Last month, four Hopkins scientists published their research on a potential way to fight against malaria in Public Library of Science Biology. They discovered that knocking out C-type lectins 4 (CTL4), a gene in Anopheles gambiae mosquitoes, results in effective resistance to the malaria parasite.
According to the Centers for Disease Control and Prevention, an individual is infected with malaria after being bitten by a female Anopheles mosquito that is infected with a Plasmodium parasite. Although it does not spread by simple human contact, malaria can be transmitted through blood transfusions, organ transplants or contact with infected blood.
George Dimopoulos, the senior author of the research and a professor of the W. Harry Feinstone Department of Molecular Microbiology and Immunology at the School of Public Health, explained the basic mechanisms the research relies on during an interview with The News-Letter.
“The mosquitoes have an innate immune system that is quite effective at fighting against pathogens, so a large portion of pathogens will be killed by various mosquito defense molecules. However, some of the parasites will make it through, and that’s why we still have disease transmission,“ Dimopoulos said. “Our lab engineers mosquitoes to make their immune system more effective.”
One of the mosquitoes’ immune defense mechanisms is a melanization-based defense system: When the immune system detects invasive parasites, this mechanism melanizes parasites in a capsule and eliminates them. However, Plasmodium is able to utilize CTL4 to hide from this defense system.
“When you remove CTL4, the parasites cannot mask themselves from the immune system, so they will be melanized and killed,” Dimopoulos said.
Similar research was completed in 2004. The same gene was studied using gene silencing, but the researchers concluded that CTL4 had no role in human malaria transmission because the expected CTL4 function was only observed in rodents.
Maria Luisa Simões, a co-author of the paper and currently an assistant professor at the London School of Hygiene and Tropical Medicine, discussed the reasoning behind a re-examination of the CTL4 gene in an interview with The News-Letter.
“Although gene silencing could be effective, it doesn’t remove the protein completely: It will only be decreased to a certain level. I think there is a lot of variability that we hadn’t taken into account, so we shouldn’t simply assume that the gene is not related to malaria transmission,” Simões said.
Dimopoulos elaborated on the new study’s research technique.
“We used a much more powerful method, CRISPR/Cas9-based genome editing, to disrupt the gene in mosquitoes so it wouldn’t produce any CTL4,” he said.
Malaria is determined as one of the oldest existing diseases, prevalent in ancient China and ancient Greece. According to the World Health Organization, there were an estimated 241 million malaria cases across the world until 2020, and it is also among the diseases that cause the most mortality.
Simões reflected on her trip to West Africa at the age of 19. Being in a region with high malaria prevalence, she had to take malaria prevention pills. That was the first time she was introduced to malaria’s severity and the importance of conducting relevant research. Despite being a cancer researcher before, Simões decided to study malaria for her PhD.
Dimopoulos, on the other hand, had a different starting point in malaria research. He started studying mosquitoes and malaria out of intellectual curiosity. He stated that progress has been made over the three decades of his malaria research career, but insecticide resistance of mosquitoes and drug resistance of parasites has made malaria control very difficult.
“This is why we need new technologies and innovations. It makes me feel excited to work on malaria research; we are not trying to improve a treatment, but to come out with something entirely new,” Dimopoulos said.
As an alum of the Carey Business School, Dimopoulos also explained how his diverse education background contributes to his research career.
“Running a lab is almost like running a business. You have to hire the right people, keep them motivated and produce products: in this case, knowledge,“ he said. “You also have to sell these products to journals and publications. There are a lot of business skills required in running a lab.”
Looking forward, Simões will dive deeper into the study of genetically modified mosquitoes. She believes that studies involving genes related to CTL4 are needed to see the complete pathway in malaria transmission.
Dimopoulos wants to work on the monitoring of pesticide effectiveness, an essential factor from a public health perspective. Collaborating with Hyris and the Centre for Research in Infectious Diseases in Yaoundé, his team is in the process of developing a molecular diagnostic technology for parasite resistance surveillance on a national scale.
“An advantage of this method is that it analyzes nucleic acid, such as DNA and RNA. We can apply this to anything. We can use this technology to assess the prevalence of pathogens in mosquitoes or humans; they could even monitor COVID spread using PCR tests,” Dimopoulos said.
At the end of the interview, Dimopoulos encouraged young students who want to go into scientific research.
“There are very few jobs today that you are paid to do your hobbies. It rarely becomes routine, because science is progressing constantly,“ he said. “If you like to have a job with intellectual freedom and creativity, academic science is the way to go.”