Researcher Tim Sellati seeks genetic clues in Lyme disease mystery
April 13, 2017 | Southern Research
Infectious disease researcher Tim Sellati, Ph.D., has spent much of his career trying to solve the central riddle of Lyme disease – why the tick-borne infection causes minor symptoms in some people but leaves others with lingering conditions such as arthritis and neurological problems.
“People should be very concerned about Lyme disease because we don’t have all the answers,” said Sellati, Distinguished Fellow and Chair of the Infectious Disease Department at Southern Research. “We don’t know who is going to develop symptoms and who is not, who is going to respond to treatment and who is not.
“If you are dealt a bad deck of genetic cards, you may suffer debilitating symptoms associated with this bacterial infection,” he said.
Sellati’s warning comes as tick activity begins to rise across the United States with the arrival of spring, triggering new cases of Lyme disease. The infection, caused by the bacterium Borrelia burgdorferi, is transmitted to humans through the bite of an infected blacklegged deer tick.
Lyme disease is the most common tick-borne illness in the U.S., according to the Centers for Disease Control and Prevention. Though the precise number is hard to pinpoint, the CDC estimates that 329,000 cases occur in the U.S. each year.
Most Lyme disease cases are concentrated in the Northeast and upper Midwest, but the illness is reported in many other states every year, including Alabama.
“This is not a deadly infectious disease, but it can take a person who is used to an active lifestyle and they can have symptoms that make it very difficult for them to even get out of bed in the morning,” Sellati said. “It truly impacts quality of life.”
Initial symptoms of Lyme disease include a rash shaped like a bull’s eye around the infected area, fatigue, headaches, and fever. In most cases, these symptoms can be successfully treated with antibiotics.
Untreated cases can result in more severe symptoms. In addition, some people develop what’s called Post-Treatment Lyme Disease Syndrome (PTLDS), which can be debilitating.
Serious symptoms include severe headaches, neck stiffness, nerve pain, short-term memory problems, irregular heart beat (Lyme carditis), facial paralysis, and inflammation of the brain and spinal cord.
As a graduate student at the State University of New York at Stony Brook on Long Island, New York, in the early 1990s, Sellati became keenly interested in another of these serious symptoms: Lyme arthritis.
“I wanted to understand why, if two individuals are infected with this bacterium that has the capacity to cause arthritis, some people develop the arthritis and some don’t.”
Unraveling the mystery is a major thrust of his research today, which broadly focuses on the host-pathogen relationship in infectious diseases transmitted by ticks and mosquitoes.
In Lyme disease, this interaction begins with the body’s response to the invading bacteria – a defensive counterattack by cells in the bloodstream called neutrophils, which act as the innate immune system’s first-responders.
“These are the equivalent of Pac-Men — they run around in the bloodstream and try to gobble up bacteria and viruses that invade our body,” Sellati said. “When the bacteria that causes Lyme disease enters the joint, it triggers these neutrophils to migrate out of the bloodstream and into the joint tissue itself.
“They are supposed to kill and clear the bacteria. They’re usually very effective at doing so,” he added. “But for some people, this works better than for others. And this begins to provide insight into why some people develop very severe arthritis and others don’t.”
Another puzzling aspect of Lyme Disease is why most individuals infected with the bacteria after a tick bite respond to antibiotics while others end up with serious symptoms despite treatment.
Sellati believes genetics plays a significant role in PTLDS, and he’s drilling down into the “genetic baggage” that these patients bring to the host-pathogen relationship for clues. This approach could lead to improved treatment options.
“If we can identify up-front those individuals with genetic markers suggesting that antibiotic treatment is not going to be sufficient, then we can investigate what else we can do to prevent the lifelong debilitating symptoms that they are genetically prone to develop,” he said.
To better understand how genetics influences the likelihood of developing Lyme arthritis, Sellati’s team at Southern Research has worked with different strains of mice, including those naturally susceptible to Lyme arthritis and those resistant to it.
“We used this mouse model to focus our attention on specific proteins that are displayed on the surfaces on those neutrophils and macrophages, another Pac Man-like cell in the bloodstream that runs around gobbling up bacteria and viruses to kill them,” Sellati said.
THE CD14 CLUE
The work helped the Southern Research team better understand the role of a gene called CD14 in the development of Lyme arthritis. CD14’s protein is a key player in the human innate immune system, the important first line of defense against infections.
“Now, the interesting question is that if you and I both have the infection, and you have very severe Lyme disease arthritis and I don’t, is that because you have less CD14 decorating the surface of your cells than I do?”
To get a definitive answer, it will be necessary to inspect individual cells for the absence of CD14’s protein. Sellati intends to do just that, using flow cytometry, a technology that suspends cells in a stream of fluid and passes them by an electronic detection apparatus.
Eventually, he would like to take a large-scale look at the genetics of the human population and those individuals who develop a very severe and persistent inflammatory response to the bacteria. These are the individuals who suffer from PTLDS.
“Is the reason these individuals fail to respond to antibiotic treatment because of a genetic defect in some of their innate immune responses that allow other individuals to rapidly, effectively clear and kill the bacteria?”
The answer to this intriguing question will inform the development of novel treatment options for those suffering with PTLDS.
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