Wednesday, June 12, 2013

How microbes can help us fight the battle against Malaria

Mosquitos are the primary vectors for malaria.
Figure 1. Anopheles gambiae (Credit: CDC's Public Health Image Library)
The World Health Organization estimates that in 2010 malaria caused 219-million clinical episodes, and 660,000 deaths. Around 91% of the deaths were in the African Region, and around 86% of the deaths globally were in children (CDC - Malaria).
Figure 2. Geo-distribution of malaria cases world wide. (Credit: CDC - Malaria)
Various control measures have been implemented, but many have proven ineffective due to the development of resistance, or practicality of the measure. New research suggests ways in which microbes can be used to make successful measures more practical (i.e. reducing the costs of production) and to develop new protective measures against malaria.

Insecticide-based control measures are the main way to kill mosquitos that bite indoors. The issue with these types of control measures is that prolonged exposure to these insecticides over a number of generations can cause mosquitos, as well as other insects, to develop resistance to the insecticide. Population control measures of mosquitos are very difficult to implement. The best method of population control seems to be preventing or destroying the ideal conditions for breeding areas of mosquitos; stagnant pools of water. However, It is nearly impossible to prevent stagnant pools of water from forming everywhere. While every effort should be made towards reducing mosquito breeding grounds, this alone isn’t enough to effectively reduce the spreading of this disease. Below is a link to an old (and somewhat outdated) video on the life cycle of mosquitos which explains the numerous habitats in which mosquitos can lay their eggs.

                            

Rather than devoting our time and efforts towards controlling mosquito populations, we should be looking at destroying the disease-causing parasites Plasmodium, or preventing them from infecting people. One way to destroy the parasite after infection is through chemotherapy. The issue with chemotherapy is the production of antimalarial drugs is a lengthy and expensive process, making it difficult to produce or obtain enough drugs for everyone. So how do we solve this issue? By exploiting microbes to synthesize the compounds for us through bioengineering.

A group of researchers at the UC Berkeley have been able to develop a strain of E. coli capable of synthesizing amorpha-4,11-diene, a precursor to the best antimalarial drug available today; artemisinin (1). A strain of Saccharomyces cerevisiae (yeast) capable of synthesizing high levels of artemisinic acid, the immediate precursor to artemisinin has also been developed (2,3). Check out the video below.

                             

The production of both amorphadiene and artemisinic acid will reduce the costs and time of artemisinin synthesis greatly. These compounds still need to be converted into the drug itself, but Dr. Keasling from the UC Berkeley suggests that won’t be a problem. ‘"Given the existence of known, relatively high-yielding chemistry for converting artemisinic acid to artemisinin or any other derivative that might be desired, microbially produced artemisinic acid is a viable source of this potent family of antimalarial drugs," says Keasling. "Upon optimization of the product, a conservative analysis suggests that artemisinin combination therapies could be offered significantly below their current prices."’(2)

Despite how amazing this sounds, the team suggested that the world will have to wait on the microbe produced antimalarial drug until the method can be widely produced and distributed (4). So while we’re waiting for this miracle synthesis to start production, what other ways can we use microbes to help fight the battle against malaria? We might start to answer this question by asking another: what makes the mosquito host immune to the disease? Researchers at the Johns Hopkins Bloomberg School of Public Health have been investigating the answer to that question, and they came to a conclusion that this immunity is due to bacteria found in the gut of the mosquito (5).

It is well known that mosquitos aren’t born with the parasite inside them; they acquire it through feeding on the blood of an infected person.
Figure 3. Life cycles of the Plasmodium parasite (Credit: CDC)
The parasite then develops inside the mosquito until it can be transmitted to another human when it feeds again. The parasite doesn’t cause malaria in the mosquito because “the microbiota of the insect gut has been shown to play a pivotal role of preventing development of pathogens.” (5) In their study, the team found that when given antibiotics, the mosquitos became more susceptible to Plasmodium infection. They also found that when introducing bacteria and Plasmodium parasites through feeding, mosquitos had lower than normal infection levels. The exact mechanism of this anti-Plasmodium effect is unknown, but the study suggests that diverse communities of microbes present in the gut of the mosquitos can modulate the anti-Plasmodium effect of some immune genes.

Dr. George Dimopoulos, senior author of the study says that “Theoretically, these bacteria could be introduced to the mosquitoes to boost their immunity to the malaria parasite and make them resistant and incapable of spreading the disease. Our current research aims at identifying those bacteria that trigger the strongest mosquito immune defense against the malaria parasite.” (6) But of course, more research is needed.

We have now covered two important ways that microbes can potentially be used to help fight against malaria: Using them to synthesize antimalarial drug precursors, and using them to prevent transmission of the parasite to humans by destroying the parasite inside the mosquitos. What about preventing mosquitos from biting us in the first place? Recent studies suggest that human sweat contains components that are attractive to anthropophilic (Human-loving) mosquitos (7,8), and that the composition of the skin microbiota affects the degree of attractiveness of human beings to mosquitos (9).

The study on the composition of the Human skin microbiota and attractiveness to mosquitos found that mosquitos were attracted to a person with a less diverse skin microbiome, and deterred by a more diverse skin microbiome.
Figure 4. How Mosquitos are Attracted to Human Sweat. (Credit: Karl Tate, Livescience.com)
In addition, the study also identified different types of bacteria associated with the level of attractiveness. More attractive men were associated with Leptotrichia, Delftia, Actinobacteria Gp3, and Staphylococcus microbes, while less attractive men were associated with a diverse array of microbes on their skin, as well as many Pseudomonas and possibly Variovorax species(10). Keep in mind that in this study, being less attractive is a good thing. The Authors state, “We hypothesize that lower attractiveness to mosquitoes is caused by a selective group of skin microbiota that emanates compounds that interfere with the attraction of mosquitoes to their human hosts and thus function as an in-built defense system.”(9) The identification of the compounds produced by these types of bacteria is likely to lead to the development of new mosquito attractants or repellants.

Humans typically think of microbes in a negative manner. We spend a large portion of our lives trying to rid ourselves of them in order to protect ourselves, when the truth is that they can actually benefit us in a number of ways. We have recently discovered new methods in which microbes can help us fight the battle against malaria, a battle that we have been losing for quite some time. These methods include exploiting microbes to synthesize immediate precursors to effective chemotherapy drugs, and exploring how diverse communities of microbes can help destroy the parasite inside the mosquito or prevent mosquitos from ever biting us. There are many more ways that microbes can help us, not just in fighting malaria, but also in fighting other diseases, as well as many other non-health related issues. It’s time that we stop the hate, and appreciate. Microbes could be the answer to everything!



Works Cited
1. Vincent JJ Martin et al. (2003). Engineering a Mevalonate Pathway in Escherichia coli for production of terpenoids. Nature Biotechnology, 796-802.
2. An Age-Old Microbe May Hold the Key to Curing an Age-Old Affliction: http://www.lbl.gov/Science-Articles/Archive/sabl/2006/May/02-antimalarial.html
3. Dae-Kyun Ro et al. (2006). Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature, 940-943: http://www.lbl.gov/Science-Articles/Archive/assets/images/2004/Mar-24/Engineering_terpenoids.pdf
4. Milestone in quest for cheap antimalarial. UC Berkeley News: http://www.berkeley.edu/news/media/releases/2006/04/12_malaria.shtml
5. Dong Y, Manfredini F, Dimopoulos G (2009) Implication of the Mosquito Midgut Microbiota in the Defense against Malaria Parasites. PLoS Pathog 5(5): e1000423. doi:10.1371/journal.ppat.1000423: http://www.plospathogens.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.1000423&representation=PDF
6. Bacteria Play Role in Preventing Spread of Malaria. JHMRI: http://malaria.jhsph.edu/news/dimopoulos_bacteria.html
7. Renate C. Smallegange, Niels O. Verhulst, Willem Takken, Sweaty skin: an invitation to bite?, Trends in Parasitology, Volume 27, Issue 4, April 2011, Pages 143-148: http://www.sciencedirect.com/science/article/pii/S1471492210002618
8. Smallegange, R. C., Knols, B. G. J., & Takken, W. (2010). Effectiveness of synthetic versus natural human volatiles as attractants for Anopheles gambiae (Diptera: Culicidae) sensu stricto. Journal of Medical Entomology, 47(3), 338-344: http://www.bioone.org/doi/abs/10.1603/ME09015
9. Verhulst NO, Qiu YT, Beijleveld H, Maliepaard C, Knights D, et al. (2011) Composition of Human Skin Microbiota Affects Attractiveness to Malaria Mosquitoes. PLoS ONE 6(12): e28991. doi:10.1371/journal.pone.0028991 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0028991
10. Mosquitoes Pick Out Human Meals With Help from Microbes: http://www.livescience.com/17663-mosquitoes-microbes-body-odor.html

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