Captain Kirk, Harry Potter, and Plasmodium Falciparum

Charleston is a paradise in the spring, in summer it is a hell, and in the autumn a hospital.  Alexander Hewatt, 1779.  (Butler, 2007, p. 77)

The people who lived in 1779 South Carolina were well aware of hte diseases they faced in their hot, semi-tropical port city, malaria, smallpox, yellow fever among many more.  While they lumped these threats together as "fevers," they well knew the dangers they posed:  perhaps 8 of every 10 babies would die at birth, those who survived were likely to die before they reached 20, and if they had their 20th birthday they would be lucky to see their 40th.  (Edgar, 1998, pp. 156-157)

Two hundred and forty years after the Reverend Hewatt's observation, smallpox has been eradicated from the world and there are effective vaccines to protect against yellow fever as well as a long list of other once deadly diseases, ensuring that Charleston is now a pleasant and healthy city in all seasons.  

Malaria, however, remains a major public health problem because nearly one-half of the world's population lives under its threat.  In 2017 malaria infected an estimated 219 million people and killed 435,000, 60 percent of whom were children under the age of five.  

While other diseases have succumbed to new drugs and antibiotics and the development of vaccines that assist the powerful human immune system to recognize and destroy bacteria and viruses, the protozoan Plasmodium falciparum which causes malaria continues to thrive using its unwilling partner, the Anopheles mosquito, to deliver it to new victims.  

Bill Gates, whose foundation has funded research to develop a vaccine for malaria, attributes the durability of Plasmodium falciparum to its ability to shape shift like creatures from fantasy or science fiction.  (Gates, 2019)

But it was neither myth nor science fiction that allowed the plasmodium to become a stowaway on slave ships, concealed in the blood and livers of the humans being taken to Portugal's colonies in South America (1525) and to colonial Virginia beginning in 1619.  Having left its anopheline mosquito host in Africa, the parasite has been able to shape shift to be accommodated into more than "34 different anopheline mosquito species" in the Americas and around the world.  (Molina-Cruz and Barillas-Mury, 2014)

The mythical Count Dracula uses shape shifting to elude Dr. Van Helsing, the vampire hunter by becoming a bat, a dog, and even a fog in order to get through locked doors to drink the blood he must have to live.  Plasmodium falciparum also needs erythrocytes, red blood cells, that are stoutly defended by the body's immune system.  The shape shifting protozoan is able to deceive that immune system with what the fictional Captain Kirk or Harry Potter would call cloaking devices but which are actual biological ways that allow it to conceal itself in a victim's liver while preparing to dine on its hemoglobin.  When it does expose itself to the immune system it is able to lay a false trail as the immune system pursues it.  

Once a number of individual plasmodium parasites have been introduced into the human by the bite of a female anopheline mosquito the parasites are able to elude (yet another story!) the immune system's frontier guards entering and clearing the blood stream very quickly and entering the liver where the parasite takes up residence in a liver cell.  Clinical malaria--the alternating fever chills will be the result of the plasmodium's invasion of the victim's red blood cells.  But before it can accomplish that, it must go through morphogenesis (changing to its blood attacking form) inside the liver cells.  When the parasite forces its way into the liver cell it captures some of the liver cell's membrane and uses it to create a small pouch that makes the parasite invisible to the body's immune system.  Thus protected it hijacks the cell's machinery to synthesize the proteins and nutrients it needs to complete its mophogenesis.  In one to three weeks a few dozen liver-stage invaders have been morphed into "hundreds of thousands of parasites" capable of eating the hemoglobin in blood cells.  (Manke, 2018)

The new blood stage plasmodium is called a merozoite and it will be responsible for the final act of the plasmodium's life cycle in the human host and prepare the beginning of a new cycle that will occur in a mosquito.  

It is therefore crucial for that hemoglobin eating form of the plasmodium to be safely transported from the liver to the host's blood stream where merozoites will use the hemoglobin to clone more of themselves while some of the merozoites will produce a different form, the gametocyte in a blood cell.  When the blood cell is destroyed the gametocyte will swim freely in the blood awaiting a mosquito to feed on the blood.  Inside the mosquito's abdomen the gametocytes will differentiate into a male and a female form, mate to produce the next generation of the plasmodium to be transmitted to the next human bitten.  

The safe transfer from the liver to the blood stream is accomplished by what researchers Graewe et. al. (2001) call a "hostile takeover," the merozoites are bundled into protective packets (merosomes) synthesized out of host cell wall materials creating a kind of cloaking device that makes the merosomes invisible to the host's immune system.  

As soon as the merosomes rupture liberating the merozoites each of them immediately forces its way into an erythrocyte (red blood cell) where it will feed on the hemoglobin and replicate (clone) itself multiple times and then release new merozoites into the blood stream.  

During the cloning the plasmodium implements yet another tactic that will delay the body's immune system from responding to the invasion.  During the first 10 to 14 hours of the red blood cell invasion, the plasmodium activates a randomly selected single gene of one of its var family while leaving the remaining 59 var genes silent.  The activated var gene codes (creates) a protein the "PtErythrocyte Membrane Protein (PfEMP)" which will appear on the surface of each invaded red blood cell.  


The body’s immune system will see the alien protein (PfEMP) on the blood cell surface and will construct an antibody to suppress or destroy it. But with each cloning, the plasmodium will turn on a different var family gene which will change the identity of the PfEMP protein with the result of leaving the body’s immune system one step behind the plasmodium. (Graewe et al., 2011), (Guizetti & Scherf, 2013)  (Gates, 2019)

This description of the plasmodium has only included two of its many shape shifting cycles but make it easy to see why researchers Ahmed, S.I. Aly, Vaughn, and Kappe (2009) observe that the “malaria parasite life cycle constitutes one of the most complicated and fascinating life cycles of any organisms and poses intriguing areas of study for cell biology, molecular biology, and immunology alike.”

Efforts to create a vaccine have been frustrated by the plasmodium’s ability to create multiple identities for its antigens since it is very difficult to create a vaccine that must address a set of ever-changing antigens.
Researchers are speculating on other strategies such as preventing the hijacked liver cells from producing proteins and nutrients for the invading plasmodium.

Note: George Clooney suffered a case of malaria that went undetected but hit him hard. It’s not simply a disease that affects people in countries “not ours.”

A graphic of the complete malaria life cycle can be found on the CDC Website.
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An excellent discussion and graphical representation of the plasmodium life cycle can be found at the Institute Pasteur Website.
 
Resources:
Aly, A. S. I., Vaughan, A. M., & Kappe, S. H. I. (2009). Malaria parasite development in the mosquito and infection of the mammalian host. Annu Rev MicrobiolAnnual review of microbiology, 63, 195-221. doi:10.1146/annurev.micro.091208.073403
 
Butler, N. M. (2007). Votaries of Apollo: The St. Ceclia Society and the Patronage of Concert Music in Charleston, South Carolina, 1766-1820. Columbia, SC: University of South Carolina Press. Retrieved from www.sc.edu’uspress

Edgar, W. (1998). South Carolina: A History.

Gales, B. (2019). The world’s deadliest shapeshifter. Retrieved from https://www.gatesnotes.com/Health/The-worlds-deadliest-shapeshifter

Graewe, S., Rankin, K. E., Lehmann, C., Deschemeier, C., Hecht, L., Froehlke, U., . . . Heussler, V. (2011). Hostile Takeover by Plasmodium: Reorganization of Parasite and Host Cell Membranes during Liver Stage Egree. PLOS Pathogens. Retrieved from https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1002224

Guizetti, J., & Scherf, A. (2013). Silence, activate, poise and switch! Mechanisms of antigenic variation in Plasmodium falciparum. Cell Microbiol Cellular microbiology, 15(5), 718-726. doi:10.1111/cmi.12115

Manke, K. (2018). Malaria-Causing Parasite Manipulates Liver Cells To Survive. Duke Today. Retrieved from https://today.duke.edu/2018/05/malaria-causing-parasite-manipulates-liver-cells-survive
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George Clooney picture from the (Irish) Independent, 2/11/2011. https://www.independent.ie/woman/celeb-news/i-was-so-sick-with-malaria-i-didnt-care-if-i-lived-or-died-26705367.html

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