Global Expression Profiling of Persistent Infections in a Major Natural Host for Tick-Borne Diseases
Abstract
Since the discovery 35 years ago that a hitherto unknown bacterium caused Lyme disease, there have been many significant advances collectively in the field, including better understanding of the biology of B. burgdorferi, how the pathogen causes disease in humans, and how our immune systems respond to it. But in many respects we are worse off than the early 1980s, when there finally was a specific diagnostic test for the infection, and antibiotic therapy for Lyme disease became the standard of care. Lyme disease has grown many-fold in frequency, and there are more states than ever in which transmission is documented. There was once a human vaccine of moderate effectiveness, but now there is none. The lab tests for infection are essentially what they have been for 30 years. While antibiotics clearly are of benefit in halting the infection, too many patients do not fully regain their health in timely way. And it is not just Lyme disease that is a risk from bites of the deer tick. Other infections, including the malaria-like disease babesiosis and a serious type of viral encephalitis, can be acquired from these blood-sucking arthropods as well. We get the infection directly from ticks, but how do ticks pick up the infection to begin with? The most common source is the white-footed mouse, Peromyscus leucopus. This rodent (which is actually closer to hamsters than to the lab mouse) is the topic of this 12-month research project. P. leucopus is the natural host for B. burgdorferi and other disease agents transmitted by deer ticks. Over the millennia there have been a series of trade-offs between the pathogen and this rodent, such that an equilibrium of sorts has been reached. The white-footed mouse becomes infected and stays infected for all of its life but does not become particularly sick (if at all) from the infection. This adequately describes the population of animals as a whole, but individual white-footed mice differ from each other in how well they contend with the infection, either in their success in fighting it off or in their ability to function well in spite of the infection. The premise of this project is that this diversity of responses to infection will provide for better understanding of the differences of responses to infection among patients with Lyme disease. I do not think this can as effectively be done with the lab mouse (often known as the "white mouse") because it is not a natural host for these pathogens. And the great majority of experiments with the lab mouse have been with inbred animals, that is, identical clones of each other. Depending on the strain, they may be missing key genetic characters that are of informative value for human disease. A study like this of white-footed mouse in the past would have been very difficult because we lacked the tools available for the lab mouse. But the power from recent advances in genome sequencing has made it feasible to leap-frog the stage of incremental accumulation of special mouse strains and reagents and go right to the animal of most relevance. The study is based on our recent success at University of California, Irvine in sequencing the genome of P. leucopus. With this information in hand, we can now begin to look at which genes are turned up and which ones are turned down during infection. This will be done by infecting P. leucopus animals with B. burgdorferi and with Babesia microti, the agent of babesiosis, either singly or in combination. The lab team then monitors the effects of the infection over a period of 3 months, a long time in the life of this rodent, and then looks at what genes are active in the blood and different tissues in these persistently infected animals. I expect to find some genes that are more active in all the infected animals and that these genes may differ depending on whether the agent is B. burgdorferi, Ba. microti, or both together. Other genes may differ markedly in their activity among infected a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710481
Entities
People
- Alan G. Barbour
Organizations
- Naval Information Warfare Center Pacific
- United States Army