NRFTD GRANT WINNERS 2012-3

Dr. Mollie Jewett
Assistant Professor
Burnett School of Biomedical Sciences
College of Medicine University of Central Florida
Project Cost: $60,000
Project Duration: 1 Year

Dr. Jewett will be examining gene regulation in B. burgdorferi, with a focus on small regulatory RNAs (sRNAs). The role of sRNAs in B. burgdorferi is still unclear, but they have been definitively shown to control the pathogenic properties of other bacterial species. Preliminary work in Dr. Jewett’s lab has led to the identification of presumed novel sRNAs that are expressed by B. burgdorferi during mammalian infection, and the NRFTD award will help her characterize this regulatory molecule, increase understanding of the genetic mechanisms employed by B. burgdorferi to survive throughout its infections cycle, and possibly lead to novel ways to treat patient with Lyme disease.


Dr. Brian Stevenson
Professor of Microbiology
Immunology and Molecular Genetics
University of Kentucky Research Foundation
Project Cost: $60,000
Project Duration: 1 Year

Dr. Stevenson has been awarded a grant to study the influence of a newly-discovered protein, called EbfC, on gene expression in B. burgdorferi. Vector-borne pathogens like B. burgdorferi are transmitted back and forth between hosts and need to sense and respond to their environment by upregulating expression of certain proteins while suppressing others, depending on their current host environment, in order to enhance their chance for survival. Dr. Stevenson has discovered that EbfC, a site-specific DNA-binding protein, regulates expression of over 50 genes in B. burgdorferi – more than 5% of its entire genome. Many of these genes are differentially expressed depending on the host environment and are likely critical to the pathogen’s ability to maintain infectivity in both ticks and mammals. By studying the effects of EbfC on different phases of the tick-mammal infectious cycle, Dr. Stevenson hopes to decipher the specific details of its regulatory role. Further, because regulatory pathways are attractive targets for the development of novel preventative and curative therapies, and because many other bacterial pathogens contain genes similar to EbfC, this work has the potential to improve prevention and treatment not only of Lyme disease, but of other significant human diseases as well.


Dr. Saravanan Thangamani
Assistant Professor
Department of Pathology
University of Texas Medical Branch in Galveston
Project Cost: $60,000
Project Duration: 1 Year

Powassan encephalitis is a serious, emerging tick-borne disease that is fatal in about 10% of its victims. Recent evidence suggests that its incidence is increasing in eastern North America, and no vaccine for the disease currently exists. NRFTD has awarded a grant to Dr. Thangamani to study tick-virus-host interactions during transmission of the Powassan virus (POWV). Specifically, Dr. Thangamani will investigate the cutaneous immune responses of mice to tick-transmitted POWV in order to determine if and how tick saliva compromises the ability of the mice to fight off infection with the virus. Tick salivary glands produce a complex mixture of bioactive molecules that frequently have an effect on transmission efficiency, pathogen establishment and disease pathogenesis. Dr. Thangamani hopes to elucidate the specific factors that determine the course of Powassan virus infection, which could aid in future vaccine development not just for this tick-transmitted disease, but others as well.


Dr. Edouard Vannier
Assistant Professor
Division of Geographic Medicine and Infectious Diseases
Tufts Medical Center
Project Cost: $60,000 Project
Duration: 1 Year

Dr. Vannier will be studying host resistance to infection by Babesia microti, the malaria-like causative agent of human babesiosis. Babesiosis is a potentially serious tick-transmitted disease characterized by fever, chills, fatigue and anemia, and can be spread by blood transfusion as well as by ticks. In certain patient populations, such as the elderly or patients who are immunocompromised, it can be severe and potentially fatal. However, the severity of illness is variable even in these groups, and Dr. Vannier hopes to characterize the host genetic factors that influence the course and severity of disease. Dr. Vannier has already identified a group of genes in mice that appear to determine host infectivity and will use his NRFTD award to create mice that lack the gene coding for this host factor in order to assess their resistance to infection. An additional aim of this work is to characterize the specific mechanisms by which these genes affect host susceptibility; once this is understood, Dr. Vannier proposes to screen libraries of small molecules that might inhibit the activity of the specific genes involved, possibly leading to novel treatments for severe babesiosis.
 

NRFTD GRANT WINNERS 2011

Linda Bockenstedt, MD
Harold W. Jockers Professor of Medicine, School of Medicine, Yale University
Project Cost: $60,000
Project Duration: 1 Year


Up to 30% of human patients treated with antibiotics early in the course of their Lyme disease infection do not experience full recovery within 3 months, and 10% of those with Lyme arthritis experience continued joint inflammation after treatment. While the induction of the immune response in Lyme disease has been well studied, there are deficiencies in our understanding of its regulation. Dr. Bockenstedt’s award will enable her to investigate the role of a recently discovered immune regulatory pathway, known as the TAM pathway, in controlling B. burgdorferi-induced inflammation and disease in the mouse model. This work will set the stage for future studies of the TAM pathway in human Lyme disease.

Charles Chiu
Associate Professor, School of Medicine
University of California, San Francisco
Project Cost: $60,000
Project Duration: 1 Year


The lone star tick, Amblyomma americanum, is the vector of the Lyme-like illness known as Southern Tick-Associated Rash Illness, or STARI. Despite intensive efforts to identify a causative agent, researchers have so far been unable to isolate a microorganism that can be convincingly linked to the disease. Now, with NRFTD funding, Dr. Charles Chiu of the School of Medicine at the University of California, San Francisco will employ a genomic approach in the form of a comprehensive microarray tool, called the TickChip, to search for tick-borne pathogens in both Amblyomma ticks and blood samples from patients diagnosed with STARI. Detailed molecular and epidemiological studies will then be performed in order to establish an association between possible infectious agents and the disease. Once the cause of STARI has been established, further research on the pathogen can be pursued and useful diagnostic tests can be developed to definitively distinguish STARI from Lyme disease.

Mingqun Lin
Assistant Professor of Research
The Ohio State University
Project Cost: $60,000
Project Duration: 1 Year


Dr. Lin will pursue a project focusing on the ability of Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis (HGA), to manipulate the cytoskeleton (the cellular protein “scaffolding”) of the host cells it invades. HGA is the second most common tick-borne infection in the U.S. after Lyme disease, and can occasionally be fatal; therefore, it is crucial to advance our understanding of the pathogenesis of this illness. Dr. Lin’s project will examine the underlying mechanisms by which a secreted bacterial protein regulates the host cytoskeleton in order to ensure bacterial survival and release, and an understanding of these mechanisms may lead to novel treatments for HGA and other intracellular infections.

Tara Moriarty
Assistant Professor, Matrix Dynamics Group
University of Toronto
Project Cost: $60,000
Project Duration: 1 Year


Dr. Moriarty will investigate the possible role of metabolic syndrome in some cases of unresolved Lyme disease. Metabolic syndrome is a combination of clinical factors that increase the risk of cardiovascular disease and diabetes, and its incidence has grown dramatically over the last few decades. Preliminary work in Dr. Moriarty’s lab indicates that when mice are given a high fat diet that induces atherosclerosis, obesity and hyperglycemia, they experience a higher burden of infection when exposed to B. burgdorferi than do mice with normal metabolism. Dr. Moriarty will continue this work in an attempt to tease out the specific metabolic factors that increase host susceptibility to disseminated Lyme disease; this may lead to novel treatments for human patients with unresolved illness.


NRFTD GRANT WINNERS 2009

Stephen W. Barthold, DVM, Ph.D
Professor and Director
Center for Comparative Medicine, University of California Davis

Project Cost: $60,000
Project Duration: 1 Year

Project Title: Borrelia burgdorferi Persistence Following Antibiotic Treatment


Previous work by Dr. Barthold’s laboratory has shown that B. burgdorferi can persist in an infectious but non-cultivatable state in mice for at least 90 days after the animals have been treated with ceftriaxone, a powerful antimicrobial often used to treat Lyme disease in humans. These bacteria can then be acquired by ticks and subsequently transmitted to other mice. In his NRFTD project, Dr. Barthold will attempt to verify these findings with additional strains of the Lyme bacterium and investigate the long-term fate of these organisms. Special fluorescence techniques will be employed to discern the morphology and location of the spirochetes and, hopefully, lay the groundwork for determining definitively whether these bacteria are capable of causing persistent disease.



Linda K. Bockenstedt, MD
Harold W. Jockers Professor of Medicine
School of Medicine, Yale University

Project Cost: $60,000
Project Duration: 1 Year

Project Title: Real-Time Imaging of Vector-Borne Borrelia burgdorferi Infection in Mice


Dr. Bockenstedt’s study will employ multiphoton microscopy, a cutting-edge form of imaging that permits the visualization of cells and bacteria in tissues of living laboratory animals. Using this technique, Dr. Bockenstedt will be able to study the behavior of B. burgdorferi spirochetes in live anesthetized mice and examine in real-time the effects of antibiotics on spirochete populations within the infected animals. These studies will provide insight into how the Lyme bacteria move between the tick and the mammal, and may yield important information with implications for the treatment of Lyme disease in humans.


Melissa Caimano, Ph.D
Instructor
Department of Medicine, University of Connecticut Health Center

Project Cost: $60,000
Project Duration: 1 Year

Project Title: Transit of Borrelia burgdorferi through the Ixodes scapularis midgut occurs in two distinct, but interrelated, phases.


Dr. Caimano’s project will investigate in detail how B. burgdorferi transits from ticks to mammalian hosts during tick feeding. Recent work by Dr. Caimano and others has shown that the migration of the bacteria out of the ticks’ midgut is considerably more complex than previously recognized: During tick feeding, spirochetes undergo a burst of replication, forming non-motile networks that adhere to differentiating tick midgut epithelial cells and only later in the feeding process become individually motile forms. Dr. Caimano will investigate the interplay between B. burgdorferi and the tick midgut epithelium; this work will likely further the long-term objective of identifying bacterial and tick gene products and regulatory pathways that enable dissemination of the Lyme spirochete within both ticks and mammals. It is possible that this work could ultimately lead to novel vaccine strategies that block the exit of spirochetes from the tick midgut during feeding.


Gustavo Valbuena, MD, Ph.D
Assistant Professor
Department of Pathology, University of Texas Medical Branch

Project Cost: $60,000
Project Duration: 1 Year

Project Title: Humanized Mouse Model of Tick-Transmitted Rickettsia rickettsii Infection


Dr. Valbuena will develop and test a novel animal model of Rocky Mountain spotted fever, the most common fatal tick-borne infection in the United States. His objective is to create a “humanized” mouse model by transplanting human immunological cells into laboratory mice. This will make it possible to then transplant human skin into the mice, expose them to Rickettsia rickettsii, the causative agent of spotted fever in the United States, and study the pathogenesis of the disease. Because little is known about the specific processes that determine disease outcome and severity in Rocky Mountain spotted fever, the development of a viable animal model that mimics human disease is crucial for increasing understanding of these mechanisms. An additional complication in studying spotted fever is that endothelial cells, the main targets of Rickettsia bacteria, are different in culture than they are in vivo (i.e., in animals themselves). Dr. Valbuena’s model will ensure that these cells will remain in their natural state as the pathogenic processes are investigated.


NRFTD GRANT WINNERS 2007

R. Mark Wooten, Ph.D.
Assistant Professor
College of Medicine/Medical Microbiology and Immunology
University of Toledo, Ohio

Project Cost: $120,000 Project Duration: 2 Years

Project title: Intravital assessment of interactions between Borrelia burgdorferi and immune cells in skin

Borrelia burgdorferi is transmitted by tick-bite to host skin tissues, where it resides for several days before disseminating to cause Lyme disease.  Little is known about how these bacteria can evade capture and clearance by immune cells that reside in skin tissues.

Because these bacteria are specifically adapted to live within either tick or vertebrate hosts, studies performed in “test tubes” do not accurately reflect how these bacteria evade host defenses. 

Dr. Wooten and his colleagues have recently developed techniques that allow them to directly assess interactions between  B. burgdorferi and immune cells directly in mouse skin.  This should accurately reflect how these pathogens truly act during the development of Lyme disease.  Dr. Wooten’s studies will use novel fluorescent (“glowing”) mouse strains, fluorescent bacteria, and powerful microscopy techniques to visualize how these bacteria interact with host immune cells directly within the skin tissues of living mice and in real-time. 

These studies will help identify critical events that allow  B. burgdorferi to escape immune clearance, and which then may be targeted for curative treatments.  By perfecting these techniques, they may subsequently be used to more accurately study other tick-borne pathogens that must also evade host immune cells that reside in the skin.

Expected Date of Completion:  December 2009

Alan G. Barbour, M.D.  
Professor of Microbiology & Molecular Genetics and Medicine
University of California, Irvine

Project Cost: $60,000 Project Duration: 1 Year

Project Title: Proteomics of ticks for identification of pathogen reservoirs

One way to control infections by tick-borne bacteria and viruses is to prevent transmission of the microbe from ticks to humans.  Examples are repellents and vaccination of people at risk.  While this could be effective for reducing vector-borne diseases such as malaria and dengue fever, which are largely maintained in nature by humans themselves, it could have limited efficacy against infections for which wildlife are the major sources.

A complementary approach would be to direct control efforts toward the wildlife reservoirs.  For Lyme disease, there are several types of animals, including different rodents, shrews, and birds that are reservoirs of Borrelia burgdorferi

Identification of the source of the infection for a tick provides for an assessment of the relative contributions of each species.  Dr. Barbour and his colleagues identified a method for identifying what a tick had fed on months earlier.  This is accomplished by detecting blood components in the tick and then determining where they came from.  With this method and a means to determine whether ticks are infected with Borrelia burgdorferi or other pathogens, field studies can be carried out to assess which are the critical sources of the agent of Lyme disease in a given area.

Expected Date of Completion:  December 2008

Linden T. Hu, M.D.
Assistant Professor
Medicine, Division of Infectious Diseases
New England Medical Center

Project Cost: $60,000 Project Duration: 1 Year

Project title:  Recognition of host molecules in environment adaptation by Borrelia burgdorferi

The mechanisms by which Borrelia burgdorferi recognizes its environment and prepares for transition from a mouse to a tick are poorly understood. 

The identification of host hormones as signaling molecules important in this process offers important insight into how the organism may accomplish its adaptation to different hosts.  Understanding the elements that are critical to host adaptation may lead to new strategies for disrupting the ability of Lyme bacteria to survive in its natural hosts, thus reducing transmission to humans.

Expected Date of Completion:  December 2008

Dennis Grab, Ph. D.
Associate Professor
Medicine/Pediatrics
Johns Hopkins University

Project Cost: $104,107 Project Duration: 1 Year

Project Title: Borrelia burgdorferi interactions with endothelium

In order for Borrelia burgdorferi, the agent of Lyme disease to enter the central nervous system, it must first cross the brain’s first line of defense against pathogen entry: specialized capillaries called the blood-brain barrier.  This barrier is made up of a special kind of blood vessel cell (endothelial cell) called a brain microvascular endothelial cell (BMEC).

Dr.Grab and his colleagues have evidence that spirochetes cause the BMEC to release enzymes that break down the connections that hold the endothelial cells together to form a barrier. They will explore which enzymes are released and the role of these enzymes in helping the spirochetes cross capillaries to enter the brain.

Expected Date of Completion:  December 2008


NRFTD 2006 Grant Winners 

Wayne Hynes, Ph.D.
Department of Biological Sciences
College of Sciences
Old Dominion University, Virginia

Project Title:
The role of defensin in the transmission of Borrelia burgdorferi

Project Cost: $60,000

Ticks are able to transmit a number of disease causing bacteria, but yet they do not become sick themselves.  This is in part due to the production of antimicrobial proteins, known as defensins, that form holes in the bacterial membrane and kills the cell.  Defensin proteins are found in the hemolymph (blood) of the dog tick but not in the hemolymph of the deer tick. This difference may, at least in part, explain why the deer tick but not the dog tick is able to transmit the bacterium borrelia burgdorferi, the causative agent of Lyme disease.  Dr. Hynes proposes to determine whether defensin plays a role in the inability of the dog tick to transmit this microbe.  This will be done in preventing expression of the gene encoding the defensin in dog ticks using RNA interference.  By interfering with the ability to produce defensin, he will address questions relating to how bacteria survive in hemolymph, and whether are they to make it through the “blood” to the salivary glands where they can be transmitted to another host, such as man.


Expected Date of Completion:  December 2008

 

Brian Stevenson, Ph.D.
Department of Microbiology, Immunology and Molecular Genetics
College of Medicine
University of Kentucky

Project Title:
Studies into the mechanism of Borrelia burgdorferi vIsE recombination
Project Cost: $60,000

The causative agent of Lyme disease, Borrelia burgdorferi, can infect humans and other animals for many years, perhaps even a lifetime.  It is thought that the bacteria’s vIsE gene plays an important role in long term infection.  During infection, the DNA sequence of the bacteria’s vlsE gene changes, due to replacement of certain DNA sequences from others supplied elsewhere in the bacteria’s genome.  The mechanism by which this occurs is not yet known, but its identification will be an important step toward understanding the ability of this pathogen to infect humans and will lead to improved, novel therapies for treatment of Lyme disease. B. burgdorferi makes at least one protein that binds to a specific region of DNA in the vlsE gene.  Dr. Stevenson proposes that this protein plays an important role in vlsE recombination.  In this project, he will identify this protein(s) and precisely define the DNA sequence within vlsE that binds the protein(s), then develop mutant bacteria that will permit examination of the effects that preventing protein-DNA interactions have upon vlsE recombination.

Expected Date of Completion:  December 2008

Jason Anderson Carlyon, Ph.D.
Department of Microbiology, Immunology and Molecular Genetics
College of Medicine
University of Kentucky

Project Title:
Identification of novel Anaplasma phagocytophilum adhesions and receptors
Project Cost: $60,000

Human granulocyctic anaplasmosis (HGA) is an emerging potentially lethal disease and the second most common tick-transmitted infection in human in the United States.  HGA is caused by the bacterium, Anaplasma phagocytoplilium that also affects dogs, sheep and horses.  After being transmitted to a human by the bite of an infected tick, A. phagocytophilium invades a specific type of white blood cell called a neutrophil.  The ensuing disease is characterized by symptoms that include fever, malaise, anemia, and impaired immune responses.  The susceptibility of neutrophils to A. phagocytophilium is due to precise molecular interactions that occur between the bacterium and the host neutrophil.  Essentially, A. phagocytophilium presents an array of “keys” (called adhesins) on its surface that interact with certain “locks” (called receptors) on the neutrophil surface.  These interactions “open the door” for the bacterium to invade its host cell and cause disease.  Dr. Carlyon is working to discover the A. phagocytophilium adhesions and the neutrophil receptors that they bind as a means for identifying new targets for therapies or vaccines for treating or preventing HGA, respectively.  This work has the potential for developing treatments against other tick-borne diseases caused by pathogens related to A. phagocytophilium.

Expected Date of Completion:  December 2008

 

Patricia J. Holman, Ph.D.
Department of Veterinary Pathobiology, College of Veterinary Medicine
Texas Agricultural Experiment Station
Texas A & M University

Project Title:
Babesia microti: in vitro culture and molecular interaction between parasite and host receptors at invasion
Project Cost: $60,000

Babesia microti is a blood parasite and is the most common cause of a disease called human babesiosis in the United States.  There are no tests for this parasite in donated blood or organs so babesiosis has resulted from transfusions or transplanted organs from infected people.  Dr. Holman will develop a method to culture these parasites, which help us design diagnostic tests, drugs for treatment and vaccines.  They will also allow us to study how the parasite gets into the red blood cell.  The exact way these parasites recognize and adhere to a cell in order to enter it is not yet known.  We will study a protein on the parasite called apical membrane antigen 1 (AMA-1) that binds with the red blood cell in order to infect the cell.  Using state of the art molecular technology, we will identify the exact red blood cell component that binds with the parasite AMA-1.  This study will provide valuable knowledge of the interaction between b. microti and the host red blood cell.  This will help us design safe and efficacious drugs for treatment or vaccines by finding a way to stop the invasion of the parasite into the red blood cell.

Expected Date of Completion:  December 2008
 


NRFTD 2005 Grant Winners

Timothy John Kurtti, Ph.D.
Professor of Entomology
University of Minnesota

Project Title: Analysis of global gene expression in Anaplasma phagocytophilium using tiling microarrays
Project Cost: $60,000

Dr. Kurtti will investigate how the parasite Anaplasma phagocytophilum, which invades certain white blood cells when transmitted to humans, survives the drastic environmental differences between warm-blooded mammals and cold-blooded ticks. Using a new genomic technology called microarray analysis, Dr. Kurtti will determine the specific genes that become active depending on whether the bacterium is in tick or human cells. The results of this work will provide crucial supplemental information to the recently completed but unannotated Anaplasma genome, and will advance current understanding of the bacterium’s ability to evade the immune response of its human host. Further, it will likely establish microarray analysis as an important new technology for studying other bacterial pathogens transmitted by ticks.

Expected Date of Completion: December 2005

Nikhat Parveen, Ph.D.
Assistant Professor Microbiology and Molecular Genetics
New Jersey Medical School
University of Medicine and Dentistry at New Jersey

Project Title: Role of alleles of Borrelia burgdorferi in Lyme pathogenesis
Project Cost: $60,000

The investigators in this project will study an outer surface protein of Borrelia burgdorferi, the bacterium that causes Lyme disease. This protein, known as OspC, is thought to play a key role during early Lyme infection. However, some strains of B. burgdorferi contain a defective OspC gene and fail to cause infection in mammals. By studying the wide variation in OspC expression among different strains of the bacterium, Dr. Parveen will attempt to tease out the specific factors that promote its ability to infect and disseminate through human tissues. This work will also have implications for improved diagnostic testing and vaccine development for Lyme disease.

Expected Date of Completion: December 2006

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