Waging War Against Malaria

Mehal Churiwal

Dr. Boyce served as part of the infantry in South Korea and Iraq before he came to UNC Chapel Hill and began medical school. After his second year of medical school, though, he left to work as the Civil Affairs Officer in Iraq where he was at the forefront of infrastructure development and other reconstruction projects, interacting with local residents to confront problems such as millions of people losing access to water in Baghdad city or having their sewer systems break down amidst the violence. He soon returned to complete medical school with a newly found inspiration to pursue public health. Now, Dr. Boyce’s whole career is dedicated to fighting this centuries-old battle in the small, rural villages of Uganda. 1 When he started his research on malaria in Uganda, there were no maps of the villages, and there was no way to identify what areas had high or low rates of malaria. Thus, he began his work walking around the communities alongside residents, asking them where their village began and ended, often receiving answers like, “Our village ends at that mango tree in the middle of the dirt road.” 2 Through the frustration and imperfection of mapping the grounds, though, Dr. Boyce soon realized that malaria as well as the geology and ecology of the region share a close relationship, co-evolving in an intricate and precise manner. His research thus follows the unique methodology of “looking for variation and mutations involved with drug resistance to malaria in a small, concentrated area... to understand heterogeneity in a micro-environment.” 2 Dr. Boyce has worked in the Western region of Uganda for about seven years, gathering enormous quantities of data on the specific biology of the land and incidence of malaria. One of the most recent and interesting topics has been to understand variation in antimalarial drug resistance with respect to altitude in the highland region of Western Uganda, specifically in the Bugoye subcounty of the Kasese District. This is a particularly diverse area of land for such a small region, with steep hillsides towards the west and lower-lying ground towards the east. The area is also where the Bugoye Health Center is located, which is where the samples for this particular study were collected. 3

Figure 1: Map of the Bugoye subcounty in Kasese District, where the Bugoye Health Center is located. Image courtesy of Dr. Boyce.

There were two main molecular markers analyzed in this study. A molecular marker is a specific mutation that indicates that the malaria is resistant to a corresponding treatment drug; thus, if a strain of malaria consists of a particular molecular marker, it cannot be cured with the corresponding drug. In this study, the first molecular marker tested was called the Plasmodium falciparum CQ resistance transporter (pfcrt) 76Tgene mutation, which indicates a form of malaria resistant to chloroquine (CQ). CQ used to be the most common, baseline treatment for uncomplicated malaria. However, due to the nearly universal development of CQ-resistant malaria, most treatment protocols switched to using artemether–lumefantrine (AL) in June of 2004. Thus, the second molecular marker tested in this study was called the Plasmodium falciparum multidrug resistance 1 (pfmdr1) Y184 mutation, which indicates a form of malaria resistant to AL. 3 How does malaria acquire immunity towards a particular drug or medication? In general, each time a disease is transmitted and replicated from one person to another, there is a chance for a mutation in the disease to develop. Some mutations may be harmful and make the disease less potent, and some mutations may be neutral, having no lasting impact. Some mutations, though, could prove very helpful by providing the disease with immunity towards a certain drug. Consequently, the more frequently a disease is transmitted and replicated, the more mutations could occur, thereby increasing the disease’s chances of gaining immunity towards the current treatment. There was a significant inverse correlation between the presence of pfmdr1 Y184 mutations and altitude. The greatest incidence of pfmdr1 Y184 mutations occur in low-lying areas of the country while the lowest incidence was seen in high elevation areas. However, the study found no significant trend between the frequency of pfcrt 76T mutations with respect to elevation or river valley; the mutation was found fairly consistently between all the different samples across the area. 3 As elevation increases, the air becomes cooler and there is less standing water, making it more difficult for the malaria-causing mosquitoes to live. Water runs downhill, indicating that runoff would accumulate towards the bottom to form pools of stagnant water. However, such a conclusion neglects all the other contributing factors. For instance, the trends in resistance may reflect the access to care available to the local population. As seen on the map, the health centers tend to be in areas of lower elevation; the areas of highest altitude in the west

are the furthest from public health centers, so they simply might have less access to AL and are thus less likely to acquire malaria resistant to AL. 2 Another dimension to consider is socioeconomics. Unlike in the United States, living on the side of the mountain is not valued because it is harder to grow crops there and one would have to walk farther to get water farther from town. When poverty’s contribution to the trend is considered, many possible influences are revealed, such as affordability of the same medical treatment, quality of housing facilities, access to appropriate transportation, and impact of proper nutrition. 2 Finding malarial trends is a valuable and significant step forward in understanding the relationship between disease and community. However, more extensive research is required to eke out all the interacting variables before it is possible to confidently identify the mechanisms of such correlations. What is important to realize is that all of these factors – and many more yet to be uncovered – are likely contributing to the overall impact in some manner, and it is just a matter of how and to what extent. Dr. Boyce’s research underscores the value of having a narrow, focused lens and taking the time to understand the influences of micro variables to make a truly impactful transformation. As he said, “I have a career where I actually get a chance to try to make a difference in their lives and I get to ask interesting questions and I get to get some jobs and support people. So, I mean, I think I have the best job in the world.” 2

References

1. Johnson, M. Bigger Picture: From Battlefield to Village, Ross Boyce ‘01 Wages War on Malaria. https://www.davidson.edu/news/2019/08/05/ bigger-picture-battlefield-village-ross-boyce-01- wages-war-malaria (accessed February 2nd, 2020). 2. Interview with Ross M. Boyce, Ph.D. 01/31/20 3. Boyce, R. M.; Brazeau, N.; Fulton, T.; Hathaway, N.; Matte, M.; Ntaro, M.; Mulogo, E.; Juliano, J. J. Prevalence of Molecular Markers of Antimalarial Drug Resistance across Altitudinal Transmission Zones in Highland Western Uganda. The American Journal of Tropical Medicine and Hygiene 2019, 101, 799–802.

Dr. Ross Boyce