Fighting Tick and Mosquito Diseases

Hameeda Sultana established her first laboratory in her childhood backyard in India.

After her older sister contracted malaria from an infected mosquito bite, Sultana, then in middle school, set out jars of water to collect mosquito eggs and larvae to conduct her own experiments with soap and detergents to fight these pests.

“Mosquitoes were always a nuisance. We had a little house with restrooms outside, and at night we had to go outside, and there were so many mosquitoes,” says Sultana, professor in the College of Veterinary Medicine’s Department of Biomedical and Diagnostic Sciences.

Her sister recovered but was sick for several months and could not go to school, leaving Sultana and her brothers to help their working parents care for their sibling.

“I was very annoyed with these mosquitoes. I had all these fun experiments, but my dad would get mad at me. He said, ‘You are doing nonsense here with all these jars for mosquitoes to lay eggs,’” she recalls. “But it promoted an interest in me.”

Today, Sultana—a molecular biologist—studies how ticks and mosquitoes transmit diseases. She discovered a novel way to fight disease at the cellular level within ticks before they transmit it to the host they are feeding on, with the hope that it will eventually result in effective transmission blocking vaccines.

Sultana and her lab collaborators recently published their findings about a glycine-rich protein transmitted through exosomes—small membrane-bound extracellular vesicles—when ticks feed that allows the virus they carry to disguise itself and pass through natural defenses without resistance.

In the lab, they suppressed the protein and studied what happened.

“When we silenced this molecule, the virus load was lower, and ticks could not take a full blood meal, reducing their body sizes and weights. It showed the transmission of the pathogen was affected because the blood feeding was affected,” Sultana says.

Her collaborators on the new discovery include alumni postdoctoral fellow Waqas Ahmed, former graduate students Wenshuo Zhou and Kehinde Fasae, current graduate student Md Bayzid, professor Girish Neelakanta and former clinical assistant professor Denae LoBato. This research, supported by National Institutes of Health funding, was published in The EMBO Journal by the European Molecular Biology Organization.

Sultana has studied tick proteins for two decades. Inspired by her backyard experiments, she dreamed of becoming a doctor or scientist. Sultana earned her bachelor’s degree in biology and minored in chemistry in India. During her master’s program in applied genetics, she studied gene expression and chose mosquitoes’ resistance to pharmaceutical compounds as her thesis subject. Sultana continued her studies in Germany, earning a Ph.D. in medical biochemistry while researching the interworking inside cells, specifically the actin cytoskeleton and endocytosis.

Afterward, she spent seven years in a post doctorate fellowship at the Yale University School of Medicine, where she specialized in flaviviruses, diseases such as Dengue, Zika, West Nile and rickettsial bacteria transmitted mostly by mosquitoes or ticks to mammals. Sultana won a National Institutes of Health grant and secured her first academic post at Old Dominion University in Norfolk, Virginia, where she set up her own lab as a principal investigator.

Her lab was the first to identify exosomes in tick saliva and salivary glands. Exosomes, tiny bubble-like vesicles, carry items like proteins, DNA/RNA and miRNA within cells and into other cells.

To understand this process, one must understand what happens when a tick bites a host. To go further, one needs to explore what happens inside the microscopic cells of the tick’s salivary glands and gut.

When ticks bite, they spit their saliva into the hosts with a needle part in their mouths. If the tick is infected with a viral pathogen, the exosomes with the protein are carried into the host through the saliva. The protein helps disguise fragments of the virus RNA from the host skin’s defenses. Sultana’s research also showed the presence of full-length viral RNA genomes and viral polyproteins transmitted securely in arthropod exosomes.

“We always thought, as virologists, that vectors transmit the viruses as naked viruses/viral particles, but maybe they can just send their RNA and proteins secured in those vesicles. Going secured is much better than going openly because they must face a lot of defenses on our human skin,” she explains.

When faced with a dangerous pathogen, skin cells secrete cytokines and chemokines, proteins that signal immune cells to fight infection. But the pathogen hiding in the vesicles mimics healthy molecules.

“They say, ‘I’m just a part of you. Don’t damage me,’” Sultana says. “Once skin cells are infected, they can easily produce their own exosomes into the blood stream and then spread the virus.”

On the macro level, this helps explain why people do not usually feel ticks when they bite. Unlike the immediate pain from a wasp sting, it can take hours or days for a host to notice a tick latched somewhere.

A vaccine could disrupt this ruse before it leaves the tick’s gut and secures itself in the saliva. If a potential host was immunized with the tick protein, the host would produce antibodies. When a tick feeds on this immunized host, the blood it’s feeding on would contain the antibodies, flood into the tick’s gut and block the pathogens from getting into the salivary glands.

The next steps for Sultana and her lab partners include testing the protein suppression again and finding a molecule common in both ticks and mosquitoes to attack viruses carried by both.

“These are very clever viruses,” Sultana says. “We cannot really tackle the flaviviruses, but we can tackle the carriers, the vectors such as ticks and mosquitoes, and block the transmission of these pathogens.”