  It's interesting to note that although the Spanish believed  the disease originated in the New World, it has been established in recent times that the disease was actually brought to the New World by the Spanish...who brought with them slaves from Africa that were likely already infected.  Today we understand far more about this devastating disease.  Because of its prevalence in tropical regions and its socio-economic impact, this disease has probably been THE most studied parasitic disease.  Billions of dollars have been spent battling the disease and the impacts that it has on countries around the world.  But let's not get too far ahead of ourselves....

Taxonomy

Plasmodium (in yellow) bursting RBCs

Malaria is caused by protozoan parasites belonging in the genus Plasmodium.  Like all protozoa, these parasites once belonged in kingdom protista, but some texts now break that kingdom into several others.  In such texts, these belong to kingdom Chromalveolata under the subgroup Alveolata, or in some cases kingdom Alveolata may be listed.  While phylogeneticists debate the true kingdom-level classification, we will move on to more solid taxonomic statuses.  There are no debates at all as to which phylum Plasmodium belongs.  Because of the collection of organelles that function in host-penetration processes known as the "apical complex", these parasites and their brethren are placed within phylum Apicomplexa.  Because they lack a conoid, they are placed in class Aconoidasida ("a" meaning "without").  They are within order Haemosporida along with other malaria-like organisms and piroplasms.  And, naturally, they belong to family...you guessed it...Plasmodiidae.  There are four species of Plasmodium that infect humans: P. falciparum, P. ovale, P. malariae, and P. vivax.

Life Cycle
Ask any undergraduate biology student with a few years of classes under their belt to draw you the life cycle of Plasmodium.  Go on...I'll wait....Did they do it?...Correctly?...Awesome!  The life cycle for this parasite is often one of the first life cycles encountered by students of biology.  Let's start with the vector.  This parasite is spread via bites from female mosquitoes belonging to the genus Anopheles.  

Anopheles Up Close and Personal

As the mosquito bites you, tiny sporozoites wiggle their way out of the salivary glands of this vector and into your blood stream.  It rides the tide of your briskly moving currents of blood until it reaches the liver, where it invades liver cells (a.k.a. hepatocytes).  Here, the sporozoites undergo a rapid form of multiple asexual divisions known as schizogony to produce merozoites.  The merozoites break out of the hepatocytes and seek out red blood cells (a.k.a. erythrocytes) to infect.  Once inside, the host erythrocytes become transformed into factories producing additional merozoites and bursting (a.k.a. "lysing") to release 8-24 new merozoites that seek out more erythrocytes.  While some merozoites are content to continue to reproduce in this manner, others will develop into gametocytes.  When an uninfected Anopheles female comes around to take a blood meal from a person housing Plasmodium, many of the gametocytes are ingested with the blood.  These cells mature in the gut of the mosquito. Eventually, male and female gametocytes will fuse to create  zygotes (a.k.a. "ookinetes" in this case), which will eventually become sporozoites.  After developing into this motile, infective form, the sporozoites move into the mosquito's salivary glands and the cycle is complete.

Outsmarting Our Immune Systems
Plasmodium is a devious little dude.  These parasites are largely protected from the treat of a host's immune system because they live within cells rather than outside of them.  This hides them from circulating immune police, such as macrophages.  However, erythrocytes are prone to aging because they work so hard for our bodies.  When these cells pass through the spleen, they are checked for signs of damage or aging, and are subsequently filtered out of regular circulation.  The parasites becomes the cutting edge of anti-aging technology for these little cells by using proteins to prop up the cells, making them seem young to the busy spleen, and saving the parasites' homes for another road trip through the circulatory system.  Some species, such as P. falciparum, will even go so far as to produce adhesive proteins that force cells to stick to walls of small vessels in order to save themselves from being processed via the spleen.

Symptoms of Malaria
The symptoms of malaria may not appear until 8-30 days post-infection.  As the parasites enter into the phase of their life cycle in which they invade erythrocytes and force them to burst, people tend to spike fevers.  In some instances, people infected by P. viviax won't display symptoms for several months or even years post-infection.  This is because this species produces hypnozoites, which allow for long incubation periods and late relapses of infections.

The most common symptoms are flu-like in nature: headache, fever, shivering, joint and muscle pain, vomiting...but some are more severe such as anemia, jaundice, and retinal damage.  The most defining symptom is paroxysm.  Paroxysm is a period of coldness followed by chills and then by high fevers and sweating.  The time frame of paroxysm states is dependent upon the type of malarial parasite with which one is infected.

The World Health Organization (WHO) splits malaria cases into two categories: "Severe" and "Uncomplicated".  To be classified as "severe", one must demonstrate any of the following: decreased consciousness, significant weakness (e.g. inability to walk), loss of ability to eat, convulsions, low blood pressure, breathing difficulties, circulatory shock, kidney failure, red (hemoglobin-rich) urine, uncontrollable bleeding, enlarged liver, enlarged spleen, pulmonary edema, low blood glucose, acidosis, high levels of lactate, or an extremely high parasite level present in the blood.  The disease can progress to an even more severe form (if infected with P. falciparum) known as cerebral malaria.  This form presents with neurological problems such as seizures and comas.
 
Diagnosis, Treatment, and Prevention
Malaria is diagnosed by finding the parasites in a blood sample.  This can be through microscopic examinations of blood smears, or through antigen-based diagnostics tests.  The later is more accurate, but also more costly, and these tests are not yet sophisticated enough to tell how many parasites are present within a sample.  Polymerase Chain Reaction (PCR) has been shown to diagnose malaria efficiently, but is not widely used due to its complexity.

People diagnosed with malaria are usually treated using chloroquine in areas where Plasmodium isn't already resistant. Because resistance is so prevalent, most patients are also given mefloquine, doxycycline, or Malarone.  To prevent resistance, many places are now instituting the use of artemisinin-combination therapys (ACTs), which involves treating with traditional anti-malarial medications in conjunction with artemisinin compounds.  ACT is about 90% effective if used to treat "uncomplicated" forms of malaria.  When treated correctly, patients can experience a complete recovery. 

Various Anti-Malarial Medications

"Severe" forms of malaria were once treated with quinine, but now artesunate is more widely used because of its efficiency.  Treatment also includes supporting patients by helping them manage high fevers and seizures as they come and go as well as monitoring respiratory rates, blood pressure, and blood glucose levels.  This form of malaria can progress so fast that it can cause death within days or in some cases hours.

To prevent malaria, most tropical regions take on a three-pronged approach:
1) They give out prophylactic medications (if they can afford to do so).
2) They work to eliminate Anopheles mosquitoes.
3) They devise ways to prevent people from getting bitten by mosquitoes.

Prophylactic medicines are often the same medicines used for treatment (mefloquine, chloroquine, Malarone, etc.).  Travelers heading to malaria-endemic regions begin taking prophylactics a few weeks before leaving and continue taking them for about a month after coming back home.  (I personally took Malarone when I traveled to Panama for two weeks, and I didn't have any problems, but many people have side effects of this and other such drugs.)  This form of prophylaxis is not typically practical for residents of malaria-endemic areas because drug resistance and partial immunity can come from prolonged use.  This is also a costly endeavor, and has had many historical roadblocks.

To prevent mosquito bites, people can use DEET-based repellents and insecticide-treated mosquito nets.  Treating the nets with insecticides reduces the chances of mosquitoes living long enough to find a way to breech the nets themselves.

A woman tucks a mosquito net into her child's mattress.

 Some places have instituted spraying for mosquitoes (both indoors and outdoors).  Indoor spraying is highly effective as the mosquitoes tend to land on wall surfaces after taking in blood meals.  The WHO advises the use of 12 insecticides for such purposes.  Like anti-malarial drugs, these insecticides should be used in combination to prevent resistance.

Community-aimed educational programs are also helpful in preventing the spread of malaria.  After all, knowledge is power!  Seriously!  Teaching people to cover areas with stagnant water that could become mosquito-breeding grounds, as well as helping people to recognize the signs and symptoms of malaria can greatly reduce the number of malaria cases reported in an area.

An old poster encouraging people to spray for mosquitoes.

Ultimately, the best approach would be to prevent malaria rather than to treat it. (More cost effective and less costly in terms of human life.)  However, the monetary costs of instituting a program for prevention are beyond the means of the countries where malaria posses the biggest threat to public health.  Luckily, there are some amazing researchers (namely Jay Keasling...go on...Google him!) working to produce an anti-malarial drug that can be mass-produced cheaply.  Thanks to this kind of research, and humanitarian efforts directed at distribution, the next few decades are sure to reduce the number of annual cases of malaria.  It will be interesting to see how things change from a socio-economical perspective in response to a decline in a disease with such wide-reaching impacts on global health and economies.

Moral of the Story 
Though I could go on and on and on about malaria, this post has already gotten rather lengthy, so we will call it quits for today.  Maybe a future post will discuss the amazing way some populations have developed genes that prevent them from contracting malaria...or we could delve deeper into the work of Jay Keasling.  Perhaps a future post could discuss the history of malaria, an exciting tale of man's ups and downs as he fights to erradicate a disease that just won't seem to die.  For now, at least you can proudly say that you know the basics about malaria.  So if you ever travel to malaria-endemic areas, be sure to take your antimalarials (before, during, and after), sleep with a special insecticide-drenched, netted canopy surrounding your bed, and be sure to invest in plenty of DEET!

P. falciparum...because I can't resist a rainbow-colored image!
(Even if it is artificially done! :p)