Here's more data regarding the research project:[snip]
Projects in the Lab
4. Role of diet-induced obesity in enhanced host susceptibility to disseminated Lyme disease
Lyme disease is the most common vector-borne disease in the northern hemisphere, and its incidence is increasing rapidly throughout the industrialized world (nearly a three-fold increase over the last twenty years). Although climate warming and associated expansion of tick habitat are thought to contribute to increasing Lyme disease incidence, the reasons for the rising prevalence of this disease are not yet fully understood. Increasing Lyme disease incidence has occurred in parallel with rising rates of obesity in the industrialized world. One of the major groups affected by Lyme disease is the middle-aged, in whom obesity and associated conditions such as diabetes and cardiovascular disease are now widely prevalent. We recently found that high fat diet-induced obesity in mice is associated with a significantly elevated bacterial burden in many tissues to which Borrelia disseminates. Currently, we are investigating the mechanisms responsible for enhanced Borrelia infectivity in obese hosts, and are examining the effects of hyperglycemia and systemic vascular inflammation to disseminated Lyme disease.
http://www.utoronto.ca/dentistry/facult ... iarty.html
This is the most recent information I could find regarding the status of the research project. If anyone comes across something more recent (e.g. a presentation or published article), please do post a link to it here on LNE.Faculty Profile - Dr. Tara Moriarty
Current Research Grants
01/2012-12/2012 National Research Fund for Tick-borne Diseases
Title: Mechanisms of metabolic syndrome-enhanced susceptibility to disseminated Lyme disease
Principal Applicant: Moriarty, T.J.
Amount: $60,000 USD
Duration: 1 year
There may be no relationship whatsoever between Dr. Moriarty's research findings and the following, however this is equally intriguing:Banting and Best Diabetes Centre
Faculty of Medicine, University of Toronto
Research at the University
Moriarty, Tara, PhD, BA, BSc
University of Toronto Appointment(s): Assistant Professor, Matrix Dynamics Group, Faculty of Dentistry;
Assistant Professor, Department of Laboratory Medicine and Pathobiology, Faculty of Medicine
Matrix Dynamics Group
FitzGerald Building, Room 235
150 College Street
Toronto, Ontario M5S 3E2
We are a newly established research group studying systemic dissemination mechanisms of bloodborne bacterial pathogens, with a focus on the Lyme disease pathogen, Borrelia burgdorferi. Lyme disease is the most common vector-borne infection in the industrialized world, and its incidence is increasing rapidly, in parallel with rising rates of obesity and diabetes. Systemic dissemination of pathogens causes most of the mortality due to bacterial infection, but remains poorly understood. One critical step in dissemination is microbe adhesion to blood vessel surfaces in the face of fluid shear force. Vascular adhesion enables pathogens to decelerate and transmigrate through vessels to reach extravascular tissues in joints, heart and brain where secondary infection is established. B. burgdorferi adheres more readily to sites of turbulent, altered blood flow (Moriarty et al., 2008). This observation, together with the epidemiological profile of Lyme disease, prompted us to examine the effect of blood flow-altering conditions such as diet-induced obesity on B. burgdorferi dissemination in mice. In a recent pilot study, we found that diet-induced obesity significantly enhances host susceptibility to disseminated Borrelia infection, with a 2.5-9-fold increase in bacterial burden in most tissues. We are now investigating the role of diabetes in host susceptibility to Lyme disease.
As of January 2012, we have not yet published our preliminary data describing the role of diet-induced obesity in promoting host susceptibility to disseminated infection with the Lyme disease pathogen. The paper below describes our most recently published work on B. burgdorferi dissemination.
Lee, W.-Y., Moriarty, T.J., Wong, C.H., Zhou, H., Strieter, R.M., van Rooijen, N., Chaconas, G. and Kubes, P. 2010. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nature Immunology 2010, 11 (4): 295-302.
http://www.sciencedaily.com/releases/20 ... 145145.htm
Here's the published article referred to in the article above:Obesity Makes Fat Cells Act Like They're Infected
Mar. 5, 2013 — The inflammation of fat tissue is part of a spiraling series of events that leads to the development of type 2 diabetes in some obese people. But researchers have not understood what triggers the inflammation, or why.
In Cell Metabolism this month (cover), scientists from The Methodist Hospital report fat cells themselves are at least partly to blame -- high calorie diets cause the cells to make major histocompatibility complex II, a group of proteins usually expressed to help the immune system fight off viruses and bacteria. In overweight mice and humans the fat cells, or adipocytes, are issuing false distress signals -- they are not under attack by pathogens. But this still sends local immune cells into a tizzy, and that causes inflammation.
"We did not know fat cells could instigate the inflammatory response," said principal investigator and Methodist Diabetes & Metabolism Institute Director Willa Hsueh, M.D. "That's because for a very long time we thought these cells did little else besides store and release energy. But what we have learned is that adipocytes don't just rely on local resident immune cells for protection -- they play a very active role in their own defense. And that's not always a good thing."
In pinpointing major histocompatibility complex II (MHCII) as a cause of inflammation, the researchers may have also identified a new drug target for the treatment of obesity. Blocking the MHCII response of adipocytes wouldn't cure obesity, Hsueh said, "but it could make it possible for doctors to alleviate some of obesity's worst consequences while the condition itself is treated."
Could the inflammation caused by a high fat diet serve any purpose, or is it a senseless response to an unnaturally caloric diet?
"The expression of MHCII in adipocytes does not seem to be helpful to the body," said co-lead author Christopher Lyon, Ph.D. "It is not at all clear what the advantage would be, given all the negative long-term consequences of fat tissue inflammation in people who are obese, including insulin resistance and, eventually, full diabetes. This just appears to be a runaway immune response to a modern high calorie diet."
Hsueh added, "The bottom line is, you're feeding and feeding these fat cells and they're turning around and biting you back. They're doing the thing they're supposed to do -- storing energy -- but reacting negatively to too much of it."
The scientists studied fat cells from obese, female humans (via biopsy) and overfed male mice. The researchers said that while they expect similar MHCII expression to occur in overweight male humans and female mice, further studies are needed to establish this.
The immunology of adipocyte inflammation is complex. It begins with the import of excess nutrients from the bloodstream, which are converted and stored as fat and stimulate the production of the hormone leptin. Excess leptin, spurred by a high calorie diet, excites CD4 T cells to produce a second signaling molecule, interferon gamma, which causes adipocytes to produce MHCII. This dialogue between adipocytes and T cells appears to initiate the inflammatory response to high fat diet -- Hsueh and her group found that overfed mice lacking MHCII experienced less inflammation.
Interferon gamma from T cells exacerbates the inflamed adipocytes' behavior and causes another type of immune cell, M2 macrophages, to be converted to their pro-inflammatory (M1) version.
"It was known that macrophages and T cells are major players," said lead author Tuo Deng, Ph.D. "But no one knew what the start signals were to ignite inflammation."
RNA was extracted from adipocytes purified from fat tissue biopsies and subjected to microarray analysis, which allowed the researchers to see what genes were increased in overweight subjects. The researchers found high expression of most MHCII complex and MHCII antigen processing genes. Similar gene expression patterns were observed in mice within two weeks of starting a high-fat diet, and this mirrored pro-inflammatory changes in fat tissue CD4 T cells. Hsueh says her group plans to investigate whether the inflammatory response in overfed mice can be blocked when MHCII expression is specifically reduced in adipocytes.
Hsueh says that if she and her group can identify the antigen(s) that MHCII is presenting to T cells in fat tissue, medical researchers would have a new approach to target adipose inflammation in obese patients. The hypothesis is that if a treatment can interfere with the production or MHCII presentation of these antigens, this would reduce the activation of fat tissue immune cells and thus reduce inflammation. Determining the MHCII antigen(s) involved in the inflammatory response of fat tissue to weight gain is one of her group's next goals, she says.
Also contributing to the Cell Metabolism paper were Laurie Minze, Jianxin Lin, Jia Zou, Joey Liu, Yuelan Ren, Zheng Yin, Dale Hamilton, Patrick Reardon, Vadim Sherman, Helen Wang, Kevin J. Phillips, Paul Webb, Stephen Wong, and Rong-fu Wang. The project was supported by grants from the John T. MacDonald Foundation, the National Institutes of Health, and the American Diabetes Association.
http://www.cell.com/cell-metabolism/ret ... 3113000570
Although the following may seem off-topic for this thread, it's too cool to leave out because some folks may not have seen this yet. This "Spirochetes Unwound" blog entry describes (and shows) some of the research already conducted by Dr. Moriarty and her team in Toronto. You'll have to click on the link below to watch the 3 videos:Class II Major Histocompatibility Complex Plays an Essential Role in Obesity-Induced Adipose Inflammation
Cell Metabolism, Volume 17, Issue 3, 411-422, 5 March 2013
Copyright 2013 Elsevier Inc. All rights reserved.
Referred to by: A New Immunological Role for Adipocyte...
Cell Metabolism, Volume 17, Issue 3, 411-422, 5 March 2013
Copyright 2013 Elsevier Inc. All rights reserved.
Referred to by: A New Immunological Role for Adipocyte
Tuo Deng, Christopher J. Lyon, Laurie J. Minze, Jianxin Lin, Jia Zou, Joey Z. Liu, Yuelan Ren, Zheng Yin, Dale J. Hamilton, Patrick R. Reardon, Vadim Sherman, Helen Y. Wang, Kevin J. Phillips, Paul Webb, Stephen T.C. Wong, Rong-fu Wang, Willa A. Hsueh
The Methodist Diabetes and Metabolism Institute, Center for Diabetes Research and Center for Inflammation and Epigenetics, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX 77030, USA Department of Surgery, The Methodist Hospital, Houston, TX 77030, USA
Adipose-resident T cells (ARTs) regulate metabolic and inflammatory responses in obesity, but ART activation signals are poorly understood. Here, we describe class II major histocompatibility complex (MHCII) as an important component of high-fat-diet (HFD)-induced obesity. Microarray analysis of primary adipocytes revealed that multiple genes involved in MHCII antigen processing and presentation increased in obese women. In mice, adipocyte MHCII increased within 2 weeks on HFD, paralleling increases in proinflammatory ART markers and decreases in anti-inflammatory ART markers, and preceding adipose tissue macrophage (ATM) accumulation and proinflammatory M1 polarization. Mouse 3T3-L1 and primary adipocytes activated T cells in an antigen-specific, contact-dependent manner, indicating that adipocyte MHCII is functional. HFD-fed MHCII/ mice developed less adipose inflammation and insulin resistance than did wild-type mice, despite developing similar adiposity. These investigations uncover a mechanism whereby a HFD-induced adipocyte/ART dialog involving MHCII instigates adipose inflammation and, together with ATM MHCII, escalates its progression.
http://spirochetesunwound.blogspot.com/ ... chete.html
TUESDAY, JANUARY 27, 2009
Watch videos of the Lyme disease spirochete escaping from the bloodstream of live mice!
Most pathogenic microbes that cause systemic infections, regardless of their route of host entry, migrate to the circulatory system, which facilitates their spread throughout the body. These invasive microbes, which include the Lyme disease spirochete B. burgdorferi, eventually exit the bloodstream and penetrate into various organs of the host. Last June in the online journal PLoS Pathogens, a Canadian research group presented some fascinating microscopic video footage of Borrelia burgdorferi traveling within and escaping from the bloodstream of live mice. We may like to think that the unique shape of the spirochete allows it to simply drill through the vessel wall, but the videos suggest that escape from the bloodstream is a little more complex.
Because spirochetes are too thin to observe by light microscopy, Moriarty and colleagues made B. burgdorferi fluoresce by transforming the spirochete with a gfp (green fluorescent protein) plasmid. To prepare the animals, they lifted the skin of anesthetized mice for observation of the underlying dermal microvasculature by fluorescence intravital microscopy (IVM), which allows visualization of cellular events in a living animal. They next injected the fluorescent spirochetes into the bloodstream of the mice, and they examined dermal postcapillary venules under the microscope as the spirochetes traveled through the field of view within the vessels.
The black-and-white video reveals several types of interactions between the spirochetes and vessel wall. The bar graph displayed below the video indicates the proportion of each type of interaction observed. Almost 90% of the contacts are transient, lasting for less than a second. About 10% of the interactions involved crawling or dragging of the spirochete along the vessel wall for up to 20 seconds. As you can see from the bar graph, these short-term interactions, although common, rarely lead to escape of spirochetes from the bloodstream. Perhaps the spirochetes crawl along the wall probing for an escape route from the vessel. When their search fails, as it usually does, they detach and float (or swim) away and try again elsewhere along the vessel wall. Occasionally, a spirochete will remain stuck to the vessel wall for many minutes. One such spirochete can be seen in the video, near the center of the screen. More careful observation of stationary spirochetes in the bloodstream of several mice revealed at least one end deeply embedded with the vessel wall, usually between endothelial cells. It is unclear whether these stationary adhesions are a necessary prelude to exit of the spirochete of the vessel as consistent outward movement of embedded spirochetes was never observed during the observation period, which lasted up to 45 minutes.
[54 second black-and-white video]
The next two videos capture spirochetes in the process of escaping from the bloodstream. The endothelium was stained by injecting the bloodstream with red fluorescent antibody to PECAM-1, a protein found within endothelial junctions. The first video shows how difficult it is for B. burgdorferi to traverse the wall of the venule. The spirochete appears to be stuck as it moves back and forth (reciprocal translation) across the vessel wall for several minutes trying to free itself. The second video shows a spirochete successfully dislodging itself and fleeing from the venule. The average escape time was 10.8 minutes (N = 11 spirochetes). The authors could not clearly determine whether the spirochetes escaped between or through endothelial cells.
[38 second video]
[25 second video]
Here's the model illustrating the steps in the escape of B. burgdorferi from the bloodstream. The spirochete first contacts and crawls (drag) across the inside surface of the vessel wall. It then crosses the vessel wall end-first. After a long period of back-and-forth motion (reciprocal translation), the spirochete finally escapes into the tissue. It is unknown whether stationary adhesion is necessary for escape.
Moriarty et al. repeated the experiments with B. burgdorferi rendered noninfectious by long-term passage in culture. They found minimal interaction of noninfectious spirochetes with the vessel wall, and not a single spirochete could be found escaping from the bloodstream. This result indicates that specific Borrelia surface molecules that are missing on noninfectious B. burgdorferi mediate interaction with and escape from the bloodstream. What are these B. burgdorferi surface molecules, and which host molecules do they contact in the blood vessel? Past in vitro experiments with cultured mammalian cells by several research groups have revealed a few candidates for such bacterial and host factors. The authors described the roles of these candidates in transient, dragging, and stationary adhesions in live mice in a follow-up study, which I will write about in my next post.
Tara J. Moriarty, M. Ursula Norman, Pina Colarusso, Troy Bankhead, Paul Kubes, George Chaconas (2008). Real-Time High Resolution 3D Imaging of the Lyme Disease Spirochete Adhering to and Escaping from the Vasculature of a Living Host. PLoS Pathogens, 4 (6) DOI: 10.1371/journal.ppat.1000090
Do inflamed blood vessels (whether caused by obesity or other health conditions) make it easier for spirochetes to latch on to them and then escape from the bloodstream? Do inflamed blood vessels in a person's brain contribute to neuroborreliosis?All material in this blog is held under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. You are free to share, reproduce, or transmit any part of this blog for noncommercial purposes as long as this blog is properly cited. No part of this blog may be used for commercial purposes without my permission.