Findings to shape vaccine development
Chapel Hill -- New research on the tick-borne bacteria responsible for Lyme disease likely will make scientists think differently about how to develop a more effective vaccine.
The findings clearly demonstrate that as a tick feeds on its host, molecular changes occur on the outer surface of the Lyme bacteria Borrelia burgdorferi that are more complex than previously known. During the tick's blood meal, its saliva transmits the bacteria to the host.
In terms of Lyme disease immunization, this is important because any truly effective vaccine must prime the immune system to mount an antibody attack against foreign antigens-the invader's outer surface proteins.
"Previous research showed there were certain surface proteins that were expressed in the tick gut and others that were expressed in the host, and that a switch occurred en route from the tick to the host. This paper shows us that things are a lot more complicated," said Aravinda M. de Silva, PhD, assistant professor of microbiology and immunology at the University of North Carolina at Chapel Hill School of Medicine.
The new findings are reported in the January 16 issue of the Proceedings of the National Academy of Sciences. Along with de Silva, co-authors are Jun Ohnishi, PhD, UNC postdoctoral researcher in microbiology and immunology and Joseph Piesman, PhD, division of vector-borne diseases at the Centers for Disease Control and Prevention.
In their study, the researchers focused on two (OspA and OspC ) of the more than 150 membrane proteins known to be associated with B. burgdorferi.
"We wanted to see how these two proteins changed as the bacteria moved from the tick gut to the host," de Silva said. "And to our surprise, what we observed was not simply a matter of one protein being expressed in the gut and another being expressed in the host, as had been previously thought. During transmission, what the tick actually spits into the host is a bacteria population that is highly variable, compared to the fairly homogeneous population found in the tick before the blood meal."
In other words, given two surface proteins there are four possible combinations. Some bacteria could express only OspA, some only OspC, some might express both, some neither.
"And in fact during the tick feeding process we found all four of these different combinations," da Silva said. Moreover, when the study team looked at another Borrelia surface gene called vlsE, they found a large number of variations generated during tick feeding, compared to only one or two when the tick was not feeding.
"We are excited by the findings because this once again supports the concept that arthropod vectors are not just flying or crawling syringes that go around inoculating bacteria. There's a developing biology going on inside this vector. The bacteria population essentially adapts during the transmission process to maximize the chance of infecting the host," de Silva said According to de Silva, individuals in the bacterial population expressing lots of different sets of surface proteins makes it easier to evade the host's immune response.
"If all the bacteria entering the host have the same set of molecules on the surface, then it's easier to for the immune system to control the infection and it's easier to develop vaccines against it," de Silva explained. "But that fact that the tick introduces so many different flavors probably explains an observation we made several years ago: Lyme spirochetes delivered by ticks are better at evading the host's immune response than cultured spirochetes injected into animals.
The process of bacterial diversity occurs during the blood meal, de Silva pointed out. "So, early on, before the blood meal, the population in the tick gut is still very uniform. Lyme disease ticks feed for 3 to 5 days, and over this period the bacterial population inside the tick as well as the bacteria moving from the tick to host become more diverse with respect to the proteins on their surface."
In their report, the researchers point to two possible approaches to developing Lyme disease vaccine candidates. One would be to focus on antigens produced within the tick at early stages of feeding (before the population diversifies) that may lead to transmission-blocking immunity. The other would be a vaccine based on those surface proteins that are indispensable and common to all the bacteria entering the host.
A Lyme vaccine based on OspA, which was recently approved for human use, is an example of the former. When a tick feeds on a OspA-vaccinated individual or animal, antibodies that have developed in response to the vaccine enter the tick gut and kill the bacteria inside the gut before the population has a chance to diversify. This prevents the transmission process from taking place, de Silva explained.
De Silva pointed out that it was luck, "pure chance," that the current Lyme OspA vaccine happened to work in the tick the way it did. "If people had known that the OspA was mainly produced within the unfed nymphal tick, they probably wouldn't have tried to develop this vaccine." In clinical trials, one year after receiving three doses of the OspA vaccine, 75-80% of people exposed to infected ticks were protected from infection. However, research indications are that protection may not be long-term.
"Understanding more about the biology of transmission may lead to better vaccines that complement or replace OspA vaccine," de Silva said.
The research was supported by grants from the National Institutes of Health and the Arthritis Foundation.
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