As a medical student at Cornell University, Erol Fikrig spent time in Brazil studying a disease called leishmaniasis, which sand flies transmit to humans. That experience piqued an interest in vector-borne diseases that Fikrig has pursued ever since. His research has led to a new understanding of the relationship between the pathogens that transmit the diseases, the vectors that carry the pathogens, and the hosts they infect. Information from his studies is suggesting new strategies to prevent and treat Lyme disease, West Nile encephalitis, and other infections by interrupting these relationships.
In 1988, Fikrig came to Yale University School of Medicine on a fellowship and was immediately attracted to research on Lyme disease. Named after the town in Connecticut where a cluster of cases was described in the 1970s, Lyme disease is caused by a bacterium transmitted to humans through tick bites. “I thought to myself that it was a vector-borne disease, a local disease, with a lot of research going on—I'd like to look at that,” he said.
His first project was developing and testing a Lyme disease vaccine with HHMI investigator Richard Flavell, who remains a frequent collaborator. The Food and Drug Administration eventually approved the Lyme vaccine for use, though its manufacturer later withdrew it from the market, citing poor sales. While the vaccine was being developed, Fikrig made the first of a series of remarkable discoveries about the life cycle of the bacterium. He demonstrated that, in moving between the tick and humans, the bacterium covers itself with a protein drawn from the tick's saliva. That protein helps the bacterium avoid attack by the human immune system.
Fikrig also discovered that the bacterium has a way of inducing the tick to make more of the protective saliva protein. “That set us thinking,” said Fikrig. “Why did the bacterium do that? It needed to protect itself. But it also needed to interact with things in the local environment if it was going to survive.”
That insight has led Fikrig to investigate the ways human pathogens interact with their environments, often by manipulating the biological mechanisms of their hosts. In particular, his laboratory focuses on tick-borne diseases like Lyme disease and human granulocytic anaplasmosis, as well as the West Nile virus, which is transmitted by mosquitoes. Through those studies, he has uncovered new ways to disrupt pathogens at various stages in their life cycles, not just when they are infecting humans.
Lyme disease, which Fikrig often sees in some of the patients he treats, provides a good example, he said. The bacterium uses the tick's biochemistry to full advantage in infecting humans. “A tick is like a little pharmacological factory,” Fikrig said. Unlike a mosquito, whose stinging bite immediately draws swats, a tick has to remain unnoticed for three to five days while it feeds on the blood of its host. To do that, it manipulates the host organism by generating anticoagulants that keep the blood flowing and proteins that prevent inflammation and protect it against the host's immune response.
In fact, the bacterium cannot survive in the tick without hijacking proteins from it. Fikrig discovered that the bacterium has a protein on its surface that binds to a receptor in the tick's gut. When the receptor in the tick is blocked by antibodies or RNA interference, the bacterium cannot gain a foothold.
Fikrig's work is suggesting innovative ways to use vaccines to combat infectious agents by disrupting a pathogen's environment. “We'd like to explore whether it's possible to make vaccines that don't target the pathogens per se but the molecules the pathogens require,” Fikrig said.
Fikrig's work suggests that the same tactic may work with other diseases. For example, he discovered that the bacterium that causes an illness called tick anaplasmosis lives within human cells known as neutrophils, which kill bacteria. The bacterium turns on genes in the neutrophil that it needs to survive and turns off others, suggesting that altering the biochemistry of the neutrophil may block the disease.
Fikrig also has been studying the inflammatory process caused by infection with the West Nile virus. In most people, the virus causes only a fever, but in the elderly and the immunosuppressed, it may cause severe inflammatory reactions that can lead to death. Fikrig is now studying the receptors on human cells that trigger this inflammation. “There is a constant battle in the host between pathogen control and excessive inflammation,” he said. It's a battle Fikrig would like to turn in our favor.