The War On Malaria: Knowing the Enemy

Building a foundation to better understand malaria

We Have a Parasite Problem

Malaria is one of the world’s deadliest diseases and remains one of the top causes of child death worldwide. According to UNICEF, malaria kills one child every 30 seconds, which translates to about 3,000 children every day1. Many children living with malaria will develop physical and mental impairments that keep them out of school and hinder social development. Even though 90% of malaria cases and deaths occur in sub-Saharan Africa, nearly half of the world is at risk. In 2017, there were an estimated 219 million malaria cases, consisting mostly of pregnant women and children, across 90 countries worldwide2. Aside from keeping families and communities from prospering, malaria also takes a huge toll on the economic growth of these countries. It is estimated that the total funding for malaria control and elimination reached approximately $3.1 billion (USD), with contributions from governments of endemic countries amounted to $900 million (USD), representing 28% of the total funding2.

A Whole Host of Issues

Caused by the Plasmodium falciparum parasite, malaria is transmitted by the mosquito, Anopheles gambiae. Upon digesting a blood meal from the host, many transcription changes occur, with over 50% of the mosquito’s genes changing expression level3. Although regulation of transcription during this process is well-documented4, post-transcriptional regulation of this process is still understudied. Currently researchers are investigating microRNAs to understand the post-transcriptional regulation of transcripts and their effect on mosquito physiology. It is known that miRNA (approximately 22 nucleotides in length) are involved in the regulation of gene expression. Mechanistically, miRNAs initiate transcript silencing by initiating degradation of their target sequence or inhibiting its translation5. Research into miRNAs function has elucidated roles in many areas, including general mRNA regulation, development switches, tissue homeostasis, etc.6-9. While studying miRNA regulation gives insight into mosquito physiology, the overall understanding for how mosquito tissues vary in miRNA abundance is still lacking. Thus, a recent report by Bryant et al. aimed to elucidate the miRNA transcriptomes across different mosquito tissues10.

Setting the Study

In their study, Bryant et al. collected four tissue groups: midgut, ovaries, fat-enriched abdominal walls, and remaining mosquito tissues including head and thorax obtained from adult female An. gambiae G3 strain mosquitoes10. The dissected tissues were then stored in DNA/RNA Shield at 4°C to preserve the genetic integrity of the samples. Following storage, they extracted the RNA by using the Direct-zol RNA Miniprep Kit and then generated libraries for RNA-seq.

Micro Steps Forward

Bryant et al. found numerous examples of miRNAs exhibiting tissue specific expression10. For example, the miRNAs, miR-989 and miR-1175, were abundant in ovary and midgut samples in both An. gambiae strain, An. coluzzi Ngousso (TEP1*S1)11 and An. gambiae G3 strain mosquitoes. Additionally, miR-8, miR-306, and miR-184 were highly expressed across tissues in both An. gambiae strains above. Moreover, Bryant et al. found that batam, miR-276, miR-263a, and miR-14 were the top twenty highest miRNAs across all tissues which were different in An. coluzzi Ngousso (TEP1*S1)11.

The authors conclude that highly expressed miRNAs were overall lacking (less than a third) when compared across the investigated tissues. However, this lays the groundwork for future investigations into the intricate regulatory networks of the mosquito. Further, this study builds the knowledge base of mosquito miRNA profiles which may prove vital to finding new and creative ways to eliminate vector-borne disease transmission. As malaria continues to be one of the deadliest vector-borne diseases, studies like this one are particularly critical to understanding the basic biology of mosquito physiology that is tightly linked to the disease transmission. Through similar research, a new generation of advanced tools can help the development of critical vector-borne disease control strategies that could be the key to eradicating Malaria and other mosquito-borne diseases such as the Zika and dengue viruses.

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References:
1. UNICEF, https://www.unicef.org/health/files/health_africamalaria.pdf
2. WHO. 2018. Malaria. (2018) https://www.who.int/news-room/fact-sheets/detail/malaria
3. Marinotti, O., E. Calvo, Q.K. Nguyen, S. Dissanayake, J.M. Ribeiro et al. 2006. Genome-wide analysis of gene expression in adult Anopheles gambiae. Insect Mol Biol 15 (1):1-12.
4. Attardo, G.M., I.A. Hansen, and A.S. Raikhel. 2005. Nutritional regulation of vitellogenesis in mosquitoes: implications for anautogeny. Insect Biochem Mol Biol 35 (7):661-675.
5. Tanase, C.P., I. Ogrezeanu, and C. Badiu. 2012. MicroRNAs. Molecular Pathology of Pituitary Adenomas 8:91-96.
6. Wheeler, B.M., A.M. Heimberg, V.N. Moy, E.A. Sperling, T.W. Holstein et al., 2009 The deep evolution of metazoan microRNAs. Evol Dev 11 (1):50-68.
7. Christodoulou, F., F. Raible, R. Tomer, O. Simakov, K. Trachana et al., 2010 Ancient animal microRNAs and the evolution of tissue identity. Nature 463 (7284):1084-1088.
8. Stark, A., J. Brennecke, N. Bushati, R.B. Russell, and S.M. Cohen, 2005 Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. Cell 123 (6):1133-1146.
9. Chen, C.Z., L. Li, H.F. Lodish, and D.P. Bartel, 2004 MicroRNAs modulate hematopoietic lineage differentiation. Science 303 (5654):83-86.
10. Bryant, W.B., et al. "Small RNA-Seq Analysis Reveals miRNA Expression Dynamics Across Tissues in the Malaria Vector, Anopheles gambiae." G3: Genes, Genomes, Genetics (2019)
11. Lampe, L., and E.A. Levashina, 2018 MicroRNA Tissue Atlas of the Malaria Mosquito Anopheles gambiae. G3 (Bethesda) 8 (1):185-193.
12. Gallup, J.L., J.D. Sachs. 2001. The Economic Burden of Malaria. American Journal of Tropical Medicine and Hygiene 64(1).