malaria-mankind-blog

[malaria-mankind-blog]

Malaria and Mankind: Host-Parasite Coevolution and Public Health

Introduction

Malaria is a disease that is caused by species of Plasmodium in humans, and as a parasite, it has coevolved with the hominid immune system since before Homo sapiens became a species. The Plasmodium genus is largely made up of parasites that specialize in feeding on birds and mammals, and the Plasmodium species that infect modern humans are ovale, malariae, falciparum, vivax, and more recently, Plasmodium knowlesi (Ollomo et. al, 2009). The disease that results from these parasites kills around half a million people a year, most of whom are on the African continent (WHO, 2006). The parasitic coevolution of the Plasmodium genus and humans, as well as their phylogenetic predecessors, is an essential aspect of understanding the modern malarial disease process and how to reduce Plasmodium case count and mortality rate; knowing how the Plasmodium parasite has undergone natural selection for virulence and contagion to combat the human immune system can offer insight into the current state of the disease. The coevolution of malaria and its host can also provide insight into the development of human immune responses, such as in the case of sickle cell trait, and the evolution of drug-resistance.

Figure 1: phylogeny of Plasmodium species featuring the recent development of human virulence in P. knowlesi. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680981/

 Malaria Today

Malaria’s current disease process revolves around vector transmission and development of schizonts; infected liver cells in which immature trophozoites (protozoa) feed and eventually rupture through the cell membrane. Figure 2 demonstrates the lifecycle of the Plasmodium protozoan when infecting a human host.

Figure 2: life cycle of malarial parasites in human hosts and mosquito vectors. Via the Center for Disease Control; https://www.cdc.gov/malaria/about/biology/index.html

For the host, the erythrocytic stages of this cycle result in the symptoms most associated with malarial infection; anemia, high fever, shaking chills, muscle aches, vomiting, and bloody stool can all be traced back to the destruction of erythrocyte membranes and schizont development.

Western medical practices, epidemiological research, and effected populations have found treatments and prevention methods to reduce the spread and mortality rate of malaria; currently, Artemisinin is a common antimalarial medication, and prevention methods largely focus on vector control. In this case, the vector of the malarial parasite is another parasite; female Anopheles mosquitoes (WHO, 2016). Mosquitoes are present throughout most tropical and temperate climates, especially areas with high precipitation. Mosquitoes breed in standing water and feed by extracting blood from their animal hosts by injecting a needle-like organ, called a proboscis, into a blood vessel and storing extracted blood in their gut. Mosquitoes consume multiple blood-meals a day, and when they feed on a malaria-infected person, if the malarial protozoa have entered the erythrocytic stage, the mosquito can carry the protozoa present in the red blood cells to their next host. From there, the newly introduced Plasmodium will incubate and reproduce in the liver, eventually spreading to the hemoglobin and beginning the cycle of infection again when the host is parasitized by a mosquito. Controlling vector transmission is the most accessible form of preventing malaria in most communities; DEET spray, mosquito nets, and clearing standing water have proven to be effective preventative measures against these vectors.

Host-Parasite Coevolution and Medicine

Like bacterial infection, malarial parasites have a fast generation time and are selectively pressured by the human immune system (Hill, 1997). This selective pressure combined with the development of drug-resistant malaria produces a complex problem for modern medicine, but the selective pressures that have influenced the evolution of the malarial parasite can also provide insight into how to develop a vaccine and treatment. Antimalarial medication was originally administered in the form of quinine, followed, but not entirely replaced by, many other medications up to the most recently used artemisinin, and the malarial parasite has developed, in many cases, resistance to these drugs except for artemisinin (WHO, 2003). The influence of natural selection in the development of resistance in malarial protozoa can be seen in the speed at which medications become obsolete in treatment; the first case of quinine resistance was recorded in 1910, and since then six different drugs have been rendered obsolete by Plasmodium and its evolution. Currently, medical treatments rely on artemisinin combined with a partner antimalarial drug.

The development of drug resistance in the malarial parasite makes understanding the host-parasite coevolution between it and hominids that much more paramount. Plasmodium species have highly variable protein-producing genes that can counteract the human immune system and have been selectively pressured over coevolutionary time to do so (Evans & Wellems, 2002). The erythrocytic stage is the most difficult stage of the parasite’s development for the human immune system to respond to because the parasite resides within red blood cells; although with other diseases the immune system can distinguish between infected and normal cells, malaria’s selected-for ability to disguise its chemical signal from the immune response makes it very difficult for the immune system to find and eliminate infected cells. The P. falciparum species of malaria produces a circumsporozite protein (i.e. PfEMP1) to enter and eventually destroy the cell membrane from within. This protein has a high genetic variance; it has multiple forms that each require a specific response from the immune system to combat, and the generation time of P. falciparum is low enough that new effective forms of the TH2R and TH3R genes that produce the circumsporozite proteins are quickly selected for, often outpacing the immune response of the host. In the liver, where the parasite first develops and reproduces, P. falciparum has been selectively pressured by the human immune system to suppress the chemical signals associated with protein development and release, subverting immune detection and avoiding killing lysis by cytotoxic lymphocytes in the organ (Hill et. al., 1997).

Outside of sickle-cell trait, occurrences of human resistance to malaria shed a relatively dim light on the genetic influences on immune system efficacy, as humans as well have a deeply complex and variable genetic code relevant to the immune system. Twin studies and other observational studies have been performed and found connections between the genes that control vitamin D incorporation and malarial resistance, as well as more specific genes that effect lymphocyte efficacy such as major histocompatibility complex (MHC) and human leucocyte antigen (HLA) genes (Hill et. al., 1997). These genes determine the efficacy of lymphocytes and other immune-responses, and therefore are a selective pressure on the TH2R and TH3R genes that produce cell-membrane destroying circumsporozite proteins in the malarial parasite. These genes have undergone mutual selective pressure since their respective species began interacting and are an important focal point in researching vaccines and human resistance to the malarial parasite as well as their evolutionary development.

My Opinion

Research into the genetic influences and interactions between the malarial parasite and the human host could lead to the development of vaccines (for malaria there are very few) and a deeper understanding of human susceptibility to malaria. The circumsporozite proteins produced by the TH2R and TH3R genes have been considered in the Hill study as potential sources of a vaccine, as providing a nonvirulent copy of the protein to the immune system could provide lymphocytes in the liver and other immune responses a chance to recognize the normally difficult-to-detect chemical signals released from the parasite during schizont development and cell membrane rupture. The well-known example of sickle-cell trait as a defense against malaria represents the medical potential of research into the MHC and HLA genes; sickle-cell creates an environment physically uninhabitable for malarial parasites but poses a double-edge in its homozygous form of sickle-cell anemia. This trait’s dimorphism poses a health risk, but the MHC and HLA genes haven’t been found to create autoimmune issues. Researching the MHC, HLA, TH2R, and TH3R genes as well as their interactions over generational time using archaeological evidence and long-term observational studies of malaria-exposed populations would result in a greater understanding of the host-parasite coevolution and therefore potentially provide an opportunity to develop a widely available vaccine, and an opportunity to calculate and prepare for susceptibility to malaria in different populations.

Bibliography

1.  Allison, A. C. “GENETIC FACTORS IN RESISTANCE TO MALARIA.” The New York Academy of Sciences, John Wiley & Sons, Ltd (10.1111), 15 Dec. 2006, nyaspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1749-6632.1961.tb31102.x.

2. G., Andrew, and Thomas E. “Coevolutionary Genetics of Plasmodium Malaria Parasites and Their Human Hosts 1.” OUP Academic, Oxford University Press, 1 Apr. 2002, academic.oup.com/icb/article/42/2/401/652729.

3. Hill, Adrian V.S. et. al., “Genetic Analysis of Host-Parasite Coevolution in Human Malaria.” Royalsocietypublishing.org, 1997, royalsocietypublishing.org/doi/pdf/10.1098/rstb.1997.0116.

4. Mahanta, Anusree et al. “Integrative Approaches to Understand the Mastery in Manipulation of Host Cytokine Networks by Protozoan Parasites with Emphasis on Plasmodium and Leishmania Species.” Frontiers in immunology vol. 9 296. 23 Feb. 2018, doi:10.3389/fimmu.2018.00296

5. Ollomo, Benjamin, et al. “A New Malaria Agent in African Hominids.” PLoS Pathogens, Public Library of Science, May 2009, www.ncbi.nlm.nih.gov/pmc/articles/PMC2680981/.

6. V., Christopher. “Evolution of Drug-Resistant Malaria.” OUP Academic, Oxford University Press, 1 Apr. 2009, academic.oup.com/trstmh/article-abstract/103/Supplement_1/S11/1908160.

7. “Why Is It Important to Combine Malaria Drugs?” World Health Organization, World Health Organization, 15 Mar. 2012, www.who.int/features/qa/33/en/.

8. “Do All Mosquitoes Transmit Malaria?” World Health Organization, World Health Organization, 19 Apr. 2016, www.who.int/features/qa/10/en/.

9. History of Antimalarials | Medicines for Malaria Venture, www.mmv.org/malaria-medicines/history-antimalarials?gclid=CjwKCAiA27LvBRB0EiwAPc8XWQAMdrQrGPS_zT9H2wuebWyeuqFsb452jyqkrKe6nVaNJFgnC3D_6hoCIKQQAvD_BwE.