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Research Question: How has Plasmodium sp. evolved in such a way that it is able utilize mosquitoes as a vector as means of infecting humans eventually leading to malaria?

Wikipedia Edits (Minimum 300 Words)
Link: https://en.wikipedia.org/wiki/Plasmodium#Evolution

Plasmodium subsequently evolved a mechanism to invade the salivary glands of mosquitoes via protein interactions, allowing for transmission from mosquito to host. Once mosquito transmission was firmly established, the previous fecal-oral route was lost within the Plasmodium genus.

The survivorship and relative fitness of mosquitoes are not adversely affected by Plasmdodium infection which indicates the importance of vector fitness in shaping the evolution of Plasmodium. Plasmodium has evolved the capability to manipulate mosquito feeding behavior. Mosquitoes harboring Plasmodium have a higher propensity to bite than uninfected mosquitoes. This tendency has facilitated the spread of Plasmodium to the various hosts.

Environmental factors play a considerable role in the evolution of Plasmodium and the transmission of malaria. The genetic information of Plasmodium falciparum has signaled a recent expansion that coincides with the agricultural revolution It is likely that the development of extensive agriculture increased mosquito population densities by giving rise to more breeding sites, which may have triggered the evolution and expansion of Plasmodium falciparum.

There are over one hundred species of mosquito-transmitted Plasmodium. Evolutionary biologists have utilized Bayesian and maximum parsimony to construct a phylogenetic analysis of these malarial parasites. The resulting phylogeny suggests that the Plasmodium of mammalian hosts forms a definitive clade that is it strongly associated with the specialization to Anopheles mosquito vector. This analysis suggests that a vector switch to Anopheles mosquitos was a major evolutionary transition that has allowed Plasmodium to exploit humans and other mammals.

Although there are therapeutic medications to treat malaria, Plasmodium has accumulated increasing drug resistance over time. A recent examination has shown that even artemisinin, one of the most powerful anti-malarial drugs, has been experiencing decreased efficacy due to the development of resistance.

Link: https://en.wikipedia.org/wiki/Malaria#Mosquito_control

Because the development of resistance to DDT and other insecticides is a major issue, principles of Darwinian medicine can be applied in order to combat malaria by controlling mosquito populations. Darwinian medicine involves the application of evolutionary principles as means of understanding and combating diseases and promoting health. Recent studies have shown promise in some cutting-edge methods of controlling mosquito populations while also curtailing the evolution of resistance. One recent study involves hormone manipulation to manage mosquito populations by interfering with the insects’ fundamental physiology. Methoprene, a Juvenile Hormone analog, disrupts mosquito metamorphosis. As a result, these mosquitos never reach adult form and eventually die in the larval stage. Studies have suggested that methoprene can be used to control mosquito populations by disrupting the intrinsic physiology and can thus lead to a reduction in the transmission of malaria.

Final Draft of Paper
'''Malaria: An Evolutionary Perspective on Plasmodium and the Mosquito Vector Matt Murtha Tues – 9:10 am'''

Malaria is one of the most devastating diseases plaguing humans today. According to the World Health Organization, recent data estimates that there were about 207 million cases of malaria and approximately 627,000 deaths due to the disease in 2012 (WHO, [Updated 2013]). Malaria is caused by various species of the protozoan genus Plasmodium. These parasites utilize mosquitoes as a vector to transmit the disease to humans. Plasmodium from the saliva of a biting mosquito is injected into humans and eventually invade human erythrocytes, causing symptoms such as chills, fever, nausea, and fatigue (CDC, [Updated 2012]). The establishment of the mosquito as a vector has been a major evolutionary transition that has led to increased fitness and accelerated transmission of Plasmodium to human hosts, leading to the many cases of malaria. The relationship between Plasmodium, the mosquito vector, and human host make malaria both an intriguing and complex disease to study in evolutionary terms.

The life cycle of Plasmodium is complex and can be viewed from an evolutionary perspective. The sporozoite form of the Plasmodium infects human livers. After liver infection, the Plasmodium cells multiply and develop into merozoites, which infect red blood cells. These merozoites destroy hemoglobin and cause lysis of red blood cells. After lysis, some of these merozoites develop into gametocytes that circulate throughout the human bloodstream. These gametocytes are then eventually ingested by biting mosquitoes. Within the mosquito gut, the haploid gametes fuse to form a diploid oocsyst. Growth and division of the oocyst results in haploid sporozoites. These sporozoites invade the salivary glands of the mosquito, allowing the insect to restart the cycle by biting another human (CDC, [Updated 2012]). The various life-cycle stages indicate the adaptations Plasmodium has developed over evolutionary time that allow it to invade and thrive in both mosquitoes and humans.

Evolutionary biologists have recently suggested that the ancestor of Plasmodium was a parasite that spread through fecal-oral transmission and infected the human intestinal wall. It is theorized that these ancestral parasites evolved means of infecting the human liver and eventually the ability to infect mosquitoes (Igweh, 2012). Within the mosquito, the parasite has evolved specific mechanisms that allow it to invade the mosquito salivary glands, which has greatly facilitated transmission. By using UV-crosslinking experiments, researchers at John Hopkins School of Public Health have determined that Plasmodium utilize Thrombospondin Related Anonymous Protein (TRAP) to bind to saglin, a receptor on the salivary gland of mosquitoes. These researchers also concluded that a point mutation in TRAP’s binding domain was deleterious and prevented invasion of the mosquito salivary gland (Ghosh et al., 2009). This research clearly shows the importance of the TRAP-saglin interaction. This binding interaction became fixated within the genus Plasmodium and the former fecal-oral route of transmission disappeared (Igweh, 2012). This change exemplifies natural selection and indicates the powerful adaptation that arose in the Plasmodium genus. The invasion of the mosquito salivary gland has allowed Plasmodium to take full advantage of the insect as a vector and has led to a drastic boost in transmission and an increase in overall fitness. Although humans infected with Plasmodium experience devastating symptoms, there appears to be little or no adverse effects of Plasmodium infection within the mosquito. One recent study published in Evolution examined if there was a relationship between vertebrate host virulence and fitness of mosquitoes carrying the parasite. These researchers infected mice with one of seven genetically different clones of Plasmodium chabaudi. Each clone differed in parasite virulence, which was defined as the harm P. chabaudi imposed on the mice. Virulence was determined by measuring weight loss and anemia in the malarial mice. Mosquitos were then prompted to take a blood meal from the various mice, and the subsequent survivorship and fitness of the mosquitoes were measured. Results indicated that there was no statistically significant relationship between vertebrate host virulence and mosquito survivorship. Surprisingly, the mosquitoes that fed on the more virulent mice actually experienced higher reproductive rates (Ferguson et al., 2003). The results of this experiment strongly show vector fitness is an important selective agent shaping the evolution of Plasmodium sp. The importance of vector fitness has led to coevolution and the emergence of a commensalistic relationship, where the Plasmodium benefits due to increased transmission while the mosquito is not adversely affected.

The propensity of mosquitoes to bite their hosts plays a major role in the transmission and fitness of Plasmodium. Interestingly, only female mosquitoes bite. This is because female mosquitoes require nutrients from blood in order to produce eggs. Consequently, female mosquitoes have adapted mouthparts that allow for penetration of skin. Because female mosquitoes risk their lives when seeking a blood meal, their propensity to bite is limited. However, Plasmodium is capable of manipulating mosquito feeding behavior in order to increase its own transmission. According to a field study from researchers at the University of Aarhus, Plasmodium manipulates mosquitoes’ feeding behavior in two critical ways. Results determined mosquitoes harboring Plasmodium falciparum, the species that causes the most severe cases of malaria in humans, were more likely to take a full blood meal and also more inclined to bite multiple people (Koella et al., 1998). The results of this study illustrate that Plasmodium has evolved beneficial adaptations in order to promote its own transmission and reproductive success by altering mosquito behavior.

It is vital for mosquitoes to feed on the appropriate host in order for the various species of Plasmodium to successfully invade. There are over one hundred species of mosquito-transmitted Plasmodium, with their respective hosts ranging from reptiles to mammals. Evolutionary biologists have utilized Bayesian and maximum parsimony to construct a phylogenetic analysis of these malarial parasites. The resulting phylogeny suggests that the Plasmodium of mammalian hosts forms a definitive clade that is it strongly associated with the specialization to Anopheles mosquito vector (Martinsen et al., 2008). This analysis suggests that a vector switch to Anopheles mosquitos was a major evolutionary transition that has allowed Plasmodium to exploit humans and other mammals. Additionally, the phylogeny depicts that the widespread success of Plasmodium in invading such diverse range of vertebrate hosts has been driven by the use of the mosquito as a vector.

Environmental factors play a considerable role in the evolution of Plasmodium and the transmission of malaria. Researchers at the University of Oxford have used bioinformatics to examine the evolution of Plasmodium falciparum. According to their study, the parasite’s genetic information has signaled a recent expansion that coincides with the agricultural revolution (Hume et al., 2003). It is likely that the development of extensive agriculture increased mosquito population densities by giving rise to more breeding sites, which may have triggered the evolution and expansion of Plasmodium falciparum. A more recent study also supports this claim and further concludes that deforestation and subsequent agricultural development has been one of the biggest factors in the emergence of widespread malaria in Africa. This study also outlines predictions of future deforestation on malaria incidence in an effort to curtail future spread of the disease (Yasuoka & Levins, 2007). Clearly, these studies demonstrate that environmental factors dictate both the fitness of mosquitoes and consequently the fitness of Plasmodium.

Although there are therapeutic medications to treat malaria, Plasmodium has accumulated increasing drug resistance over time. A recent examination has shown that even artemisinin, one of the most powerful anti-malarial drugs, has been experiencing decreased efficacy due to the development of resistance (Ashley et al., 2014). Due to the development of drug resistance, alternative solutions must be considered to mitigate the disease. Because mosquitoes play such a monumental role in the transmission of malaria, these insects have emerged as a possible target in combatting the disease. During the 1950s and 1960s, the insecticide DDT was used extensively to control mosquito populations and prevent the spread of malaria. Although DDT was initially successful, the overuse of the insecticide imposed directional selection on mosquito populations and led to the evolution of DDT-resistant mosquitoes (CDC, [Updated 2012]). As a result, the success of DDT was short-lived and the emergence of resistance caused cases of malaria to once again skyrocket. Consequently, the development of resistance and the harmful effects on the environments led many governments to ban the use of DDT as means of controlling mosquito populations (CDC, [Updated 2012]). Furthermore, mosquitoes have developed cross-resistance to a wide range of insecticides, including the commonly used pyrethroid (Prasittisuk et al., 1977).

Because the development of resistance to DDT and other insecticides is a major issue, principles of Darwinian medicine should be applied in order to combat malaria by controlling mosquito populations. Darwinian medicine involves the application of evolutionary principles as means of understanding and combating diseases and promoting health. Recent studies have shown promise in some cutting-edge methods of controlling mosquito populations while also curtailing the evolution of resistance. One recent study involves hormone manipulation to manage mosquito populations by interfering with the insects’ fundamental physiology. Mosquitoes proceed through four stages in their life cycle: egg, larva, pupa, and adult. During the larval stage, mosquito endocrine glands secrete Juvenile Hormones that regulate development and metamorphosis. High concentrations of Juvenile Hormones prevent metamorphosis while low concentrations signal development into a pupa and eventually an adult. According to researchers at Brooklyn College, methoprene, a Juvenile Hormone analog, disrupts mosquito metamorphosis and eventually leads to the death of the larva. In this study, researchers cultured larvae of several different mosquito species. The group of mosquitoes that were exposed to methoprene experienced disruptions in metamorphic midgut remodeling. DNA staining indicated that high methoprene concentration prevents diploid cell division and disrupts the programmed death of polytene cells. As a result, these mosquitos never reach adult form and eventually die in the larval stage (Nishiura et al., 2003). The study suggests that methoprene can be used to control mosquito populations by disrupting the intrinsic physiology and can thus lead to a reduction in the transmission of malaria.

In summary, examination of the Plasmodium and mosquito relationship from an evolutionary perspective provides valuable understanding and insight towards the devastating disease of malaria. The complex relationships and adaptations that have developed over evolutionary time in both Plasmodium and mosquitoes make malaria a particularly destructive disease for human populations. However, by further studying environmental factors and Darwinian techniques, we may be able to reduce the cases of malaria and get one step closer to combatting the disease once and for all.

References

Ashley E.A., Dhorda M., Fairhurst R.M., et al. 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med.;371(5):411-23.

CDC: Malaria [Internet]. [Updated 2012]. Center for Disease Control and Prevention; [cited 2014 Oct 26]. Available from: http://www.cdc.gov/malaria/about/index.html

Ghosh A.K., Devenport M., Jethwaney D., et al. 2009. Malaria parasite invasion of the mosquito salivary gland requires interaction between the Plasmodium TRAP and the Anopheles saglin proteins. PLoS Pathog. 5(1):e1000265.

Hume J.C., Lyons E.J., Day K.P. 2003. Human migration, mosquitoes and the evolution of Plasmodium falciparum. Trends Parasitol. 19(3):144-9.

Igweh J.C. 2012. Biology of malaria parasites. Dr. Omolade Okwa (Ed.), ISBN: 978-954-51- 032604, InTech.

Ferguson H.M., Mackinnon M.J., Chan B.H., Read AF. 2003. Mosquito mortality and the evolution of malaria virulence. Evolution. 57(12):2792-804.

Koella J.C., Sørensen F.L., Anderson R.A. 1998. The malaria parasite, Plasmodium falciparum, increases the frequency of multiple feeding of its mosquito vector, Anopheles gambiae. Proc Biol Sci. 265(1398):763-8.

Martinsen ES, Perkins SL, Schall JJ. 2008. A three-genome phylogeny of malaria parasites (Plasmodium and closely related genera): evolution of life-history traits and host switches. Mol Phylogenet Evol. 47(1):261-73.

Nishiura J.T., Ho P., Ray K. 2003. Methoprene interferes with mosquito midgut remodeling during metamorphosis. J Med Entomol. 40(4):498-507.

Prasittisuk C., Busvine J. 1977. DDT-resistant mosquito strains with cross- resistance to pyrethroids. Pesticide Science. 8 (5): 527-533.

Yasuoka J., R Levins. 2007. Impact of deforestation and agricultural development on anopheline ecology and malaria epidemiology. The American Journal of Tropical Medicine and Hygiene. 76 (3): 450-60.

WHO: Factsheet on the World Malaria Report [Internet]. [Updated 2013]. World Health Organization; [cited 2014 Oct 26]. Available from: http://www.who.int/malaria/media/world_malaria_report_2013/en/

Wikipedia Assignment Due October 15
-Monitored and Responded to input on Plasmodiumtalk page.
 * "Sounds good, thanks for the feedback. I will look into this." --Murtha.22 (talk) 04:08, 15 October 2014 (UTC)

Wikipedia Assignment Due October 1
Identify 3 ways that the article could be improved.

1) Article: Plasmodium  https://en.wikipedia.org/wiki/Plasmodium

Topic that Needs Improvement: Evolution & Mechanism of Mosquito Infection and Transmission


 * Although the Evolution section of this article mentions how Plasmodium has evolved to infect the human liver and eventually red blood cells, it does not mention the evolutionary aspects and mechanism(s) that Plasmodium utilize to infect mosquitoes.

2) Article: Plasmodium falciparum   https://en.wikipedia.org/wiki/Plasmodium_falciparum

Topic that Needs Improvement: Ecology and Evolution of Plasmodium falciparum


 * In the Evolution section of this article, ecological explanations can be added to help explain how Plasmodium falciparum has led to widespread malaria in Africa. For example, this article can mention how the agricultural revolution increased the breeding sites for mosquitoes and may have triggered the evolution and expansion of Plasmodium falciparum throughout Africa and other parts of the world.

3) Article: Plasmodium   https://en.wikipedia.org/wiki/Plasmodium

Topic that Needs Improvement: Evolution- Mosquito Fitness & Transmission


 * The Evolution section of this article states that Plasmodium "survive and infect" mosquitoes. This may seem to imply that Plasmdodium decreases the fitness of mosquitoes. However, the mosquitoes that transmit Plasmdodium do not have a decreased fitness. This result indicates that vector fitness is an important selective agent shaping the evolution of Plasmodium. I have added a sentence and citation to the article.

Add one sentence and one citation to the article.

Link: https://en.wikipedia.org/wiki/Plasmodium#Evolution

Sentence: The survivorship and relative fitness of mosquitoes are not adversely affected by Plasmdodium infection which indicates the importance of vector fitness in shaping the evolution of Plasmodium.

Citation: Ferguson HM, Mackinnon MJ, Chan BH, Read AF. 2003. Mosquito mortality and the evolution of malaria virulence. Evolution. 57(12):2792-804.

Annotated Bibliography
1) Ferguson HM, Mackinnon MJ, Chan BH, Read AF. Mosquito mortality and the evolution of malaria virulence. Evolution. 2003; 57(12):2792-804.


 * The authors, researchers at the University of Edinburgh, tested whether the virulence of the rodent malaria parasite was correlated with the fitness of the mosquitoes it subsequently infected. Interestingly, the researchers found that were was no correlation between virulence in mice and mosquito mortality which suggests that vector fitness is an important selective agent shaping the evolution of Plasmodium sp. phenotypes. This article can be incorporated into the Wikipedia project because it indicates the importance of maintaining mosquito fitness throughout the evolutionary course of Plasmodium sp.

2) Ghosh AK, Devenport M, Jethwaney D, et al. Malaria parasite invasion of the mosquito salivary gland requires interaction between the Plasmodium TRAP and the Anopheles saglin proteins. PLoS Pathog. 2009;5(1):e1000265.


 * The authors, researchers at the Johns Hopkins University, identified the mosquito salivary protein saglin as the receptor for the Plasmodium sp. ligand SM1. This ligand-receptor interaction allows for the invasion of the mosquito’s salivary gland and eventually the injection of Plasmodium sp. into humans. Although this is more of a biochemical approach, this article can be incorporated into the Wikipedia project because it discusses some of the processes of how mosquito bites can lead to transmission of the parasite and raises some evolutionary questions of how this has come to be.

3) Hume JC, Lyons EJ, Day KP. Human migration, mosquitoes and the evolution of Plasmodium falciparum. Trends Parasitol. 2003; 19(3):144-9.


 * The authors, scientists at the University of Oxford, use bioinformatics to examine the evolution of Plasmodium falciparum - the protozoa that cause the most severe form of malaria. The article discusses that the agricultural revolution increased the breeding sites for mosquitoes and may have triggered the evolution and expansion of Plasmodium falciparum. This can be incorporated into the Wikipedia project because it discusses how both Plasmodium sp. and mosquito ecology and evolution have influenced the spread of malaria.

4) Liu W, Li Y, Learn GH, et al. Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature. 2010; 467(7314):420-5.

5) Martinsen ES, Perkins SL, Schall JJ. A three-genome phylogeny of malaria parasites (Plasmodium and closely related genera): evolution of life-history traits and host switches. Mol Phylogenet Evol. 2008; 47(1):261-73.
 * The authors, researchers at the University of Alabama at Birmingham, used fecal samples from apes that were infected with Plasmodium sp. and analyzed mitochondrial and nuclear sequences. These researchers determined that Plasmodium falciparum, which causes the most severe form of human malaria, is of gorilla origin. Furthermore, the article mentions the limited levels of genetic diversity reflect a relatively recent selective sweep. This can be incorporated into the Wikipedia project because it explores how Plasmodium sp. has evolved in such a way that it has been able utilize mosquito vectors to infect gorillas and more recently humans.


 * The authors, researchers at the University of Vermont, utilized sequence data and Bayesian and maximum parsimony analyses to construct a phylogenetic analysis of malarial parasites. The researchers suggest that the Plasmodium of mammal hosts forms a well-supported clade and that is it strongly associated with the specialization to Anopheles mosquito vector. This can be incorporated into the Wikipedia project because the article provides insight into the evolutionary history of malarial parasite, especially vector switching and life-cycle changes.